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Archive for the ‘Hormone Clinic’ Category

TSH tells thyroid gland to make more hormone – New Castle News


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BYLINE: By Keith Roach, M.D.


DEAR DR. ROACH: I am a 71-year-old female in very good health. I have been taking a thyroid replacement since I was 12 years old. I currently take 125 mcg of thyroxine once daily, as well as 60 mg of Cymbalta. Other than arthritis and obesity, I have no health problems. My question is regarding my lab results. My TSH is 0.04 (the normal range is 0.30-5.5); my T3 and T4 are in the normal range. My physician assures me that as long as my T3 and T4 are normal, the TSH is of no concern. I cannot lose weight, no matter what I try. Would you suggest I see an endocrinologist, or is my primary doctor correct? -- D.A.

ANSWER: The thyroid stimulating hormone is a signal from the pituitary gland to the thyroid to "tell" the thyroid to make more hormone. Since your TSH level is low, it suggests that the dose of replacement thyroid hormone is too high. This is despite the fact that the T3 (the active form of thyroid hormone) and T4 (thyroxine, the major thyroid hormone, which T3 is made from) are normal, and despite the fact that you report no symptoms. The range of normal for T3 and T4 is very broad, and the low TSH is good evidence that those levels are too high for you.

Excess thyroid hormone can cause bone disease and predispose to heart problems, such as atrial fibrillation. I think an endocrinologist is likely to say that your dose of thyroxine should be decreased.

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DEAR DR. ROACH: I have a history of C. diff. I had the shingles vaccine, and developed severe diarrhea, which has lasted eight weeks. Could the vaccine have instigated this? I'm now on vancomycin, and it is helping. -- M.G.

ANSWER: Clostridioides difficile is most commonly associated with antibiotic use, but can be acquired in a hospital or other nursing facility or even out in the community. I have never heard of C. diff as a complication of a vaccine, so I did a search on the VAERS database of vaccine side effects. I found no reported cases of C. diff with the shingles vaccine. I really didn't expect to.

Vaccines are a powerful public health tool, and like all medicines, they have the potential for side effects. It is human nature, when presented with a health change, to ascribe it to any new event, such as a new medicine or vaccine. Sometimes they are linked, but sometimes they are not. In this case, I think they most likely are not.

DEAR DR. ROACH: I had my first pneumonia injection (PCV13) in October 2015 and the second injection (PPSV23) in October 2016. My primary care physician sends me reminders that my pneumonia shot is past due. The head nurse at the same primary care clinic reviewed my medical files and says I do not need additional pneumonia shots for the rest of my life. I have asked my cardiologist, urologist and gastroenterologist if I need to update my pneumonia injections, but they avoid answering me. I am 72 years old and have health problems. Since the COVID virus affects the lungs and many suffer from pneumonia, I am concerned about my protection, although I have both Moderna vaccinations. Should I get a pneumonia shot? -- C.V.

ANSWER: Your nurse is correct, you are not recommended for any additional pneumonia vaccines at this time. These pneumonia vaccines protect against only one bacterium, Streptococcus pneumoniae, with no protection against COVID-19. You should get your third dose of Moderna when it's recommended (expected at the time of this writing to be eight months after your second dose). That is, unless the recommendations have changed by then -- this is a fast-moving area!

* * *

Dr. Roach regrets that he is unable to answer individual letters, but will incorporate them in the column whenever possible. Readers may email questions to or send mail to 628 Virginia Dr., Orlando, FL 32803.

(c) 2021 North America Syndicate Inc.

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TSH tells thyroid gland to make more hormone - New Castle News

Glucocorticoid therapy withdrawal in polymyalgia rheumatica | IJGM – Dove Medical Press


Polymyalgia rheumatica (PMR) and remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE syndrome) are diseases of unknown etiology that affect elderly persons. They are characterized by pain of sudden onset that continues and elevated erythrocyte sedimentation rate and C-reactive protein levels.1 Once the symptoms develop, they greatly impair patients quality of life. With the aging of the population, an increase in the number of such patients has been reported from the UK.2 The incidence of PMR has been found to be higher in individuals of Scandinavian background, lower in Southern European countries, and unknown in Japan.3,4 Although the symptoms improve markedly with glucocorticoid (GC) treatment, prudent tapering of GC is required.5 Although GC could be decreased from the initial dose in all PMR patients, it is difficult to stop GC treatment, as has been previously reported.6 Past studies reported that relapse has been variably associated with female sex, longer duration of morning stiffness, peripheral arthritis, higher erythrocyte sedimentation rate at diagnosis, persistent elevations of C-reactive protein, interleukin-6 levels, and soluble interleukin-6 receptor levels, larger initial doses of prednisone, and a faster rate of tapering.7 Furthermore, reports of GC continuation and risk factors for relapse in Japanese PMR patients are few.4 To better estimate GC treatment duration, the percentage of patients who could stop GC treatment and the baseline variables associated with inability to withdraw GC after the time when the GC continuation rate stopped decreasing were examined. In particular, sex differences were examined.

A total of 105 patients (64 women) who were started on GC treatment for PMR and/or RS3PE syndrome at Ikeda City Hospital from July 2004 to December 2019 were evaluated. Birds criteria8 were used up to 2014, and the EULAR/ACR polymyalgia rheumatica interim standard of classification9 was used between 2015 and 2019 for PMR diagnosis. Patients who showed pitting edema of both hands and both lower extremities and did not fulfill the diagnostic criteria of rheumatoid arthritis,10 spondyloarthropathy,11 or other diseases were diagnosed as having RS3PE syndrome. Both PMR and RS3PE syndrome were diagnosed in patients with PMR who showed pitting edema of both hands and both lower extremities without other cause.

The GC dose was left to the discretion of the attending physician. The initial dose of prednisolone is generally 10 to 16 mg/day, and the aim is to discontinue it by 24 years. The dose was actually reduced by 2.5 mg/day every 24 weeks in patients treated with >10 mg/day, and by 1 mg/day every 24 weeks in patients treated with 10 mg/day.7 When symptoms returned with GC reduction, the attending physician increased the dose promptly. GC was continued when it was resumed for disease recurrence once it had been stopped.

The days from GC initiation to GC withdrawal were calculated. If GC could not be stopped, the last observation day was used. The GC continuation rate during the observation period was then estimated by the KaplanMeier method, creating KaplanMeier curves by sex.

Furthermore, cases that had stopped GC (withdrawal group) and cases that had continued GC for 7.5 years (continuation group) were identified, and the following were compared between them: Age at time of starting GC treatment; sex; type (PMR and/or RS3PE syndrome); erythrocyte sedimentation rate, C-reactive protein, hemoglobin, ferritin, aspartate aminotransferase, and alanine aminotransferase levels before starting GC; days from onset of symptoms to GC initiation; GC maximum dose; GC dose half a year after it was started; presence of relapse (GC restarting or increasing due to deterioration of symptoms); and the presence of concomitant malignant disease. Cases belonging to neither the withdrawal group nor the continuation group constituted the intermediate group. Patients with malignant diseases were counted when they were diagnosed with them within 6 months since GC was started for PMR or RS3PE syndrome. It was thought that cases in the intermediate group included cases that would be reclassified to the withdrawal group or the continuation group if they were observed for a longer time. It was expected that the parameters associated with GC continuation in the intermediate group would be between those of the withdrawal group and the continuation group and totaled the parameters in the intermediate group.

This survey was based on a chart review, but a telephone poll of patients whose charts could not be reviewed was conducted.

Statistical analyses were performed with IBM SPSS Statistics, version 27. KaplanMeier curves were compared using the Log rank test. Comparisons between the withdrawal group and the continuation group were made with Students t-test for independent continuous variables, and the chi-squared test was used to compare categorical data between groups.

This investigation protocol adopted the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ikeda City Hospital Ethics Committee (approval number A20010). The data accessed from the medical records were de-identified in this report. Because this report contains no individual persons data, and this investigation was observational and noninterventional, the Ikeda City Hospital Ethics Committee waived the need for patient consent.

There were 58 cases diagnosed by Birds criteria, 43 cases diagnosed by the EULAR/ACR polymyalgia rheumatica interim standard of classification, and 4 cases with pure RS3PE syndrome. There were 32 cases in the withdrawal group and 17 cases in the continuation group.

The dose of GC could be reduced from the initial dose in all patients.

The duration from the onset of symptoms to GC therapy starting was 79.579.6 days (meanSD) in all patients.

The GC continuation rate 7.5 years after starting GC was 52.5% in all patients, 69.2% in women, and 27.1% in men. The rates remained unchanged for 15 years (Figures 1 and 2). The GC continuation rate was significantly higher in women (Log rank test). No patients were prescribed immunosuppressants.

Figure 1 Glucocorticoid continuation rate of all cases (KaplanMeier method).

Figure 2 Glucocorticoid continuation rate by sex (KaplanMeier method). The glucocorticoid continuation rate is higher in women (P=0.020).

P values by Students t-test or the chi-squared test are shown in the table for the other survey items, including numbers of cases, with data displayed as mean standard deviation (Table 1). Since there was a case with suspected temporal arteritis at the beginning in the withdrawal group that was treated with prednisolone 50 mg/day, this case was excluded as an abnormal value for the GC maximum dose and the GC dose half a year after its initiation. In the withdrawal group, there were few women (P=0.016). In all patients, hemoglobin levels (mean SD) before starting GC were lower (10.51.6 g/dL) in women than in men (11.41.8 g/dL) (P=0.014). In the withdrawal group, they were 10.91.5 g/dL in women and 11.91.6 g/dL in men. In the continuation group, they were 10.41.9 g/dL in women and 10.02.8 g/dL in men. Relapses were fewer in the withdrawal group than in the continuation group (P=0.0003).

Table 1 Clinical Features of the 105 Patients

In this study, the duration of GC treatment for PMR and RS3PE syndrome in Japanese patients was longer than in previous reports in English.12 GC treatment was needed for a longer time in women than in previous reports, and it was difficult to stop GC treatment in cases with severe anemia.

Although it has been reported that female sex is a risk factor for long-term GC treatment by Narvez et al13 and Cimmino et al,14 there has been no English-language report from Japan. Aoki et al reported the GC treatment duration of Japanese PMR patients, and they found no difference between men and women.12 They classified their patients into two groups by whether they had stopped GC therapy as of 24 months. Therefore, their observation period was shorter than in the present study. Two important factors causing sex-based disparities are genetics and sex hormones.15 Estrogen enhances B cell differentiation and immunoglobulin production.16 Several studies reported an immunosuppressive role of testosterone on different components of the immune system.15 Furthermore, the small number of GC receptors or low GC receptor affinity in woman may have an effect.14

In the present study, although the GC continuation rate fell to 55.6% at 7 years and 5 months, it did not fall further. The necessity for continuing GC differed among reports. Aoki et al reported that the median time of remission was 16 months.12 Cimmino et al reported that about 26% of the patients required GC treatment for 6 years or more.14 Shbeeb et al reported that the median GC treatment period was 5.95 years.17 Although the present study found a longer GC treatment period than previous reports, a prudent approach to GC dose reduction may have been one reason, given the report of a certain rate of disease recurrence in the report by Aoki et al.12 In 17 patients in the continuation group, three patients have not relapsed. This may show that our treatment is sometimes passive with respect to reducing the GC dose. Although there may have been a bias among certain institutions for longer GC treatment, the bias among institutions cannot explain the sex difference. There sometimes were newly suspected patients who received no GC treatment while waiting for spontaneous resolution. This study included no spontaneously resolved patients. The duration from the onset of symptoms to the start of GC therapy in all patients was over 2 months. This might be one reason for the long GC continuation in this study, and it might be a characteristic of Japanese/Asian people.

There are many more female than male patients. In Ikeda City, in which our hospital is located, the population aged 60 years and over as of March 31, 2020, included 18,880 women and 14,506 men.18 Therefore, it cannot be said that the incidence is higher among women than men.

Since PMR and the RS3PE syndrome often merged, they were considered together in one group.1,19 Since there are few pure RS3PE syndrome cases, whether there are differences between PMR and RS3PE syndrome in GC continuation and by sex is unknown. Aoki et al observed peripheral edema in 41 of 93 PMR patients.12 Such cases would be considered combined PMR and RS3PE syndrome cases according to the definition used in the present study.

Origuchi et al reported that GC dose and CRP 1 year after starting therapy were high in men with RS3PE syndrome.20 In the report by Origuchi et al, the observation period was 1 year, shorter than in other reports.20 In the present study, the womens continuation rate was also not high until 1.4 years after starting.

The present data showed severe anemia in the GC continuation group. Narvez et al reported that hemoglobin levels were low in women with PMR.13 They considered that anemia reflects intense inflammation. The range of ferritin was large for every case, and the difference between the withdrawal group and the continuation group was not clear. Ferritin levels were high in all groups, reflecting the impaired iron utilization in these diseases.

As a limitation of the present investigation, the number of patients was insufficient for a multivariable statistical analysis of the GC continuation rate and anemia. In addition, because some of the patients were interviewed by telephone, recall bias may have occurred. Because this study was retrospective, sex hormone levels were not measured before treatment; it is a future task to measure them in order to identify causes of the sex difference.

When considering the future treatment strategy for PMR and RS3PE syndrome in Japan, it is important to note that it is difficult to stop GC treatment for women and for those with severe anemia.

It is difficult to stop GC for PMR and/or RS3PE syndrome in women in Japan, especially in cases with severe anemia.

All authors have no conflicts of interest that should be declared. All authors take full responsibility for the content of this paper.

1. Mimori A. Polymyalgia rheumatica/PMR & remitting seronegative symmetrical synovitis with pitting edema/RS3PE (in Japanese). In: Mimori A. Physicians Notes on Rheumatology: The Process of Clinical Consideration. 4th ed. Tokyo, Japan: Japan medical journal; 2019:413426.

2. Partington RJ, Muller S, Helliwell T, Mallen CD, Sultan AA. Incidence, prevalence and treatment burden of polymyalgia rheumatica in the UK over two decades: a population-based study. Ann Rheum Dis. 2018;77(12):17501756. doi:10.1136/annrheumdis-2018-213883

3. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Care Res. 2009;61(10):14541461. doi:10.1002/art.24459

4. Nishioka K, Tanaka T. [Rheumatology: Progress in diagnosis and treatments. topics: III. Rheumatoid arthritis and allied conditions; 2. Allied conditions. 2) polymyalgia rheumatica]. Nihon Naika Gakkai Zasshi. 2014;103(10):24402448. Japanese. doi:10.2169/naika.103.2440

5. Hernndez-Rodrguez J, Cid MC, Lpez-Soto A, Espigol-Frigol G, Bosch X. Treatment of polymyalgia rheumatica: a systematic review. Arch Intern Med. 2009;169(20):18391850. doi:10.1001/archinternmed.2009.352

6. Muratore F, Pipitone N, Hunder GG, Salvarani C. Discontinuation of therapies in polymyalgia rheumatica and giant cell arteritis. Clin Exp Rheumatol. 2013;31(4 Suppl 78):S86S92.

7. Docken WP. Treatment of polymyalgia rheumatica [homepage on the Internet]. Wolters Kluwer; 2018 [Updated September 7, 2018]. Available from: Accessed February 21, 2020.

8. Bird H, Esselinckx W, Dixon AS, Mowat A, Wood P. An evaluation of criteria for polymyalgia rheumatica. Ann Rheum Dis. 1979;38(5):434439. doi:10.1136/ard.38.5.434

9. Dasgupta B, Cimmino MA, Kremers HM, et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European league against rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheum. 2012;64(4):943954. doi:10.1002/art.34356

10. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheumatism. 1988;31(3):315324. doi:10.1002/art.1780310302

11. Dougados M, Linden SVD, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheumatism. 1991;34(10):12181227. doi:10.1002/art.1780341003

12. Aoki A, Kobayashi H, Yamaguchi Y. Predictors of long-term therapy with glucocorticoid in polymyalgia rheumatica. Modern Rheumatol. 2020;31(2):417426. doi:10.1080/14397595.2020.1777680

13. Narvez J, Nolla-Sol JM, Valverde-Garca J, Roig-Escofet D. Sex differences in temporal arteritis and polymyalgia rheumatica. J Rheumatol. 2002;29(2):321325.

14. Cimmino MA, Parodi M, Caporali R, Montecucco C. Is the course of steroidtreated polymyalgia rheumatica more severe in women? Ann N Y Acad Sci. 2006;1069(1):315321. doi:10.1196/annals.1351.030

15. Trigunaite A, Dimo J, Jrgensen TN. Suppressive effects of androgens on the immune system. Cell Immunol. 2015;294(2):8794. doi:10.1016/j.cellimm.2015.02.004

16. Moulton VR. Sex hormones in acquired immunity and autoimmune disease. Front Immunol. 2018;9:2279. doi:10.3389/fimmu.2018.02279

17. Shbeeb I, Challah D, Raheel S, Crowson CS, Matteson EL. Comparable rates of glucocorticoid-associated adverse events in patients with polymyalgia rheumatica and comorbidities in the general population. Arthritis Care Res. 2018;70(4):643647. doi:10.1002/acr.23320

18. Ikeda City Office [homepage on the Internet]. Populations in Ikeda city by age and sex (in Japanese); April 2, 2020. Available from: Accessed July 25, 2020.

19. Cantini F, Salvarani C, Olivieri I, et al. Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome: a prospective follow up and magnetic resonance imaging study. Ann Rheum Dis. 1999;58(4):230236. doi:10.1136/ard.58.4.230

20. Origuchi T, Arima K, Umeda M, et al. Clinical outcomes in the first year of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. Modern Rheumatol. 2017;27(1):150154. doi:10.1080/14397595.2016.1192744

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Glucocorticoid therapy withdrawal in polymyalgia rheumatica | IJGM - Dove Medical Press

Focus on These Data When Making Treatment Decisions in Breast Cancer – Targeted Oncology

Komal Jhaveri, MD, discussed the case of a 63-year-old patient with HER2-positive metastatic breast cancer during a Targeted Oncology Case-Base Roundtable event.

During a Targeted OncologyTM Case-Based Roundtable event, Komal Jhaveri, MD, the section head of the Endocrine Therapy Research Program, clinical director, of Early Drug Development Service, and a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, NY, discussed the case of a 63-year-old patient with HER2-positive metastatic breast cancer.

Targeted OncologyTM: How typical is the presentation of this patient in your clinical practice, and what data are most relevant to you in choosing a treatment approach?

JHAVERI: According to the recently updated NCCN [National Comprehensive Cancer Network] guidelines in systemic therapy options for recurrent stage IV disease, we use a taxane with a dual HER2 blockade, which is trastuzumab and pertuzumab in the first line.1 This is obviously based on the unprecedented progression-free survival [PFS] and overall survival [OS] benefit in the CLEOPATRA trial [NCT00567190].2 The paclitaxel was based out of a phase 2 trial that was conducted by my colleague, Chau Dang, MD, here at Memorial Sloan Kettering Cancer Center, and we did not see any febrile neutropenia with the paclitaxel, so that has really become our go-to regimen in the first line.3

What data support treatment options in the second-line setting?

In the second-line setting, we have data from the EMILIA trial (NCT00829166), which led to T-DM1, or ado-trastuzumab emtansine, an antibody-drug conjugate [ADC], the first one for breast cancer.4 This is despite this trial not having patients progressing on trastuzumab, but in clinic this is our contemporary choice...for our patients. Additionally, we have a plethora of options that patients can receive on the third line and beyond. These include tucatinib [Tukysa] plus trastuzumab plus capecitabine [Xeloda] and fam-trastuzumab deruxtecan-nxki [Enhertu].1 We also have other chemotherapies with trastuzumab, such as capecitabine with trastuzumab and capecitabine with other TKIs [tyrosine kinase inhibitors]. There are targeted therapies, including a recent approval for margetuximab-cmkb [Margenza], an Fc-optimized antibody that was approved for use with chemotherapy in this last year.5

We have these many options, but what we do not know is the optimal sequence for third-line therapy and beyond.

Now, what is interesting here is that the triplet of tucatinib plus trastuzumab plus capecitabine, per the NCCN guidelines, is preferred in patients with both systemic and CNS progression on ado-trastuzumab emtansine.1 However, it may be given even in the second-line setting. Fam-trastuzumab deruxtecan is preferred in patients with visceral metastases [if there is disease] progression on ado-trastuzumab emtansine. [However, it is] contraindicated for patients with known pneumonitis or interstitial lung disease.

What makes this ADC special? Why is it distinct from T-DM1?

I think there are a few key attributes that we might want to think of [in] T-DXd [trastuzumab deruxtecan]. One is that the drug-to-antibody ratio [DAR] is 8 molecules of chemotherapy that can be delivered. Now, to put this into context when we think of T-DM1 therapy, that DAR is 3.5. So we are delivering more chemotherapy to the tumor cell. The payload itself is a topoisomerase I inhibitor, which we do not regularly use for our HER2- positive patients.

It is a highly potent payload, which the patients have not their regimens, and it has a very short half-life, so the free payload has a very short half-life, which is great. The linker is stable, and it is a tumor selective cleavable linker. Once this is delivered to the tumor, it is the pepsin in the tumor that makes the linker cleave and then deliver the payload. It is very tumor selective, so one can potentially expect less off-target toxicity.

And another important attribute to keep in mind is the bystander effect. It has membrane permeability, and so this payload can be membrane permeable and go to the neighboring cells, which might not necessarily be HER2 overexpressing. But that is why we have also seen activity in what we now call HER2 low, which is HER2 IHC 1+ and 2+ patients who have shortened benefit with T-DXd and other novel inhibitors that are also being developed and have this bystander effect. Of note, T-DM1 does not have that. And as we know, we do not utilize T-DM1 for patients who do not have HER2-amplified or HER2- expressive tumors.

Please discuss how the DESTINY-Breast01 trial [NCT03248492] has affected decisions for this patient.

[These data that] led to the approval of trastuzumab deruxtecan [were from] an open-label, multicenter, phase 2 trial [that enrolled] patients 18 [years] or older with unresectable metastatic breast cancer who had centrally confirmed HER2-positive disease and who had prior T-DM1.6,7 Patients with a history of interstitial lung disease were excluded.

This was because [of what] we had already learned from an adjudication committee that was put in place with the phase 1 experience of this agent. And stable, treated brain metastases were allowed to enroll on this trial. These patients were then enrolled in 2 parts. Part 1 included a PK [pharmacokinetic] stage and a dose-finding stage. In the PK stage, we studied 3 doses of which two, 5.4 mg/kg and the 6.4 mg/kg, moved on to the dose-finding stage. Based on the PK data and the safety data, the 5.4 mg/kg [dose] was selected to move forward and is the current recommended and approved dose.

This was the dose that moved into the continuation stage, where most of the patients had TDM-1 resistant disease. There were 4 patients who had TDM-1 intolerance, for a total of 184 patients [who] were treated with this dose, 5.4 mg/kg, with a primary end point of ORR [overall response rate]. One thing that I would like to highlight is that these patients have received up to 6 prior lines of therapy, and [approximately] two-thirds received prior pertuzumab therapy.

Additional baseline characteristics [also should be considered]. Median age was [approximately] 55 years. These were patients predominantly with a good performance state. [Approximately] 50% of these patients were hormone receptor positive. [Approximately] 84% had HER2 positivity by IHC 3+ expression. The remaining were IHC 2+ or 1+ or ISH [in situ hybridization] positive. Visceral disease was present in 92% of patients, of whom 57% had lung metastases. This is important to remember for the discussion of our case. Liver metastases were present in 30%, and the rest also had bone disease. There were 24 [13%] of these patients enrolled in the trial who also had stable, treated brain metastases.

How do the updated data from the DESTINY-Breast01 trial affect treatment decisions?

In the updated DESTINY-Breast01 trial data from June 2020, all but 4 patients had tumor shrinkage.8 The overall response rate, despite this [population being] heavily treated with a median of 6 prior lines of therapy, was 61.4%, including patients who had a complete response. The median duration of response, which is also very important to understand for our patients who are heavily pretreated, was 21 months in this phase 2 trial. And this response was seen rather early: time to response was 1.6 months. So if you are really worried about somebody with extensive disease or burdened disease, this was a quick response with this drug.

The median PFS in DESTINY-Breast01 was 19.4 months. This is rather impressive for such a heavily pretreated population. Just to put this into context and into perspective, when we think of other trials in the third line and beyond, whether it was the TH3RESA trial [NCT01419197] that studied TDM-1 with physician choice therapy, the NALA study [NCT01808573], the HER2CLIMB study [NCT02614794], or the SOPHIA trial [NCT02492711], the median PFS for the patient population [in the] third line [was approximately] 7 to 8 months.9-12 The PFS [in DESTINY-Breast02] of 19.4 monthsin such a heavily pretreated population, I think it is really unprecedented.8 The median OS data at 21 months was 25 months, but what I would really like to highlight here is that this is just 35% maturity of data, and we really need follow-up maturity now to understand the implications. [Approximately] 119 patients were already censored, and 17 were thought to have events at month 2, so at 18 months we had 74% alive, but [these are] still immature data.

Did these data show progression of disease in other areas?

A subgroup analysis for the 24 patients [13%] in the CNS subgroup was presented at ASCO [American Society of Clinical Oncology Annual Meeting] this year.13 Seventeen patients had brain lesions at baseline, and the data [were] available to evaluate responses in the brain for 15 of the 17. Though this was a small subgroup, it was important that there were responses seen in patients with stable brain metastases; 41% had a partial response and another 41% had disease stabilization in the brain. Again, this subgroup also had median of 6 lines of therapy, the same as the total population. Median follow-up here was 11 months, the CNS subgroup, the ORR, PFS, and duration of response were comparable to those in the total patient population treated at the same dose. The median PFS in this population with brain metastases was 18 months [95% CI, 6.7-18.1]. There was also an additional case report where we saw 55% regression of a metastatic brain lesion.

The most common sites when we looked at progression were the liver, lung, and lymph nodes, which was similar in all patients total and the CNS subgroup. Meaning, once you were in the CNS subgroup or the total patient population and then you progressed, the common types of progression were within the liver, lungs, and lymph nodes. Progression in the brain was not as common. There were only 4 of 48 patients who had progressed in the brain, including 2 out of the 8 patients with baseline CNS metastases.

What is the safety profile of T-DXd?

I think the most common adverse events [AEs] that we see, and that were seen in more than 10% of the patients in the study, were nausea, vomiting, alopecia, fatigue, and neutropenia.14 But an important AE that we want to keep in mind is the drug-related ILD [interstitial lung disease] or pneumonitis. The ILD incidence that was reported initially with the August 2019 data cutoff was 25 patients [13%] who developed ILD or pneumonitis. The majority had grade 1 or grade 2 ILD or pneumonitis; however, there were 4 fatal events. The median time to developing ILD was 4.1 months. At the additional 1-year cutoff, and overall median cutoff, there were 3 additional ILD cases determined by the independent adjudication committee.

ILD events were seen mostly within the first 12 months, and after the 12-month mark, only 1 patient developed ILD, perhaps suggesting that ILD is not a cumulative AE. But this is something that we really must be aware of, and not just us, but also our frontline nursing staff who are fielding the calls when the patient calls in. [If there are symptoms that may indicate ILD or pneumonitis,] whether they have shortness of breath, a new cough, extreme fatigue, [we need] to quickly interrupt therapy, get pulmonology involved, and give patients steroids. [There are] patients who are asymptomatic, [so we have] to keep a very close eye on this to make sure that we are not missing anything.

We have become more trained look for these [potential AEs] given that there are so many classic agents with breast cancer that cause pneumonitis: checkpoint inhibitors and everolimus, and [also] CDK4/6 inhibitors....I think we all have become a little more vigilant about keeping a close eye on symptoms for our patients and for also for keeping an eye on the scans to make sure that we are not missing the so-called ground glass opacities for which we might want to interrupt or discontinue therapy. Fortunately, the heart events or cardiac events were very low, including left ventricular ejection fraction decreases or cardiac failure, as is seen with trastuzumab.

What was the design of the HER2CLIMB phase 2 trial?

[Lets move on] then to the phase 2 HER2CLIMB trial of tucatinib [Tukysa] and capecitabine and trastuzumab, which studied patients with HER2-positive metastatic disease who had prior treatment with trastuzumab, pertuzumab, and T-DM1.15 What was key in the study was that active brain metastases not needing local therapy were allowed, but they were not required. So you could have had treated, stable brain metastases, but you were also allowed to have active brain metastases. What is important to remember here is that these are patients with small tumors, less than 2-cm tumors, who do not have symptoms warranting local therapy. They did not require immediate radiation and they were [still] considered eligible.

[More than] 600 patients were enrolled410 in the tucatinib arm and 202 in the placebo arm.15 And they were well-balanced groups with a median age of [approximately] 55 years, all with predominantly good performance status; 60% were hormone receptor positive; overall, they had received 4 prior lines of therapy. Forty-eight percent had a history of brain metastasis. Of these 48%, 60% [of the brain metastases] were stable and treated. The remaining were what was called active, which could be untreated brain metastases. Untreated [meant] no local therapy or systemic therapy or [that they had been] treated in the past with some kind of local therapy but [were] progressing again. Even though they are progressing again, they are not symptomatic enough to warrant additional local therapy.


1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 7.2021. Accessed August 20, 2021.

2. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0

3. Dang C, Iyengar N, Datko F, et al. Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2positive metastatic breast cancer. J Clin Oncol. 2014;33(5):442-447. doi:10.1200/JCO.2014.57.1745

4. Diras V, Miles D, Verma S, et al. Trastuzumab emtansine vs capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742. doi:10.1016/ S1470-2045(17)30312-1

5. FDA approves margetuximab for metastatic HER2-positive breast cancer. News release. FDA. December 17, 2020. Accessed August 20, 2021. fda-approves-margetuximab-metastatic-her2-positive-breast-cancer

6. Krop IE, Saura C, Yamashita T, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: a phase 2, multicenter, open-label study (DESTINY-Breast01). Abstract presented at: San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Accessed August 20, 2021. pp8/#!/7946/presentation/2039

7. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/ NEJMoa1914510

8. Modi S, Saura C, Yamashita T, et al. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer. Abstract presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Accessed August 20, 2021. https://www. pdf?ver=2020-12-09-104626-337

9. Krop IE, Kim SB, Martin AG, et al. Trastuzumab emtansine vs treatment of physicians choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18(6):743-754. doi:10.1016/S1470-2045(17)30313-3

10. Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine vs lapatinib plus capecitabine in HER2-Positive metastatic breast cancer previously treated with 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38(27):3138-3149. doi:10.1200/JCO.20.00147

11. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609

12. Rugo HS, Im SA, Cardoso F, et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2021;7(4):573-584. doi:10.1001/jamaoncol.2020.7932

13. Jerusalem GHM, Park YH, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2+ metastatic breast cancer with brain metastases: a subgroup analysis of the DESTINY-Breast01 trial. J Clin Oncol. 2021;39(suppl 15):526. doi:10.1200/ JCO.2021.39.15_suppl.526

14. Jerusalem GHM, Park YH, Yamashita T, et al. CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Ann of Oncol. 2020;31(suppl 2):S63-S64. doi:10.1016/j. annonc.2020.03.239

15. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2021. Accessed August 20, 2021.

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Focus on These Data When Making Treatment Decisions in Breast Cancer - Targeted Oncology

What Is Aspirin-Induced Asthma? Causes, Symptoms & More – Healthline

Aspirin-induced asthma (AIA) is a condition where asthma symptoms can develop after taking aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Its also known as aspirin-exacerbated respiratory disease (AERD) or Samters Triad.

The American Academy of Allergy, Asthma, and Immunology (AAAAI) estimates that 9 percent of adults have asthma and that 30 percent of adults who have asthma and nasal polyps may also have AERD.

Read on to learn more about the underlying causes and risk factors of AIA as well as how this condition may be treated.

Acetylsalicylic acid (aspirin) is a type of NSAID used to relieve pain, inflammation, and fever. Similar medications include ibuprofen (Advil) and naproxen (Aleve).

Aspirin and other NSAIDs interact with an enzyme known as cyclooxygenase-1 (COX-1). While the exact triggers are unknown, its thought that people with AIA have a sensitivity to the way these medications inhibit this enzyme.

You may be more prone to AIA if you have all three of these conditions:

A doctor may still recommend aspirin for the treatment of other conditions, such as preventing heart attacks or strokes, in cases where a person may have already experienced one of these conditions and when the benefits outweigh the risks of triggering asthma symptoms.

Symptoms of AIA tend to develop shortly after taking aspirin or other NSAIDs often within minutes or hours after exposure.

While its important to address any suspected symptoms of AIA with a doctor, heres a breakdown of mild symptoms as well as more severe symptoms that require immediate medical attention.

Mild symptoms of AIA may include:

More severe symptoms of AIA can make it harder to breathe even if you take a rescue inhaler. Although rare, these acute symptoms can be life threatening.

Seek emergency medical help if you experience the following:

People who develop AIA are usually between ages 20 and 50 years old and likely have a combination of:

You may also be more susceptible if you experience the following on a recurring basis:

Age is another consideration. You more generally can become more vulnerable to side effects from NSAIDs as you age past your 50s.

Its also possible that reactions to aspirin could be induced by drug allergies. Besides NSAIDs, other common drug allergies include:

Symptoms of AIA may also be further exacerbated if you also drink alcohol. The AAAAI estimates that 75 percent of people with the condition may experience symptoms after drinking alcohol along with aspirin use.

AIA is typically diagnosed with the help of an asthma specialist, such as an allergist, pulmonologist, or immunologist.

Theres not just one test that can diagnose AIA. Instead, a diagnosis is made with a combination of the following factors:

A doctor may also recommend ordering a test called an aspirin challenge to rule out drug allergies. This involves taking aspirin either in the doctors office or at the hospital while under medical supervision. Any reactions you have to taking aspirin can then be identified and treated.

Along with avoiding NSAIDs, treatment for AIA involves managing symptoms of asthma, sinusitis, and nasal polyps.

You can also talk with a doctor about the following options.

Home treatments can include:

A doctor may recommend one or more of the following medical treatments:

Besides exacerbated asthma symptoms, complications of AIA may include hives (urticaria). The AAAAI estimates that between 20 and 40 percent of people who have chronic hives may have worsening symptoms if they also experience AIA. A type of swelling called angioedema can also occur.

Its also important to consider long-term side effects of taking aspirin and other NSAIDs, especially when taken for longer than recommended. These include:

Avoid mixing aspirin with the following, too:

Aspirin is a type of NSAID primarily used to relieve pain. But be careful using aspirin if you have a history of asthma, sinusitis, and nasal polyps. These underlying conditions may put you at a higher risk of developing AIA.

Talk with a doctor if youre concerned about the risks or side effects of taking NSAIDs or if you have a history of side effects after taking these types of medications. They can help diagnose and treat potential AIA along with related medical conditions.

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What Is Aspirin-Induced Asthma? Causes, Symptoms & More - Healthline

AHN Performs Its First Islet Cell Transplants to Treat Chronic Pancreatitis – PR Web

Leading clinicians at Allegheny General Hospital support first islet cell transplant to treat chronic pancreatitis.

PITTSBURGH (PRWEB) October 05, 2021

Allegheny Health Network (AHN) today announced a groundbreaking new capability for treating patients who suffer from chronic pancreatitis, an inflammation of the pancreas that occurs over many years and, in severe cases, can be life-threatening. Every year, more than 80,000 people are diagnosed with the disease, according to the National Pancreas Foundation.

Surgeons at Allegheny General Hospital (AGH) have joined a select group around the country performing islet cell transplantation to restore the functions of a diseased pancreas. AGHs Institute of Cellular Therapeutics, is one of just a few in the nation that specializes in islet cell isolation, a highly sophisticated process in which islet cells, such as those that produce insulin, are extracted from the patients removed pancreas and transplanted back into the body. For the past six years, the institutes Islet Cell Isolation Laboratory has extracted and processed these life-saving cells to assist in the care of patients at select islet cell transplant centers around the country. With the launch of its own transplant program, AHN becomes one of just a few medical centers in the nation able to provide the comprehensive therapy from start to finish.

Pancreatic islets are tiny clusters of cells scattered throughout the pancreas. Included among these islets are beta cells, which produce the hormone insulin that helps the body absorb glucose from the bloodstream and use it for energy. Diabetes develops when the pancreas does not make enough insulin, the bodys cells do not effectively use insulin, or a combination of both. Massimo Trucco, MD, Director of AHNs Institute of Cellular Therapeutics and an internationally preeminent diabetes researcher, leads the islet cell extraction team at the hospital.

The islet cell transplant is critical for patients with immense pain and have failed other therapies. Dr. Trucco and his staff collaborate with AHNs gastroenterology, abdominal transplant, endocrinology, psychology and social services teams to complete the procedure and provide wrap-around patient support.

Chronic pancreatitis is a debilitating disease that can lead to frequent hospitalizations, higher use of narcotic pain medication and a lower quality of life, said Abhijit Kulkarni, MD, FASGE, an AHN gastroenterologist who evaluates patients for the islet cell transplant procedure. This treatment really represents the pinnacle of pain management for pancreatitis care and can be a true lifeline for the most critically ill patients.

According to Rita Bottino, PHD, from AHNs Institute of Cellular Therapeutics, the poor condition of the pancreas can make extraction of islet cells challenging. We sometimes have to be a little creative in finding a way to inject enzymes into the organ that will break the matrix that holds the cells together. By injecting enzymes, clusters of cells or single cells will be released from the organ and those are the kind of insulin-producing cells that we ultimately want to transplant back to the patient.

Once the islet cells are extracted and ready for transplant, AHN surgeons Harry Williams, MD, Ngoc Thai, MD, PhD, and Tadahiro Uemura, MD, PhD, transplant the cells into the patients own liver through the portal vein. Called an autologous islet cell transplant (TPAIT), the cells continue to produce insulin to control blood sugar levels in the body, eliminating the risk of becoming diabetic.

So we remove the diseased organ, which is causing debilitating symptoms for the patient, while creating a new pathway for insulin production in the body. And the advantage of a smaller time interval between extraction and transplant of these cells is significant and we believe will result in even better outcomes for our patients, said Dr. Williams.

Thus far, AHN has completed one TPAIT procedure and prepared more than 100 islets for regional hospitals including UPMC and The Cleveland Clinic. In addition to treating patients, AHN supplies research donor islets to Mt. Sinai Hospital, Stanford University Medical Center, Vanderbilt University Medical Center, and the universities of Pennsylvania, Miami and San Francisco, among others.

Our ultimate goal when starting our islet cell isolation lab several years ago was to ultimately develop the transplant capabilities and become one of the few one stop shops for this highly specialized care in the country, said Dr. Thai, Director of AHNs Center for Abdominal Transplantation. Having some of the worlds foremost experts in this field at our institution, like Dr. Trucco and his team, has afforded us with an extraordinary opportunity to build an internationally leading program.

To learn more about AHNs Cellular Therapeutics Institute or Transplant program, please visit

About the Allegheny Health Network: Allegheny Health Network (, a Highmark Health company, is an integrated healthcare delivery system serving the greater Western Pennsylvania region. The Network is composed of 13 hospitals, ambulatory surgery centers, Health + Wellness Pavilions, an employed physician organization, home and community based health services, a research institute, and a group purchasing organization. The Network provides patients with access to a complete spectrum of advanced medical services, including nationally recognized programs for primary and emergency care, trauma care, cardiovascular disease, organ transplantation, cancer care, orthopedic surgery, neurology and neurosurgery, womens health, diabetes, autoimmune disease and more. AHN employs approximately 21,000 people, has more than 2,500 physicians on its medical staff and serves as a clinical campus for Drexel University College of Medicine and the Lake Erie College of Osteopathic Medicine.

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AHN Performs Its First Islet Cell Transplants to Treat Chronic Pancreatitis - PR Web

An old idea from a German Jewish scientist spared by the Nazis is getting new life: Prevent and treat cancer by cutting out sugar – The Philadelphia…

Otto Warburg probably would have been sent to a concentration camp if the Nazis werent hoping he could cure cancer.

Warburg was a Jewish gay man living openly in Berlin with his partner as Hitler rose to power. Warburg was also a biochemist, as brilliant as he was arrogant. In the 1920s, he discovered a hallmark of cancer, now called the Warburg effect. Malignant cells are ravenous for glucose, or blood sugar, consuming 10 times more than healthy cells. He dedicated his career to studying this strange metabolic anomaly because he believed it was the root cause of cancer.

He won the 1931 Nobel Prize for his work. But it was mostly forgotten by the 1950s, eclipsed by the molecular genetics revolution that set off a search for mutated, cancer-causing genes. He died in 1970 at age 86.

The rise, fall, and recent resurgence of research into cellular metabolism is the subject of Ravenous: Otto Warburg, the Nazis, and the Search for the Cancer-Diet Connection. Author Sam Apple, a journalist based in the Philadelphia suburb of Wyndmoor, weaves together this complex narrative in a way that makes arcane science accessible and fascinating.

The book is also thought-provoking for anyone interested in avoiding cancer and who isnt?

Its not obvious to me that there would be a breakthrough cancer therapy if Warburgs focus on cellular metabolism had not been shunted aside, Apple said in a recent interview. More likely, there would have been more attention to the relationship between our diets and the metabolism of the whole body and cancer. I think this could have had a dramatic impact on cancer prevention. But the link is still is not widely appreciated.

Otto Warburg was related to a wealthy German Jewish clan of bankers, scholars, and influencers. He was groomed for scientific greatness by his father, Emil Warburg, a leading physicist of the time.

The pinnacle of Otto Warburgs career happened to coincide with the rise of the Third Reich. When Warburg refused to sign a declaration of Aryan descent, the Nazi customs official tasked with asking Warburg to lie endeavored to get him punished by the Kaiser Wilhelm Society, the parent organization of Warburgs scientific institute.

Warburg not only managed to get off scot free, but he asked the Wilhelm Society president to ask the Reich Ministry of Finance to rewrite racial decrees so that non-Aryan institute directors would be treated like Aryan directors.

In 1934, at a moment when Hitler had already begun sending Germans to concentration camps, Otto Warburg, a gay man of Jewish descent, wanted Nazi laws rewritten according to his personal needs, Apple writes in the book.

As the author explains, cancer rates were inexplicably rising in Germany and other developed countries, and the Nazis fear of the disease ran almost as deep as their antisemitism and homophobia They despised Warburg, but needed his scientific genius.

Warburg invented several new tools to study the metabolism of cells, including the manometer, an instrument used to measure the force exerted by a gas or liquid.

He knew that in a healthy cell, blood glucose was normally converted to energy in a process using oxygen. This process, which involves enzymes that Warburg spent years identifying, occurs in the cells power stations, now known as mitochondria.

He discovered, to his amazement, that cancer cells broke all the metabolic norms. In addition to overconsuming glucose, the cells turned it into energy using an inefficient process that did not require oxygen even though plenty of oxygen was available.

The cancer cells were chopping glucose molecules in half and spitting the fragments right back out of the cell, Apple writes in an elegantly simple description of anaerobic glycolysis, or fermentation, the biochemical process that also gives us beer and wine. Cancer cells, Warburg realized, were fermenting glucose just as simple organisms like yeast and bacteria do.

But why? Warburg hypothesized more like proclaimed that cancer cells mitochondria were somehow defective, so the cells had to resort to a backup power generator, namely fermentation.

Today, while the search for answers continues, the evidence suggests that fermentation is not a response to a defect. Rather, it gives malignant cells an advantage as they turn into uncontrollable, immortal renegades.

Glucose molecules are the building blocks that cancer needs to create daughter cells, Apple boiled it down during the interview. The most influential scientists now think its about the cancer cells bioenergetic needs.

Following the 1953 discovery of the structure of DNA the genetic instructions for everything cells do oncology researchers became focused on finding and fixing the defective genes that give rise to cancer.

In that postwar era, Warburgs focus on cell metabolism was seen as outmoded, like studying the fuel line in hopes of understanding a high-tech engine.

Beginning in the 1990s, however, some leading researchers realized that certain cancer-causing genes known for their role in cell division also regulated cells glucose consumption. One of those scientists, Chi Van Dang, former director of the University of Pennsylvanias Abramson Cancer Center and now scientific director at the Ludwig Institute for Cancer Research, showed that MYC, a family of genes regulating cell proliferation, also targets an enzyme that can turn on the Warburg effect.

Metabolism-centered cancer therapies that effectively starve tumors are no longer just a concept. Two drugs, ivosidenib and vorasidenib, have already been approved by the Food and Drug Administration for a form of leukemia and are now being tested in brain cancer patients. Rafael Pharmaceuticals experimental therapy, devimistat, has had impressive early results in bile duct cancer trials.

But as Apple points out, cancer is an incredibly persistent foe. It can mutate to evade chemotherapy, molecularly targeted therapies, and even newer immune-boosting therapies. The same thing may happen with metabolic therapies. Whats more, virtually all cancer treatments come with significant side effects.

Thats why the implications for preventing cancer in the first place are so important.

Population-wide studies have directly linked 13 cancers including breast, bladder, lung, colon, liver, and gynecological cancers to the same metabolic abnormalities that are driving the twin worldwide epidemics of obesity and diabetes. The most striking thing that the cancers, obesity and diabetes have in common is resistance to insulin, the vital hormone that enables cells to absorb blood glucose and turn it into energy. To compensate for this resistance, the pancreas pumps out more and more glucose.

The hypothesis is that patients high blood sugar impacts tumor growth by providing cancer cells with an abundance of the fuel they thrive on.

Apple spends almost half his book taking deep, incisive dives into research on the insulin connection. Refined sugar, which is a combination of glucose and fructose called sucrose, contributes to insulin resistance, So does fructose, or fruit sugar especially when it is concentrated in high-fructose corn syrup, the ubiquitous processed-food additive. Consuming fructose, a carbohydrate, also appears to make people add fat tissue more readily than actual fats, such as such as butter.

Precisely how much sugar is too much may be different for each person, depending on genes and age and exercise habits and capacity to store fat safely, he writes. But the path from refined sugar added to our diets to insulin resistance ... to cancer is now well understood and based on widely accepted science.

He touches only glancingly on a fundamental problem: Even if sugars role as a cancer-promoter becomes an article of faith, cutting back on it is tough. And controversy, not to mention quackery, abounds in the field of nutrition. The ketogenic diet, for example, restricts carbohydrates, which are converted to glucose in the body. The diet has shown promise in weight loss studies, as well as in relieving neurological disorders such as epilepsy. But the esteemed Mayo Clinic says the diets high level of saturated fats, combined with limits on nutrient-rich fruits, veggies and grains, is a concern for long-term heart health.

In the final chapter, Apple weaves in a chilling anecdote:

Sugar, of course, cannot be blamed for Nazism or for turning Hitler into a madman. But as his madness grew, so, too, did his taste for sweets. It wasnt only his cherished Viennese pastries. On any given day, Hitler might consume two full pounds of chocolates. He even added sugar to his wine.

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An old idea from a German Jewish scientist spared by the Nazis is getting new life: Prevent and treat cancer by cutting out sugar - The Philadelphia...

Chemotherapy for Prostate Cancer: When It’s Used and What to Expect – Healthline

The American Cancer Society says that nearly 250,000 American men are expected to be diagnosed with prostate cancer in 2021. And about 1 in 8 men will be diagnosed with prostate cancer at some point in their lives.

Prostate cancers tend to grow slowly and have a fairly good outlook compared to many types of cancer. From 2010 to 2016, the 5-year survival rate in the United States was 97.8 percent, according to the National Cancer Institute.

Chemotherapy is a drug therapy thats sometimes used to treat prostate cancer. Its most commonly used to treat aggressive tumors or advanced prostate cancer that hasnt responded well to other treatments.

In this article, we break down when your doctor may recommend chemotherapy for prostate cancer and what you can expect while taking chemotherapy drugs.

Chemotherapy is a cancer treatment that involves taking drugs that kill rapidly dividing cells. Chemicals in these drugs can kill cancer cells and healthy cells in your body that quickly divide such as bone marrow and hair cells.

According to the American Cancer Society, chemotherapy is not a standard treatment for early prostate cancer. Its most likely to be used for aggressive cancer or cancer that has started growing outside the prostate.

Most men receiving chemotherapy for advanced prostate cancer will also receive androgen deprivation therapy (ADT) or anti-hormone therapy.

Chemotherapy may also be used to treat castrate-resistant prostate cancer (CRPC). CRPC is a type of prostate cancer that stops responding to hormone therapy. Prostate cancer needs male sex hormones to grow, and hormone therapy aims to lower male sex hormones to slow tumor growth.

A 2018 research review showed that docetaxel (developed in 2004) is the first chemotherapy drug that improved the survival rate of men with prostate cancer. Today, its the most commonly used chemotherapy drug to treat prostate cancer.

Docetaxel falls into a group of drugs called taxanes. These drugs block cellular processes cancer cells need to divide.

Docetaxel is often combined with the steroid prednisone. A 2016 research review showed that prednisone may help:

If docetaxel treatment doesnt work best for your health needs, doctors often recommend trying cabazitaxel. Cabazitaxel falls into the same class of drugs as docetaxel.

The following treatments are newer treatment options that often work when hormone therapy doesnt work for you:

However, there are no studies available yet directly comparing these drugs, and its not clear which is most effective.

Enzalutamide and apalutamide are in a class of drugs called androgen receptor inhibitors. They block male sex hormones from binding to receptors on your prostate.

Abiraterone is in a class of drugs called androgen biosynthesis inhibitors. They work by blocking the production of testosterone.

Other chemotherapy drugs that may be used to treat prostate cancer include:

Chemotherapy drugs are typically administered intravenously (through an IV) by a doctor who specializes in cancer treatment. The medications can be administered at a:

Drugs are administered in cycles to help give your body time to recover. Cycles are often 2 to 3 weeks long, and each session takes roughly an hour, according to the American Cancer Society.

The schedule of your cycle depends on which drugs are being used. You may only be given chemotherapy drugs on the first day of your treatment or for several days in a row.

The total length of your treatment depends on how well the chemotherapy is working and your side effects.

Some types of chemotherapy drugs like enzalutamide can be given as oral pills.

Chemotherapy can cause your red and white blood cell counts to drop, so youll likely have a blood test before each of your sessions.

If you have a very low white blood cell count, your doctor may recommend lowering the dose or stopping treatment.

Chemicals in chemotherapy drugs kill cells that divide quickly, but they cant differentiate between cancer cells and healthy cells in your body.

Many of chemotherapys side effects are due to drugs targeting healthy cells that divide rapidly such as cells in your:

Some common side effects of chemotherapy include:

Severity of symptoms can vary between people. Many of the side effects of chemotherapy go away shortly after treatment.

Docetaxel and cabazitaxel can cause neuropathy, or nerve dysfunction, that leads to the following feelings in your hands or feet:

A 2014 research review showed that about 10 percent of participants have grade 3 or 4 neuropathies, which are the highest classifications of nerve dysfunction. Your chances of developing neuropathy depend on your dose.

According to the American Cancer Society, the drug mitoxantrone can cause leukemia in rare cases, and estramustine increases your risk of developing blood clots.

Its important to discuss prostate cancer treatment options with your doctor. They can help you understand the pros and cons of chemotherapy and answer any specific questions you have about your treatment.

An oncologist, a doctor specializing in cancer, can help you develop strategies to lower your chances of developing side effects.

An oncologist can also put you in touch with support groups in your area. Many people find it helpful to talk with other people who have gone through the same treatment.

You can find online support groups or support groups in your area from these websites:

Chemotherapy is most commonly used to treat prostate cancer that has spread beyond the prostate. Chemicals in chemotherapy drugs kill cancer cells and other cells in your body that rapidly divide such as cells in your hair follicles and digestive system.

Your doctor can help you determine if you may benefit from chemotherapy. You may also find it helpful to join a support group that connects you with other people who have undergone the same treatment in the past.

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Chemotherapy for Prostate Cancer: When It's Used and What to Expect - Healthline

What If I Had Gotten a Head Start on Hormones? – The Cut

Photo: Getty Images/EyeEm

Last week, Arkansas lawmakers passed a bill that could have life-threatening consequences for transgender youths. HB1570 the Save Adolescents From Experimentation (SAFE) Act bans any trans person under 18 from receiving gender-affirming health care, including puberty blockers and hormone therapy. Arkansas is the first state to pass these extreme measures, though at least nine other states are considering similar bills and more than 45,000 trans youths could be affected.

While the lawmakers who support HB1570 claim to be protecting kids from making medical decisions they cant take back, they are actually putting them at risk. Studies have shown that not only do transgender children very rarely regret these treatments but their rates of depression and suicide are greatly reduced by them. One study found that access to hormone therapy over the course of one year decreased suicide rates in transgender youths by 75 percent. This law cuts them off from potentially life-saving options.

The Cut spoke with 19-year-old Vaniel Simmons, who was raised in Arkansas, about how access to gender-affirming health care saved his life.

By the time I was 15, I felt confident that I was trans. I started wearing a binder and three layers of clothing to hide my body, even in the summer. A year earlier, I had come out to my family as bisexual, but that never felt quite right. They were more or less supportive but would still pressure me to wear makeup or dresses. It made me incredibly uncomfortable, but I couldnt articulate why. I couldnt put into words why I would have a panic attack every time my mom tried to take me shopping. I just knew that I couldnt stand looking at myself in the mirror. I started getting really depressed and began self-harming. I starved myself and overexercised, thinking weight was the reason I didnt like my body.

I did not fit in at my school, which was filled with homophobic or incredibly religious people. Every day, other students would tell me, Youre gonna go to hell. You need to come to a Christian fellowship group. One girl walked around wearing a T-shirt that spelled fag in sign language, and the teacher and principal said they couldnt do anything about it. But every year on National Coming Out Day, I would do a fun outfit when I showed up in a rainbow cape, they said I had to take it off. By my junior year, I had decided to transfer somewhere else. I applied to a boarding school in Hot Springs, Arkansas, where people dyed their hair blue and green and wore sparkly shoes. My mom was supportive, since it was a very academically prestigious place, and as I was a low-income student, they would pay the tuition. I felt a desperation that I needed to be anywhere but here.

I started finding online LGBTQ groups where people explained trans identities. I started thinking, Maybe thats me, and using he/him pronouns. I began researching hormone treatments. I was watching famous trans YouTubers and Googling, What does testosterone do to your body? and How can I get top surgery? Any provider I called said I had to be 18 to make an appointment, and I didnt have a family doctor I trusted enough to talk about these kinds of issues. I was resigned to waiting.

I felt stuck. I knew that starting hormone therapy would help. Knowing what I needed to do and not being able to do it was soul-crushing. By the time I was 16, I couldnt picture a future. That Christmas, I had a full panic attack. My family kept misgendering me, and I remember sitting on the floor of my room, crying. My grandmother came in, and I told her: Im a guy. I dont know why they cant see that. She is very accepting; whatever makes me happy will make her happy. About a month later, I got in an argument with my mom I dont remember exactly what about and I stormed out of the house. My stepdad would make uncomfortable comments about my body, and we were arguing a lot about him. My grandmother followed me to the nearby lake, and I told her, Im hiding who I am at school. I dont feel safe at home. I would rather not exist at all than continue to exist like this. That was my lowest point. And she was like, So youre going to move in with me.

I didnt expect to live long enough to have access to the health care I needed. If a teenager can make the major life decision to want to harm or kill themselves, why wouldnt they be able to make major life decisions about their health? I couldnt stand the thought of living this way any longer. Every single day was a hellscape. That feeling is more torturous than taking testosterone and deciding later on I dont want to do this anymore.

In 2018, I started boarding school, and my first semester was definitely the hardest. Everyone there was great, and they didnt mess up pronouns but I still had to live in the female hall with the girls. Then I found a booth for the Arkansas Childrens Hospital Gender Spectrum Clinic at a pride event and booked my first appointment to talk about hormone therapy. I was 16 at the time. I told my mom that if she refused her support, Id just do it when I was 18 and resent her. She showed up for the first appointment but not to any others. They did a full psychological evaluation of me, my mother, and my grandmother. They wanted every detail. Then the doctors conferred to make sure hormones were the right option for me, and there was another three- or four-month waiting period to make sure I was feeling consistent. I wasnt able to actually start the treatment until seven months after the first consultation. But while waiting, I successfully petitioned the school to move me to the guys hall in my second semester. The other students just started letting me exist as a dude, though it was still slightly dysphoric for me. They all had their deep voices, and I was still trying to get there.

About six months into testosterone treatment, my voice finally started to drop. I was 17. I remember walking into school after the Christmas break and greeting a counselor. She said, I didnt recognize your voice for a second because of how much it had deepened. It felt like, Youre finally able to hear me as I actually am. That feeling was like Christmas all over again.

These lawmakers dont understand that these treatments arent just something trans people want; they mean actual life or death for a lot of us. This bill is a death sentence. It takes away peoples chances to live. I am happy with myself now I had top surgery last August. But theres always the thought in the back of my head, How much further could I be had I gotten a head start on hormones? My teenage years were mostly spent hating my body and isolating myself so I didnt have to be around people who saw me as a woman. I didnt get to experience having casual fun with my friends on the weekends. It took me years to get to the place where Im at now. I could have spent all those years being happy.

In the U.S., the National Suicide Prevention Lifeline is 1-800-273-8255.

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What If I Had Gotten a Head Start on Hormones? - The Cut

New Ontario clinic offers diverse health and beauty services – Richland Source

ONTARIO Jenny Swisher opened The CRU Clinic at the beginning of April. It is a business not so common in the area.

She said the diversity of CRUs services differentiate it from others. The clinic offers aesthetics services, IV hydration, testosterone replacement and weight loss programs.

CRU stands for contemporary, refined and unique. Swisher said the business goal is to provide contemporary care for refined wellness that is unique to each individual.

Richland Area Chamber and Economic Development held a ribbon-cutting ceremony for CRU on Thursday afternoon.

Richland Area Chamber and Economic Development held a ribbon-cutting ceremony for CRU on Thursday afternoon. Richland County commissioners Cliff Mears and Tony Vero and Ontario Mayor Randy Hutchinson joined the event and welcomed the new business.

Swisher, a certified nurse practitioner, said the IV hydration service is nutrient infusion therapy. Depending on the need, customers can get anything from calcium to vitamin B complex through the infusion.

When you take oral vitamins, you only get about 50 percent (of what you eat) if you have a good GI (gastrointestinal tract)absorption system. But sometimes, less than 50 percent is actually absorbed, Swisher said.

And with the IVs, you get 90 to 100 percent of what you get infused.

She said the service is rare in the area and some people have been driving to Columbus or Cleveland for it.

Those who are nutritionally deficient would benefit from the infusion, Swisher said. It can help rehydrate a hangover as well. For those who do weight-lifting or activities consuming a lot of energy within a short time, the infusion will help them replenish essential nutrients quickly.

Swisher said the aesthetics services have been popular since the clinic was open. It offers Botox injection, lip fillers and dermal fillers. The owner filled her own lips about a week ago to get rid of some wrinkles around.

She said she wanted to be able to experience what her patients go through during the process.

CRU also targets male customers with hormone replacement therapy. Swisher said men go through andropause just like women go through menopause. They might feel fatigued, be unable to gain muscle or have a decline in sex drive. The clinic can tailor the therapy and meet an individuals needs.

The CRU Clinic is located at 2293 Village Park Court. It opens from 8 a.m. to 5 p.m. on weekdays. Swisher said most services are provided through appointments, but walk-in IV infusions are available from 10 a.m. to 2 p.m.

Those interested can check The CRU Clinics website or call 419-775-5457 for more information.

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What Are the Most Common Sexual Side Effects Survivors of Cancer Face, And How Are They Treated? –

A month after Alegra Woodard received a diagnosis of stage 1 cervical cancer, she underwent a radical hysterectomy, a surgery that removes the uterus, ovaries, fallopian tubes, left and right pelvic nodes, cervix, tissue around the cervix, and the upper part of the vagina. She was just 36 years old, a wife and mother working as an information technology practitioner in Honolulu.

Her life changed overnight.

The next day I felt like another person, Woodard says. The change was drastic. I went into full menopause. I started sweating, my sexual desire (was) nonexistent, and intercourse became very difficult because it felt like someone had poured sand in my vaginal area.

Woodard isnt alone. A study out of Sidney Kimmel Cancer Center (SKCC) at Thomas Jefferson University in Philadelphia found that 87% of survivors of breast, pelvic, endometrial, prostate, bladder and rectal cancer said treatment affected their sexual function or desire. Although sexual side effects are more often reported by women, they affect men as well.

Steven Dupin, a personal trainer, comedian, author and patient advocate for the Prostate Cancer Foundation, (visit their site to learn more about the side effects of prostate cancer), lives in Los Angeles and was 42 when he started having problems with frequent urination and prostate pain. However, he didnt receive a diagnosis of prostate cancer until two years later, when his doctor ran a routine PSA blood test, which is used to screen for prostate cancer. Dupin says that his biggest fear, besides dying, was that he would have problems with sexual intimacy as a result of treatment. Both of these fears are common.

The No. 1 question I get from other men I talk to is Does the plumbing still work? Dupin says. I always say, Sure. The only difference is that now instead of ejaculate, fairy dust and glitter come out.

That last part, of course, isnt true. But the stories patients tell of sexual side effects resulting from cancer treatment are.

So, what causes these problems, and what solutions are available for survivors?

The SKCC study found that the most common sexual side effects were painful intercourse (73%), body image distortion (54%) and the inability to achieve orgasm (42%).

According to Ashley Arkema, a nurse practitioner in the Female Sexual Medicine and Womens Health Program at Memorial Sloan Kettering Cancer Center, the most common concerns reported by the patients she sees are low libido, sexual pain, diminished arousal and changes in body image. Fatigue, anxiety and depression can also affect sexual function. And she attributes these problems primarily to cancer treatment, including surgery, chemotherapy, hormone therapy and pelvic radiation, which often cause sexual side effects that are associated with hormone depletion. For younger patients this is especially true. Abrupt early surgical menopause or chemical menopause causes a rapid drop in estrogen, leading to more severe and sudden symptoms. Hormone therapy, including tamoxifen and aromatase inhibitors, commonly used in breast cancer treatment, can also have a negative impact on sexual function. And pelvic radiation can lead to menopause, vaginal narrowing and scarring.

Dr. Mindy Goldman, director of the Gynecology Center for Cancer Survivors and At-Risk Women at the University of California, San Francisco, who serves as the chair of the menopause panel and the co-chair of the sexual function panel for the National Comprehensive Cancer Network (NCCN), agrees that the lack of estrogen causes many of the most common forms of sexual dysfunction in women. However, there are other causes.

There are many aspects of cancer treatment that can cause sexual dysfunction, and the causes are often multifactorial, Goldman says. Vaginal dryness can lead to pain and decreased desire. Surgeries can lead to body image changes. Stem cell transplants can cause graft-versus-host disease that can lead to scarring, pain and decreased arousal. Radiation can lead to pain and scarring. The cancer itself can cause pain. And then (a lot of women) also have cancer-related stress, anxiety and depression that can affect their overall sexual functioning.

She says the key to treating patients is a multifactorial approach and finding safe and effective options, especially for those who shouldnt use hormone therapies.

Dr. Gregory Broderick, a urologist at Mayo Clinic and a professor of urology with Mayo Clinic Alix School of Medical Education in Jacksonville, Florida, sees male patients who have cancer whove experienced sexual dysfunction, incontinence (loss of bladder control) and urethral strictures (scarring that narrows the tube that carries urine out of the body).

Together, Goldman and Broderick co-chair NCCNs panel on sexual health. NCCN is a nonprofit alliance of 30 cancer centers that partner to improve cancer care and survivor issues by reviewing and updating guidelines. They want to make sure certain side effects (like this one) are not overlooked.

The most common problems he sees are erectile and ejaculatory dysfunction, loss of libido, incontinence or other urinary problems like climacturia (when a man leaks urine as he ejaculates). There can also be body image challenges, especially for men who live with a stoma or ostomy bag after colorectal or bladder surgery.

In terms of the prostate surgery, a significant risk to a mans erectile function status is whether or not the pelvic nerves that regulate erection can be spared at the time of surgery, Broderick says, noting that a more recent approach to the operation, called robotic prostatectomy, has advantages because patients dont require a large abdominal incision, have much less bleeding, and can get back to work sooner.

Dupin was able to have robotic surgery, and he is able to have sex and achieve orgasm. He doesnt have problems with a lack of libido or incontinence. The only sexual side effect hes experienced is the loss of ejaculate.

After Woodwards surgery in 1999, she was prescribed a topical vaginal medication called Premarin (conjugated estrogens) to lubricate and improve dryness. But this still left her unsatisfied.

All of the large guiding organizations say to use over-the-counter topical agents first, Goldman says. This includes things like moisturizers, pH balanced gels, soothing agents, oils and lubricants. Some of these things can alleviate symptoms if theyre used regularly.

Arkema says her first few recommendations include a variety of over-the-counter products, but these solutions dont always work for everyone.

Goldman notes there are vaginal hormones that can help treat dryness and sexual pain by targeting the tissue directly. The most common are vaginal estrogens which exist in a cream, a ring formulation and a suppository.

Furthermore, Goldman says there are now Food and Drug Administration (FDA) approved prescription medications that treat various types of sexual dysfunction. Osphena (ospemifene) and Intrarosa (prasterone) are approved for treatment of painful sex. Finally, there are also female versions of Viagra, as well as the FDA approved Addyi (fibanserin) and Vyleesi (bremelanotide), which are both approved for treatment of hypoactive sexual desire disorder in women.

I think theres a common misconception that nothing can be done, Goldman notes. Some providers assume the only treatment options are hormones, and for many breast cancer patients these are contraindicated (not advisable). Even so, there are lots of other options.

Broderick says that when meeting with a new patient, he starts by looking into how they were treated because the type of therapy often dictates the sexual side effects and recommendations. The primary treatment options include PDE5 inhibitors (which block the PDE5 enzyme, allowing blood vessels to relax and increasing blood flow), such as Viagra (sildenafil cirate), Levitra (vardenafil), Cialis (tadalafil) or Stendra (avanafil); penile injectable therapy; penile prosthesis; and the use of a vacuum erection device.

Although robotic surgery has come a long way, some men still struggle with incontinence, which quickly becomes a critical sexual side effect.

When a male patient comes to me with incontinence and erectile dysfunction, I start by asking where their partner is sleeping, because one thing Ive learned is that partners will not sleep in the bed with someone who is incontinent, Broderick notes. And theyre less likely to become intimate with someone who isnt in the same bed. So, you really need to address the incontinence first.

After a prostatectomy, Broderick says all patients go through a phase of neuropraxia (when the nerves arent working quite right). It takes time to return to normal erectile status. Generally, erectile function begins to come back after about six months. He says if it hasnt come back by 18 months, it probably wont.

Furthermore, radiotherapy, which is good at killing cancer, affects small-vessel blood flow, so patients who have been through radiation can have difficulty initiating and maintaining erections. Most of these patients, however, respond to PDE5 inhibitors like Viagra. On the other hand, a man who has lost nerve function from a prostatectomy needs direct vascular stimulants like penile injectable therapy.

So, I have a counseling plan for patients depending upon whether Im seeing him six, 12 or 18 months after his operation and his willingness to undergo rehabilitative strategies, Broderick says. Some patients come in and theyre part of a couple who are both in their 70s, and the erectile dysfunction is not as impactful for them simply because they werent all that sexually active prior to the surgery. Maybe his partner has gone through menopause and is less receptive of penetrative sex. What shes really looking for is the maintenance of their intimacy without penetrative sex. Sometimes my job is just getting the two partners to understand where they both are with all of that.

Although the range and severity of sexual side effects can vary greatly, one thing that helps across the board to increase treatment rates is talking about whats going on.

Findings from the SKCC survey of 400 survivors found that 87% said they experienced sexual side effects but most also said their oncologist had not asked them about these side effects. And patients often dont bring up the topic themselves, reporting that they feel embarrassed, think theres no help for the problem or dont know which type of physician to talk to about it.

Woodard says she wishes someone would have talked to her about what to expect before her surgery, but at the time she was being treated in a military clinic. She received her diagnosis from a nurse practitioner and then transferred to the hospital to meet with the surgeon and oncologist.

I remember that session when I met with the oncologist who looked at my chart and said, You have cancer? Thats odd, Woodard recalls. These conversations were never about gutting me out like a fish and what would happen afterward.

She went into surgery without any idea about what was coming.

Theres a stigma or discomfort for many physicians in talking about this, Goldman says. Theres a study that showed that if the patient feels discomfort coming from their provider, they often wont bring the issue up. So there (are) a lot of people who may assume that this is something they have to live with.

Goldman sees no reason that sexual dysfunction cant be talked about like the other side effects of treatment, such as neuropathy, hair loss and pain.

At Mayo Clinic, Broderick says they train their surgeons to do exactly that: talk about all the possible side effects.

Fortunately for Dupin, the possibility of sexual side effects was addressed. His doctor told him he may experience erectile dysfunction and gave him a prescription for Viagra that he decided not to use.

Sexual side effects of cancer treatment are common, and Goldman wants patients to understand this and feel comfortable asking about what treatments are available.

Woodard, who now volunteers with the National Cervical Cancer Coalition, (their website can help patients and survivors understand their side effects more and offers support), agrees that patients need to speak up.

My advice is to be more demanding, she says. Ask for resources. Often treatment is not only a physical procedure but one that affects your mental and emotional health. You should be in touch with an advisor or someone that can help you navigate the emotional part of this.

More importantly, Woodard wants patients to know theyre not alone. There (are) a number of us out here, she says. Seek help, ask questions, be persistent and dont give up. Dont give in.

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Tolmar Publishes Study in the February Issue of Journal of Urology on the Impact of Late Dosing on Testosterone Suppression with Two Different…

BUFFALO GROVE, Ill., April 12, 2021 /PRNewswire/ --Tolmar Pharmaceuticals, Inc., a privately held specialty pharmaceutical company, announced the publication of a manuscript entitled "Impact of Late Dosing on Testosterone Suppression with Two Different Leuprolide Acetate Formulations: In Situ Gel and Microsphere An Analysis of US Clinical Data" in the February issue of Journal of Urology.

This retrospective analysis of real-world data is a more detailed follow-up of the results to "The Impact of Late Luteinizing Hormone-Releasing Hormone Agonist Dosing on Testosterone Suppression in Patients with Prostate Cancer: An Analysis of United States Clinical Data," which was published in the April 2020 issue of Journal of Urology. Leuprolide acetate is the most commonly used drug for androgen deprivation therapy (ADT) in men with advanced prostate cancer. The article reported the impact on testosterone suppression of late dosing of GnRH agonists in general.

Androgen deprivation therapy (ADT) is the standard of care for the treatment of advanced prostate cancer. It aims to reduce circulating testosterone (T) to castration levels in order to remove the 'fuel' that simulates cancer cells to grow. The goal is to reduce testosterone (T) to <50ng/dl, however there is a strong body of evidence recommending <20ng/dl as the benchmark.

"This new study reflects Tolmar's ongoing commitment to furthering research on the treatment of advanced prostate cancer through peer-reviewed publications," said David Crawford, M.D., Clinical Professor of Urology, University of California San Diego

This study was supported by Tolmar Pharmaceuticals, Inc. For more information, please click here

About Tolmar and ELIGARD

Tolmar is a fully integrated pharmaceutical company focused on the technology-driven development, approval, manufacturing, and commercialization of specialty pharmaceuticals. The Company's lead product, ELIGARD, is a luteinizing hormone releasing hormone (LHRH) agonist indicated for the treatment of advanced prostate cancer.

"Tolmar" refers to Tolmar Holding, Inc. and its wholly owned operating subsidiaries, Tolmar Inc., Tolmar Therapeutics, Inc., and Tolmar Pharmaceuticals, Inc. ELIGARD was developed and is manufactured by Tolmar Inc. Tolmar global headquarters, product development and manufacturing facilities are based in northern Colorado, while TOLMAR Pharmaceuticals' U.S. commercial business is based in Buffalo Grove, Illinois. For more information about the company, please visit Information about ELIGARD is available at


ELIGARD (leuprolide acetate for injectable suspension) is a medicine for the treatment of advanced prostate cancer. It works by reducing the amount of testosterone in the blood. It is not a cure.

ELIGARD should not be used by anyone who is allergic to any of the ingredients in ELIGARD or to any medicines that reduce testosterone the same way. ELIGARD should not be used by women who are pregnant or may become pregnant. ELIGARD can cause pregnancy loss or harm to an unborn baby if used in pregnant women.

Severe and possibly life-threatening reactions called anaphylaxis have occurred in people receiving ELIGARD.

Increased risk of heart attack, sudden death due to heart problems and stroke have also been reported in men taking ELIGARD. ELIGARD may also affect electrical activity in the heart that can cause an irregular heartbeat. Your doctor will monitor you for heart conditions.

Elevated blood sugar and an increased risk of developing diabetes have been reported in men receiving ELIGARD. Your doctor will monitor blood sugar levels.

ELIGARD causes an increase in testosterone during the first few weeks of therapy and some men may experience new or worsening symptoms of prostate cancer e.g., bone pain, urinary symptoms, or nerve problems such as numbness, during this period. If your cancer has spread to the urinary tract or spine, urinary blockage or pressure on the spine that can lead to paralysis may occur. Your doctor will discuss with you the benefits and risks of taking ELIGARD.

The most common injection site reactions are transient burning and stinging, pain, bruising, and redness. The most common side effects include hot flashes/sweats, fatigue, weakness, muscle pain, dizziness, clamminess, testicular shrinkage, decreased erections and enlargement of breasts. Other side effects, including thinning of bones that may lead to fracture, and rare but serious problems with the pituitary gland in the brain, have been reported with ELIGARD.

Please see Full Prescribing Information for additional important safety information.

Media Contact Information:

Julie Ferguson[emailprotected](312) 385-0098

SOURCE Tolmar Pharmaceuticals, Inc.

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Tolmar Publishes Study in the February Issue of Journal of Urology on the Impact of Late Dosing on Testosterone Suppression with Two Different...

Why the Transgender Conversation Is Changing –

Last Friday, a bill that would ban transgender athletes from competing in middle, high school, and college sports passed in the West Virginia legislature. At least 20 different state legislatures have introduced transgender athlete bans in 2021. While South Dakotas governor Kristi Noem vetoed a proposed ban, Tennessee, Arkansas, and Mississippi have signed these changes into law.

Arkansas governor, Asa Hutchinson, did, however, veto legislation that would have banned gender confirming treatments or sex reassignment surgery for transgender youth under 18. That bill would have been the first in the country to ban this practice. Meanwhile, last Monday, GOP legislators in North Carolina introduced a bill that that would prevent doctors from performing sex reassignment surgery for transgender people under the age of 21.

This flurry of state billsa month ago LGBT advocacy group Human Rights Campaign had counted more than 80has once again provoked impassioned fighting, much of it centered around children. Its led to questions of fairness in youth sports, if adolescent judgement and diagnosis should be trusted, and what role and what say parents should have in how their children express their gender.

Mark Yarhouse is a pyschology professor at Wheaton College and the director of the Sexual and Gender Identity Institute. His books include Understanding Gender Dysphoria and most recently, Emerging Gender Identities. He joined global media manager Morgan Lee and editorial director Ted Olsen on this weeks episode of Quick to Listen.

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The transcript is edited by Yvonne Su and Bunmi Ishola

What is the same and what has changed in the conversation around gender over the past five or six years?

Mark Yarhouse: The conversation around gender has become more pronounced and centered into cultural discussions.

You see an increase in the number of people who identify as transgender or what I refer to as emerging gender identities. There's a splintering of gender categories into different experiences, different language for describing people's experiences.

Things have become more polarized as well. You saw that with the reaction to legislation like the bathroom bill, and you see that now with the law passed in Alabama. 20 or more states have gender identitychange laws in place for minors to keep that from happening. Theres an increase on both sides of a divisive topic.

What led to this development?

Mark Yarhouse: When I wrote my first book on understanding gender dysphoria, I was trying to introduce evangelical Christians to the concept of transgender experiences. Gender dysphoria is this experience that's distressing when a person's gender identity doesn't align with their biological sex.

When I talk about emerging gender identities, it's beyond that basic framework of transgender. Young people say that theyre gender-expansive, theyre gender-creative, theyre bi-gender, theyre pan-gender and the different identifiers go from there.

It helps us as Christians to be thoughtful in how we engage in a culture that's shifted so dramatically and where language has been shifting. You're interacting now with younger people for whom these are taken-for-granted realities and the generation that went before them had a limited scope of categories and language. Theres a real high likelihood of our misunderstanding and talking past one another.

Do the lessons about transgender issues from before map onto the emerging gender identities?

Mark Yarhouse: Some of the lessons learned will map onto that. It's challenging to know exactly how to, as Christians, enter into this conversation because we have had norms around sexuality and gender that we want to be able to articulate.

But sometimes when we articulate those norms, we can do it in ways that seem to cast doubt on the experience of other people around us, who don't use those same norms as anchor points that we do. It ends up becoming more of a risk of speaking past each other or being entrenched in not understanding.

You can both teach norms around sexuality and gender and recognize that there are exceptions to those that are likely the result of a fallen world and the challenges that people face in that space. There are also clinical differences and issues from a classic transgender presentation and some of the emerging gender identities.

To seek common ground, is it helpful to talk about how we also have dysphoria or dont conform to cultural or biblical notions of what it means to be male or female?

Mark Yarhouse: There are an upside and a downside to that approach. Christians would hold that we have so much in common as we bear the image of God and we should start there. People are beloved by God. God wants a relationship with people. Theres so much in that sense as a starting point for shared human experience.

But if you overplay that, you look past how some people's experience is so far on the margins that you might not fully appreciate the challenges that they're facing, particularly when it is dysphoria, a painful experience that you've never experienced.

There are also people saying that this is willful disobedience on your part. We're not speaking the same terms here about people's experiences.

How do you define gender dysphoria? Is the term interchangeable with the idea of transgenderism?

Mark Yarhouse: Gender dysphoria is the discomfort or distress that's associated with the lack of concordance between someone's biological sex, usually thought of in terms of chromosomes, genitalia and gonads, and the person's gender identity, their experience as a man or a woman or a different gender identity than that.

When that's distressing to them, it's dysphoria versus euphoria, a positive emotional state. It's a negative emotional state. I don't think of that as synonymous with transgender but many people who would identify as transgender would report gender dysphoria. It can vary in severity from mild to severe, and it can ebb and flow in severity in a person's life.

Historically, gender dysphoria was thought of as having an early onset. A boy or a girl is aware of their gender between ages two and four, developmentally. They're aware that they're a boy or a girl, or they're going to express a different experience than that.

What we've seen in the last six years has been a remarkable increase in the number of cases that we would call late-onset. That means at or after puberty, the person is reporting dysphoria that they didn't appear to have much evidence of, if at all, in childhood.

That's what's concerning to some mental health professionals and others. Theres not been a satisfying explanation that accounts for that increase.

Is it true that, before the last five or six years, people that were saying Im trans most likely started feeling those feelings well before puberty?

Mark Yarhouse: Most of the cases had been what we would call early onset. Parents would wonder if their child was going through a phase. They would probably go to a specialty clinic when that child turned six or seven, maybe when they were going to preschool or kindergarten, when the comparison would be their peer group, rather than at home with their family.

Historically, that would be the more typical presentation. It was more often biological males rather than females, at about a four- or five-to-one ratio that would be referred to these specialty clinics. That was probably the result of having a narrower box for what a boy can be like.

If they're outside of that expectation, then it raises more flags for parents. Whereas girls can have a little more latitude in how they present; and if they're gender atypical in some ways, you have positive language for that. They could be tomboyish and no one's going to be particularly concerned.

That probably accounted for that ratio, but now you're seeing quite a flip. Now we're seeing not just the late-onset cases at a higher rate, but also seeing it among biological females at a higher rate than you do males. We don't understand what's going on with that switch.

How do you distinguish between someone who expresses themselves outside the cultural understanding of masculinity or femininity, versus someone who feels uncomfortable being a particular gender?

Mark Yarhouse: When you meet with somebody to make a diagnosis of gender dysphoria, you rule out that they're within the range of what a boy or girl, or a man or a woman, would be like. They maybe have different characteristics, different presentations, different ways different interests, and so forth that are gender atypical. They don't fit into maybe stereotypes, but they're not gender dysphoric.

So how do you make that distinction? Several things go into that. You can have a conversation with an adult and theyre telling you. It's harder when you're trying to make that determination with a child who might not be able to pull all that together. But there are certain criteria that you follow around what they're able to say about their gender identity.

It's usually their response to primary and secondary sex characteristics. It's the desire for the sex characteristics of the other gender. These things aren't for a few weeks or a few months; it's over time and it's significant. It's significant in their body image and how they experience and see themselves. It's distressing to them.

What advice would you give to adults who have recently learned that a young person in their life is trans?

Mark Yarhouse: Christians typically have this skill set. We are used to applying it to other groups of people whose individual characteristics are different than our own. For example, we don't seem to have difficulty relating to our agnostic neighbors, even though their characteristics around their religious identity are different than ours.

We have a sense of how to relate to that person who's different in terms of racial or cultural background. When people's characteristics vary from ours, we can relate to them, talk with them, recognize God's love for them, value them as a person, to encourage them to bring all of their experiences into the relationship that we're forming with them as an acquaintance and maybe a friend.

You use the same skill set here. It's doesn't have to be more difficult than that.

I don't normally speak into the lives of adolescents around me unless I have a relationship with them and I'm invited into that space. It would run a significant risk of me overstepping the nature of the relationship I have with them, and then likely speaking past them. Then what they may know about me is that I'm a Christian whos now a witness to them. I have this top-down approach where I'm telling them that they're at-risk or they're doing something wrong.

I would probably take the position more with an adolescent than I do as a neighbor, as a family friend, or something like that. To listen more about what their experience has been like, remember that they're navigating at their age.

Their generation has a lot more categories for language around categories and linguistic constructs around gender and sexuality than my generation did. They're probably deeply shaped by what's been made available to them and they're interacting with those categories and they're making sense to them, or they might not make sense to me.

I might have a reaction to that, but it would be better to understand how the language functions for an adolescent rather than begin with the place that they're wrong or that they need to be corrected. That kind of mutational strategy does not work with adolescents period. It doesnt work in this conversation because our connection to their language has been so different and they've been exposed to so many different categories.

How do you counsel people on the basic questions of name and identity?

Mark Yarhouse: If a person is able to live in a way that reflects their birth sex, its going to be less complicated.

There are so many layers of complexity. Some people are in this place where they're considering a social transition or a partial transition, and they're trying on different names and pronouns.

If the person's trying to do that because they've been suffering from gender dysphoria and it's been distressing to them, and they've used other strategies to manage that (like the clothing they wear, the way they keep their hair, and these things have taken the edge off that dysphoria and been helpful to them), but it's sufficiently distressing that they think that using pronouns that they would prefer might be helpful to them, then I'd like to understand what's behind the request and how it's functioning for them.

That's not an uncommon strategy that people use. They try to use these strategies usually in a trial-and-error way and in a stepwise fashion. They can always reverse and go back to their original pronouns.

They can always do that; they're trying to figure this out. I don't want to be overly reactive to that. I want to meet them where they are. I want to have a sustained relationship with them. I err on the side of hospitality towards somebody to be in a relationship with them rather than do things on the front end that would sever the tie that they might otherwise want to have with me.

What advice do you have for parents as they try to understand where their child is coming from?

Mark Yarhouse: When you have early onset, parents are not that surprised when a child says to them, I'm transgender, or I experience my gender identity differently than most people do, or however they frame it. Parents knew something was going on. They just didn't have language for it. But when you have late-onset cases, it is blindsiding. Parents feel like their world has been rocked and there's no reference point for what their teenager is saying. There's little or no history to understand it.

There has been some concern that there might be teens who have other issues going on in their life and they're finding a sense of identity and community in something that has such social salience today. It's moved to the center of some of the cultural discourse around sexuality and gender, where some time ago, being gay had occupied that space.

The transgender conversation has moved into that space culturally and maybe a generation ago, a young person might've landed in a different area and explored different aspects of themselves. But today this has the kind of salience that might be appealing to some people where they might not have gender dysphoria.

There may be other things going on and they're finding something in this space. I want to be careful when I say that because I don't think that's most of what I'm seeing in my clinic. Some people have been trying to research that as a possible phenomenon.

Is that something that is trending among adolescents and we should be cautious about? I want parents to be wise and discerning to check things out with a provider, someone who has expertise in this area and to realize there could be multiple things going on here and it would take discernment and time to figure out what's going on.

Are there important ways that we should differentiate between dysphoria and transgender issues, versus same-sex attraction issues?

Mark Yarhouse: They are different experiences. When someone describes themselves as gay, they're talking about their attraction towards the same sex and their orientation towards the same sex. When someone says that they're transgender, they're talking about their experience of their gender identity as a man or a woman or a different gender identity than that.

Gender identity doesn't have to do with who you're physically, emotionally, or sexually attracted to. A lot of times when people are wrestling with dysphoria, they're often being asked about their sexual orientation. That's a confusing topic for some people.

They're not sure what they could even say about that. They're trying to figure out what's going on around gender. Sometimes Christians are more preoccupied with sexual behavior. I don't think that's where a lot of people are when they're figuring out gender. That's a different thing for them. Distinguishing that is helpful. S

Some Christians see that Scripture speaks more to the question around sexual behavior than it does to gender identity. That complicates this conversation more. It's not that Scripture doesn't say anything about gender, but it doesn't certain passages that stand out around sexual behavior. It's not quite as clear if you're looking for direct scriptural passages.

What effect do you expect banning surgery for young people to have?

Mark Yarhouse: There are several things that minors might consider, like whether to block going through puberty. That's right at the beginning of the development of puberty. Then young people might consider using cross-sex hormones at some point, maybe a year or two later. If they did the puberty-blocking intervention, then that becomes a consideration. Some of the legislation may be looking at that. There are surgical procedures as well.

On both sides of this debate, people have young people's best interests at heart. They're both trying to address vulnerable young people that they're concerned about, but they're landing diametrically in places to express their concern. Those who are saying we shouldn't allow these types of procedures are saying young people dont have the capacity to make these kinds of decisions, to understand the consequences of these decisions, and what that could mean for them five or 10 years out.

Other people believe that young people are at great risk and that these are the kinds of things that medical and psychiatric providers think should be on the table and considered for a young person. They can make that decision.

What are some of the consequences that people proposing these bans are concerned about? To what extent are they valid or exaggerated?

Mark Yarhouse: With the use of cross-sex hormones, this would be a lifelong regimen that a young person would have to take to have the clinical effects of using the other hormones of the other sex. If you stop taking the hormone, you stop having that clinical benefit.

We don't have the kind of long-term research on the effects of an adolescent using cross-sex hormones over 30 years. The greatest risk would be the risk for sterility.

Another topic that people are concerned about is that a young person at 16 or 17 doesnt understand what that would mean in 10 years. Do they understand the risks that they're taking there?

I'm not a fan of legislating around these complex clinical issues on either side. Once you move towards legislation on either side of these complex issues, ultimately, it ends up not being nimble enough to respond to the needs of the next person in front of you. I'd love for those needs to be met more by the mental health profession and the people who are working with them.

Those that regulate the mental health professions, that's where typically complaints would be adjudicated. It would be through the people who were licensing the providers to provide services rather than through legislation that creates a statement that's applied to everybody across the board. That doesn't end up being as flexible on members as we would.

Have you seen any examples of school districts figuring out how to have trans girls and women play in youth or collegiate sports without resorting to laws?

Mark Yarhouse: We need more time to research how to measure advantage and what that looks like. When you develop a policy like the NCAA has tried to, looking at the length of time to be on hormones, there's good intention to try to figure that out. What gives someone a competitive advantage? How do you safeguard that without excluding people from being able to compete when this is what they have trained to do?

They're good at this, and you want to allow them to do this. There have been controversies at every level of competition; this is not going to be resolved quickly. There hasn't been enough work done on clarifying what those standards would need to be across the board. Maybe they need to be applied more on a case-by-case basis than having one length of time that's applied to everybody. I wonder if it's more complicated than it's been made out to be.

How should we understand stories of people who have transitioned, then transitioned back? What kind of attention should they get?

Mark Yarhouse: Sometimes it's referred to as de-transitioning. I haven't seen a very well-designed study that would show us how common that is. In the Netherlands, they recently published a report on 30 years of people using different interventions, including surgical procedures.

The rate of regret continues to be low. I don't think that you're seeing a dramatic rise in regret that would typically correspond with de-transitioning. You could have regrets about surgery and elect not to be transitioned. We need to study that more to see how common that is, but based on the rates of regret that were published more recently, I don't see a rise in that.

I am concerned that we could see a rise in that for the reasons that I've talked about: atypical presentations, late onset, the gender ratio flip towards more cases of female adolescents with later onset. Where will they be in five or 10 years? We don't know yet.

Most actually don't make medical transitions at this point, but if they were to, would we see a rise in regret? I'd be curious.

How do you recommend we pray for people who are experiencing gender dysphoria?

Mark Yarhouse: We pray for God to continue, if He's already been speaking to them, to continue to speak to them; to speak to me, to guide me, to help me know best how to see the person, to love this person, that they would know that they are loved by God. For me and them to have wisdom and discernment moving forward. For wisdom and discernment on how I relate to them as someone that God cares deeply about.

Those are the types of prayers that I pray. I also provide ministry outside of my role as a psychologist. That's been helpful to me in walking with people. I mentioned that most people don't make a medical transition at this point. I think in the last transgender survey, about 44% of something like 26,000 transgender persons had indicated that they were using hormone treatment and only about 25% had used any type of gender confirmation surgery.

That's been a helpful conversation to have in the back of my mind.

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Why the Transgender Conversation Is Changing -

Diabetes and a Metallic Taste in the Mouth: Causes and Treatments – Healthline

Diabetes is a chronic condition where the body doesnt make enough insulin or use insulin properly. Insulin is a hormone that allows sugar to enter the bodys cells, where its then used for energy.

When the body doesnt make enough or use insulin properly, sugar accumulates in the bloodstream. This leads to high blood sugar.

Uncontrolled diabetes or high blood sugar can cause a range of problems such as nerve damage and kidney damage. But these arent the only side effects of diabetes. Some people with diabetes may also develop a metallic taste in their mouth.

The reasons for taste disturbance vary, but might include medication or poor oral hygiene. Sometimes, a metallic taste in the mouth is also an early sign of diabetes.

Here are a few causes of a metallic taste in the mouth related to diabetes.

Metformin is an oral medication commonly prescribed to treat type 2 diabetes. It reduces the amount of glucose (sugar) produced by the liver. This helps lower blood sugar levels to a safe range.

But although Metformin can stabilize blood sugar thus reducing the risk of serious diabetes complications some people who take this medication complain of a metallic taste in their mouth.

The reason isnt quite clear, but this taste disturbance is likely due to the prescription drug excreting into saliva.

The good news is that this taste problem is often temporary, with taste returning to normal after 1 or 2 weeks.

Parageusia is a taste disorder that can occur alongside diabetes. Its also known to cause a metallic taste in the mouth. But, whats the connection between parageusia and diabetes?

Simply put, your central nervous system (CNS) affects how your brain perceives taste, and its possible that uncontrolled diabetes can affect your nervous system.

Prolonged high blood sugar slowly damages the nerves in your body. This can include the nerves in the:

Parageusia occurs when injury or damage to the CNS distorts taste and smells. Taste disturbances such as a metallic taste in the mouth develop when the nerves that affect taste become damaged.

Oral health issues are another common cause of a metallic taste in the mouth.

Many people think of diabetes only affects blood sugar. But too much sugar in your blood can cause problems with your mouth, too.

High blood sugar also increases the sugar level in your saliva. And if your saliva contains more sugar, youre at a higher risk for cavities, gingivitis, and periodontitis. The latter two can cause a metallic taste in the mouth.

Diabetic tongue is another oral health problem that can cause a metallic taste in the mouth. This occurs when a combination of too much sugar in your saliva and a dry mouth triggers oral thrush.

Thrush develops when a fungus that occurs naturally starts to grow out of control. It can affect the gums, tongue, and the roof of the mouth.

A metallic taste in your mouth due to diabetes might improve over time. It all depends on the underlying issue.

If you take the drug Metformin, a metallic taste should subside after a few weeks once your body adjusts to the medication. If taste disturbance doesnt improve, see a medical professional.

Adjusting your dosage or finding an alternative drug might improve your taste.

If a metallic taste is due to sugar in the saliva, controlling your diabetes can also help improve your taste. Additionally, if you develop an infection due to poor dental hygiene, seeing a dentist and treating the infection might improve taste.

If taste disturbance occurs due to nerve damage, the severity of nerve damage may determine whether your taste returns to normal.

Even if you adjust your medication, improve your oral hygiene, and take steps to control your blood sugar, a metallic taste in your mouth might not improve immediately.

As you wait for your condition to improve, here are a few tips to help your food taste better:

See a doctor if a metallic taste in your mouth does not improve after a couple of weeks. Its important that you dont ignore this taste disturbance, as it can indicate problems with blood sugar control.

If you havent been diagnosed with diabetes, yet you notice a metallic taste in your mouth, see a medical professional. This taste disturbance is sometimes an early sign of diabetes.

A metallic taste in your mouth can distort the taste of foods and beverages, making it difficult to enjoy your favorite foods. Although taste disturbances have different underlying causes, its important to see a doctor for symptoms that dont improve.

This can be an early sign of diabetes, as well as blood sugar that is not in target range.

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Diabetes and a Metallic Taste in the Mouth: Causes and Treatments - Healthline

Multimodal Care Is Key Focus at Breast Cancer Conference – Targeted Oncology

As long-awaited results from pivotal trials are revealed during major medical conferences, community oncologists in the clinic look forward to the resulting approvals with much anticipation. That focus continues to be the hallmark of the upcoming 20th Annual International Congress on the Future of Breast Cancer West, hosted by Physicians Education Resource, LLC (PER).1

Cochair Sara A. Hurvitz, MD, said the intensive, 2-day conference provides a multimodal perspective on care that includes medical oncology, radiation oncology, and surgical oncology.

Its a fantastic way for physicians to [learn about] the latest research results that can be translated for use in the clinic, she said in an interview with Targeted Therapies in Oncology. Hurvitz is an associate professor in the Department of Medicine at the David Geffen School of Medicine, codirector of the Santa Monica-UCLA Outpatient Hematology/Oncology Practice, and medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit at UCLA in Los Angeles, California.

Hurvitz is moderating the morning session on July 30, which will cover breast cancer management with curative intent. One of the presentations during her session is being made by Joyce OShaughnessy, MD, cochair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center and The US Oncology Network in Dallas, Texas, and cochair of the conference. Hurvitz expects OShaughnessys presentation, Neo/Adjuvant CDK4/6 Inhibitors: Ready for Prime Time? to address updated results from the monarchE trial (NCT03155997) and the MONALEESA-7 trial (NCT02278120), both of which evaluated various CDK4/6 inhibitors combined with estrogen therapy.

In monarchE, investigators demonstrated that adding abemaciclib (Verzenio) to standard adjuvant endocrine therapy continued to improve invasive diseasefree survival among patients with high-risk, node-positive, early-stage, hormone receptorpositive, HER2-negative breast cancer.2

In the phase 3 MONALEESA-7 trial, patients with hormone receptorpositive, HER2-negative breast cancer had a significant improvement in overall survival (OS) and chemotherapy delay when treated with ribociclib (Kisqali) plus endocrine therapy compared with placebo.3

At a median follow-up of 53.5 months (range, 46.9- 66.4), the median OS with ribociclib plus endocrine treatment was 58.7 months vs 48.0 months with placebo/endocrine therapy (HR, 0.763; 95% CI, 0.608-0.956), translating to a 24% relative reduction in the risk of death with the CDK4/6 inhibitor.

Moreover, data from a subgroup analysis examining survival in relation to endocrine partner, results showed that patients who received a nonsteroidal aromatase inhibitor (NSAI) experienced a median OS of 58.7 months with ribociclib/endocrine therapy versus 47.7 months with placebo/endocrine therapy (HR, 0.798; 95% CI, 0.615-1.04).

Turning to immunotherapy in breast cancer, Hurvitz acknowledged that it is an exciting strategy for certain tumor types but that in breast cancer, results have been somewhat limited.

Immunotherapy in breast cancer has been shown to be somewhat beneficial, but those benefits are limited to tumors that are PD-L1 positive in the frontline setting, rather than in later lines, Hurvitz said.

For example, updated efficacy results from the IMpassion130 trial (NCT02425891) evaluated 902 patients; 451 were randomly assigned to receive atezolizumab (Tecentriq) plus nab-paclitaxel, and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population).4

Median overall survival in the intention-to-treat patients was 21.0 months (95% CI, 19.0-22.6) with atezolizumab and 18.7 months (95% CI, 16.9- 20.3) with placebo (stratified HR, 0.86; 95% CI, 0.72-1.02; P = .078). In the exploratory OS analysis in patients with PD-L1 immune cell positive tumors, median OS was 25.0 months (95% CI, 19.6-30.7) with atezolizumab versus 18.0 months (95% CI, 13.6-20.1) with placebo (stratified HR, 0.71, 95% CI, 0.54-0.94).

Somewhat limited benefits have also been reported for other immune checkpoint inhibitors. Improved progression-free survival (PFS) was observed with pembrolizumab (Keytruda) and chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer in the KEYNOTE-355 trial (NCT02819518).5

At the second interim analysis for KEYNOTE-355, median follow-up was 25.9 months for patients in the pembrolizumab-chemotherapy group and 26.3 months in the placebo-chemotherapy group. Among patients with a combined positive score (CPS) of 10 or more, median PFS was 9.7 months with pembrolizumab-chemotherapy and 5.6 months with placebo-chemotherapy (HR, 0.65; 95% CI, 0.49-0.86; P = .0012). Median PFS was 7.6 and 5.6 months (HR, 0.74; 95% CI, 0.61-0.90; P = .0014), respectively, among patients with a CPS of 1 or more and 7.5 and 5.6 months (HR, 0.82; 95% CI, 0.69- 0.97) among the intention-to-treat population.

The benefits of pembrolizumab were restricted to those patients with a CPS of 10 or greater, which is not the majority of patients with triple-negative breast cancer, Hurvitz said.

Turning to CDK4/6 inhibitors, Hurvitz noted that despite the benefits observed in PFS and OS for this particular class of drugs, resistance continues to be a challenge, prompting investigators to evaluate next-generation CDK4/6 inhibitors.

The success of CDK4/6 inhibitors in drug development has been outstanding, she said. My hope for the future is that were going to have better agents for triple-negative breast cancer and [that] well see an improvement in survival with this disease subtype in the future, Hurvitz said.


1. 20th Annual International Congress on the Future of Breast Cancer West. Physicians Education Resource, LLC (PER). Accessed March 16, 2021.

2. OShaughnessy J, Johnston S, Harbeck, N, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract GS1-01.

3. Tripathy D, Im S-A, Colleoni M, et al. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with endocrine therapy (ET) +/- ribociclib. Presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD2-04. https://bit. ly/3cGIzQq

4. Schmid P, Rugo HS, Adams S, et al; IMpassion130 Investigators Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;21(1):44-59. doi:10.1016/S1470- 2045(19)30689-8

5. Cortes J, Cescon DW, Rugo HS, et al; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828. doi:10.1016/S0140-6736(20)32531-9

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Freezing Sperm: Cost, Effectiveness, and More – Healthline

Sperm donors arent the only ones who bank their sperm. People with no plans to donate do it too, especially if theyre not ready to have a baby just yet but know they want to one day.

The process of sperm banking, otherwise known as sperm freezing or cryopreservation, is a great way for couples (or single folks) to preserve their chances of conceiving a biological baby in the future especially if the partner with testes is in a high-risk profession or about to undergo certain medical procedures or treatments.

If you think this might be something youre interested in, were here to break down everything you need to know about the procedure.

If youve been diagnosed with testicular or prostate cancer, you may have been told that treatment can involve surgeries that remove one or both testicles.

And actually, anyone with testicles who has cancer including adolescents might want to freeze their sperm if theyre about to undergo treatment. Cancer treatments, including chemotherapy or radiation, can cause a decline in sperm quality or cause infertility.

Unfortunately, in an older 2002 study of oncology staff physicians and fellows, 48 percent of respondents reported that they never brought up the option of sperm banking or mentioned it to less than a quarter of eligible people.

Even though sperm freezing is more widely recognized as an option today, its still important to advocate for yourself if youre interested in it.

If youre approaching older adulthood, you might choose to freeze your sperm to preserve your chances of having children. Semen quality decreases with age because sperm concentration, morphology (size and shape), and mobility all decline, per a 2011 review.

Not only do the risks for autism, schizophrenia, and other conditions increase with age, theres also evidence that seminal volume declines. In fact, some people simply become infertile.

If you work at hazardous worksites or are deployed in the military, you may opt to bank your sperm, just in case of accidents or chemical exposures that could damage sperm or fertility.

Some people freeze their sperm if theyre going to be traveling to areas of the world with Zika, a virus that can be passed to someone else via semen.

If youre undergoing certain surgeries such as gender confirmation you might decide to do this to preserve your chances of having a biological child.

In addition, you may decide to bank your sperm if youre getting a vasectomy in case you change your mind about having children in the future.

Some medical procedures can also impact the ability to ejaculate, so sperm banking is often offered before those procedures are scheduled.

Other people who might consider freezing their sperm include:

The best place to freeze sperm is at a sperm bank or fertility clinic, says Dr. Juan Alvarez, board certified reproductive endocrinologist with Fertility Centers of Illinois.

This is because, he explains, sperm should be processed within 1 to 2 hours of collecting a sample.

You can also use an at-home banking kit, such as Legacy or Dadi. These kits allow you to collect your sperm at home and ship it in special containers to a lab for testing and freezing.

However, Alvarez says, he only advises using those if there are no sperm banks or fertility clinics nearby. This is because he thinks its important to talk with a fertility doctor if youre deciding to freeze sperm.

Based on the reason for pursuing a sperm freeze, a physician can help you determine how much and when to complete a freeze, he explains.

Before banking your sperm, youll give blood so you can be screened for sexually transmitted infections (STIs). Youll also fill out a lot of paperwork, including a questionnaire, contract, and legal forms.

Before depositing a sample, youll be asked to abstain from sex for 2 to 3 days.

If you feel comfortable, youll give your sample in a private room at the fertility clinic or sperm bank.

This allows the sperm to be frozen when its freshest. (Within minutes of ejaculation, the number of living sperm cells and activity begins to drop off.)

Youll deposit your sample in a sterile cup after masturbation. Some places allow your partner to assist.

If you dont feel comfortable doing this at a clinic or bank, you can collect your sample at home. Just know that the sample will need to be brought to the clinic within an hour.

Samples are analyzed for sperm quantity, shape, and movement, which will help determine how many more samples are needed. In general, about three to six specimens are collected for each desired pregnancy, but itll depend on the quality of your sperm.

The samples are then separated into multiple vials and frozen by a lab technician who specializes in cryoprotectant agents to protect the sperm cells.

If sperm arent present in the sample or if you arent able to ejaculate, its possible to have a surgical retrieval. In this case, a healthcare professional will remove sperm directly from the testicle.

Sometimes, sperm freezing is covered by insurance if youre doing it for a medical reason.

Otherwise, the cost is usually less than $1,000 and that includes all required testing and freezing for the first year, says Alvarez. Afterward, he says, annual cryopreservation costs for sperm are roughly $150 to $300.

Sperm freezing has been done successfully since 1953. Its a highly effective process for people looking to preserve their fertility.

Of course, some sperm dont survive the freezing process.

The thaw survival of sperm is over 50 percent, Alvarez says.

If the sample is of high quality, this reduction isnt an issue for successfully conceiving a healthy baby. This is because the average sperm count ranges from 15 million to more than 200 million sperm per milliliter of semen.

In terms of sperm quantity, we only need 10 million motile sperm for inseminations and one sperm for each egg in IVF [in vitro fertilization], Alvarez explains.

Plus, he says, sperm does not lose its effectiveness with a freeze/thaw and it has the same fertilization capacity as fresh sperm [and] there is no difference in fertilization between frozen and fresh sperm.

Theres also no evidence that using frozen sperm increases the risk of health issues in babies.

In theory, sperm could probably be frozen indefinitely as long as its stored correctly inside liquid nitrogen and it was a high-quality sample to begin with.

Frozen sperm doesnt have a definitive end date, Alvarez explains. Due to modern cryopreservation techniques being so advanced, the health and integrity of sperm is maintained in the process.

There has been success with sperm that has been frozen for over 20 years, he adds.

The short answer is yes.

When you sign up to freeze your sperm, youll sign legal paperwork that will determine what happens to your sperm if you dont pay your storage fees, for example. Youll also set up the rules for how you or your partner can use (or discard) the sample, including in the event of your death.

For example, you can sign an agreement that either terminates your agreement if you die or allows a legally authorized representative (like your spouse) to use or terminate it.

Some clinics may require you to get a witness or have a notary public watch you sign the form.

Sperm freezing if you have the financial means to do it can be a great option if youre looking to preserve your chances of having a biological child.

This is especially true if youre:

The process is highly effective and carries few risks. Talk with a fertility expert if you think it might be a good option for you or your family.

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Freezing Sperm: Cost, Effectiveness, and More - Healthline

Recognizing the importance of energy availability in the young athlete – Contemporary Pediatrics

Case A

A female high school rower, aged 17 years, presents to your clinic for upper back pain. She is preparing for her senior year and would like to row competitively in college. Her back pain has been present for 2 months. Initially pain was only with rowing, but it has been progressively worsening and now she has pain at rest. Reviewing her medical record, you notice that she has lost 33 pounds since her last visit about 9 months ago. Her body mass index (BMI) was 24.3 kg/m2 (75.6% percentile) 9 months ago and today it is 18.6 kg/m2 (11.7%). On review of systems, you learn that she has not had a menstrual period in the last 6 months. Menarche occurred when she was aged 12 years. She endorses feelings of depression, but no suicidal ideation. Academically, she is a straight-A student.

Case B

A male cross-country runner with right lower leg pain for 2.5 weeks, aged 15 years, presents to your clinic. He was previously running about 30 miles per week but recently increased his mileage to 60 miles per week. He has a history of shin splints but his current pain feels like it is in the bone of [his] lower leg. The pain is focal to his midtibia. Pain is present with weight-bearing and he has a limp with walking due to pain. He stopped running a week prior, but he likes to be physically active and has been cross-training with core and upper-body resistance training. He has a history of a right tibial stress fracture from the past year. On review of systems, you learn that the patients BMI has decreased from 19.3 kg/m2 (29% percentile) to 18.0 kg/m2 (3%) over the past 2 years. He is a vegetarian. X-ray today demonstrates a stress fracture (Figure 1).

What is the female athlete triad?

The female athlete triad was first described in 1997 as the interrelationship among amenorrhea, osteoporosis, and disordered eating. In 2007, the triad was revised to better identify athletes at risk, recognizing that presentation can be on a spectrum, ranging from optimal health to subclinical and clinical disease (Figure 2). The 3 components are now called menstrual function, bone mineral density (BMD), and EA,1 with low EA being the root cause of the triad. Acknowledging the existence of a spectrum of disease allows athletes to be identified earlier and to receive earlier intervention. If an athlete has any of the 3 components, a more thorough investigation should be performed to evaluate for the other components, which may have subclinical presentations.

Prevalence. Due to the spectrum of disease, it can be difficult to accurately estimate the prevalence of the female athlete triad. An athlete may have 1, 2, or all 3 components. It is estimated that all 3 components are present in 1.0% to 1.2% of high school athletes, 2 components in 4% to 18%, and 1 component in up to 54%.2

Which athletes are most at risk? Any athlete can develop aspects of the triad, but athletes in sports that emphasize endurance, appearance, or weight class are most at risk. Sport specialization at an early age can also increase risk (Table 1). The Female Athlete Triad Coalition Consensus Panel recommends screening during the pre-participation physical exam or if there are concerns that an athlete may have the triad (Table 2).

Components of the triad


EA is the amount of dietary energy (calories) remaining for physiologic function after exercise. Low EA is the root cause of the triad as it may affect bone health and lead to hormonal disturbances in the athlete.

Many athletes low EA is not intentional and they do not display pathologic eating or weight control behaviors. When this is the case, simply increasing caloric intake will treat the patient. However, restriction of caloric intake can be intentional in athletes who are trying to maintain a weight class or achieve a certain appearance. Disordered eating is estimated to occur in 6% to 45% of female athletes.3 Athletes who have specialized diets (vegan, vegetarian, pescatarian, etc) may also be at increased risk. In cases where the athlete has intentional disordered eating, psychological intervention and treatment may be required.

According to a study of 1000 female athletes by Ackerman et al, those with low EA were more likely to have negative performance effects, including decreases in coordination, concentration, endurance, and training response. In the clinic setting, it may be helpful to discuss with the athlete how decreased EA can negatively affect performance.4

A low BMI is a strong predictor of low bone mineral density and stress fractures. An adolescent should be screened carefully if they have a BMI that is less than 17.5 kg/m2. An athletes goal weight should be >90% of expected body weight.1 However, it is important to keep in mind that even athletes with a normal BMI may still have low EA.4

If you are able to work with a dietitian, you can calculate fat free mass (FFM) for your athlete patient. In order to have normal menstrual function, 30 kcal/kg of FFM/day are needed, but 45 kcal of FFM/day is ideal.1 Because this calculation can be difficult, it is helpful to have the athlete see a sports dietitian and exercise physiologist, if possible.

Even in the absence of amenorrhea, disordered eating can be associated with lower BMD in athletes.


Adolescence is the most crucial time for bone mass accumulation, so the presence of the athlete triad can be particularly harmful during this time. Maximum rate of bone formation usually occurs between the ages of 10 and 14 years, and 90% of peak bone mass is attained by 18 years.2 Diet, weight-bearing activities, and genetic makeup all contribute to an individuals bone mass accrual. Achieving sufficient bone mass is important to decrease the risk of fracture and to prevent osteoporosis in adulthood. Lower estrogen and lower EA increase bone resorption and suppress bone formation and remodeling.

Stress fractures are often the initial presenting symptom in patients with the triad. Stress fractures usually occur due to chronic, repetitive micro-trauma that cause tiny cracks in the bone. Athletes with menstrual irregularities are more likely to have bone stress injuries. As with the other aspects of the triad, a spectrum of stress injury exists, ranging from stress reaction (intermediate injury; bone marrow edema) to fracture (when enough trauma has occurred to cause a break in the cortex).

A dual-energy radiograph absorptiometry (DXA) can be used to assess bone density and should be considered in athletes with a history of stress fractures, and/or menstrual dysfunction, and/or low EA for at least 6 months. Notably, DXAs are usually ordered on postmenopausal women, and separate standards exist for performing DXAs on children or adolescents. Therefore, DXA should ideally be done at a facility whose staff is familiar with interpreting results based on the patients age and gender. In adults, BMD is interpreted using the T-score, which compares the patients BMD with the maximum expected BMD achieved aged between 25 and 30 years. Pediatric bone density, however, is assessed using the Z-score, which compares the patients BMD with those of others of similar age and race. Further details are available in the guidelines provided by DeSouza et al.1 It may be helpful to discuss these with the performing radiologist.

Athletes who participate in high-impact and resistance activities would be expected to have a BMD that is 10% to 15% higher than those of athletes participating in nonimpact sports. This should be taken into consideration when interpreting DXA scans. Z-scores of less than 1.0 may be abnormal in an athlete, alerting concern for low BMD, but that score may be normal in a nonathlete. An athlete who has a Z-score of less than 1 should undergo further evaluation.


It is not normal for female athletes to have menstrual dysfunction; they should not lose their period during their sport season (a phenomenon most classically seen in cross-country runners). Functional hypothalamic amenorrhea (ie, amenorrhea with the female athlete triad) is a diagnosis of exclusion, so if an athlete is experiencing amenorrhea or oligomenorrhea, it is crucial to rule out other causes (Table 2).5,6 Primary amenorrhea is absence of menarche by age 15 years. Secondary amenorrhea is defined as absence of menses for 3 months or longer, while oligomenorrhea is defined as cycles lasting longer than 35 days.2 Maintaining normal menstrual function is important for the athletes bone health.1 As such, exogenous hormones (ie, birth control pills) may be perceived as beneficial. However, many studies have shown that oral contraception is not an effective way to restore bone health. An athlete with menstrual dysfunction may use oral birth control pills to prevent pregnancy, but it is important to let her know that having a period on birth control does not mean her bone health is improving.

Menstrual dysfunction can also negatively affect cardiovascular health in athletes. The results of some studies in ballet dancers and endurance athletes have shown that athletes with oligomenorrhea and amenorrhea had increased risk for high cholesterol and other vascular findings that correlate with the development of atherosclerotic disease.5,6

It may take up to 1 year or longer to resume menses after EA restoration. Decreased bone density, the result of female athlete triad, may be irreversible, although it can improve with increasing EA. Early intervention is key, so it is crucial to screen for those at risk.

Relative energy deficiency in sport (RED-S)

The term RED-S was introduced in 2014 by the International Olympic Committee to encompass males and to acknowledge that energy deficiency can affect other aspects of an athletes health. These may include issues involving the endocrine, metabolic, hematologic, cardiovascular, gastrointestinal, and immunologic systems as well as growth and development. Research done by Ackerman et al demonstrated that athletes with low EA were more likely to have many of the ill effects of RED-S than those with appropriate EA.4

The male athlete triad

The male athlete triad is a term used in males to describe the interrelationship of low EA, impaired bone health, and reproductive suppression. Low EA has been associated with decreased testosterone in male athletes due to a suppressed hypothalamicpituitarygonadal axis. True prevalence of low testosterone from hypogonadotropic hypogonadism is unknown.7 Low testosterone can have numerous effects on the male athlete, including decreased physical performance, sleep disturbances, fatigue, decreased motivation, sexual dysfunction, loss of muscle mass, sperm abnormalities, lower BMD, and depression.

Male athletes with recurrent bone stress injuries or with initial injury in a trabecular region (pelvis, sacrum, femoral neck) should be evaluated for nutrition and hormone function, especially if the athlete has other risk factors such as low BMI. Tenforde et al recommend screening for low BMD with DXA, nutritional evaluation (including a 25-hydroxy vitamin D test), and endocrine work-up (including free and total testosterone) in athletes with high-risk stress fracture in areas such as the pelvis or femoral neck, although more evidence-based guidelines are needed.7


Restoring EA is the mainstay of treatment of both male and female athlete triad. This can be accomplished if the athlete increases caloric intake and decreases physical activity/energy expenditure. Working with a sports dietitian to increase EA to >45 kcal/kg FFM per day is ideal, but increasing calories by 300 to 600 per day and decreasing exercise by 1 day per week can be a productive starting point. This should be done on an individual basis depending on the athletes training regimen and expenditure. The goal is to increase BMI to >18.5 kg/m2 and to restore normal menstrual function. Working with a multidisciplinary team that includes a PCP, dietitian, psychologist, athletic trainer, and sports medicine specialist is helpful.

In the past, oral contraceptive pills were commonly used to restore menses; however, as mentioned above, this may offer a false sense of security and should be avoided unless they are necessary for other indications. Bisphosphonates are also generally not recommended in the pediatric/adolescent population. No evidence exists for their effectiveness and they may be teratogenic if an athlete were to become pregnant.2

Calcium and vitamin D are important for bone health. The recommended daily amount of calcium is 1300 mg; if this is not achieved with diet alone, it should be supplemented. The recommendation for vitamin D for patients aged between 1 and 18 years is 600 IU, although higher doses may be considered depending on climate and deficiency. A recent systematic review of military submariners determined that the combination of vitamin D and calcium has a synergistic effect, and that vitamin D levels were most effectively increased with supplementation levels of 2000 IU/day.8 Weight-bearing exercise is also important for enhancing the accrual of bone mass.2

Because the consequences of the athlete triad can be irreversible, affecting long-term bone, reproductive, and possibly cardiovascular health, a PCP must have a high index of suspicion for the triad in an athlete presenting with any of the above components. The annual well-child exam or sports physical is an opportunity for the PCP to screen patients for the athlete triad.

ACKNOWLEDGMENTS: We would like to thank Amanda Weiss Kelly, MD, for her mentorship and expertise on this topic.


1. De Souza MJ, Nattiv A, Joy E, et al. 2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad: 1st International Conference held in San Francisco, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013. Br J Sports Med. 2014;48(4):289. doi:10.1136/bjsports-2013-093218

2. Weiss Kelly AK, Hecht S; Council On Sports Medicine and Fitness. The female athlete triad. Pediatrics. 2016;138(2):e20160922. doi:10.1542/peds.2016-0922

3. Bratland-Sanda S, Sundgot-Borgen J. Eating disorders in athletes: overview of prevalence, risk factors and recommendations for prevention and treatment. Eur J Sport Sci. 2013;13(5):499-508. doi:10.1080/17461391.2012.740504

4. Ackerman KE, Holtzman B, Cooper KM, et al. Low energy availability surrogates correlate with health and performance consequences of Relative Energy Deficiency in Sport. Br J Sports Med. 2019;53(10):628-633. doi:101136/bjsports-2017-098958

5. Hoch AZ, Papanek P, Szabo A, Widlansky ME, Schimke JE, Gutterman DD. Association between the female athlete triad and endothelial dysfunction in dancers. Clin J Sport Med. 2011;21(2):119-125. doi:10.1097/JSM.0b013e3182042a9a

6. Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, Lindn Hirschberg A. Amenorrhea in female athletes is associated with endothelial dysfunction and unfavorable lipid profile. J Clin Endocrinol Metab. 2005;90(3):1354-1359. doi:10.1210/jc.2004-1286

7. Tenforde AS, Barrack MT, Nattiv A, Fredericson M. Parallels with the female athlete triad in male athletes. Sports Med. 2016;46(2):171-182. doi:10.1007/s40279-015-0411-y

8. Sivakumar G, Koziarz A, Farrokhyar F. Vitamin D supplementation in military personnel: a systematic review of randomized controlled trials. Sports Health. 2019;11(5):425-431. doi:10.1177/1941738119857717

Recognizing the importance of energy availability in the young athlete - Contemporary Pediatrics

EP. 3: Defining PSA Nadir After Definitive Therapy in Prostate Cancer – Urology Times

Raoul S. Concepcion, MD, FACS: Brian, how do you define PSA [prostate-specific antigen] nadirs, because I think this is an important point, in the surgical patient and in the radiotherapy patient?

Brian Helfand, MD, PhD: Ultimately after surgery, when we take out the entire prostate, were really expecting that PSA to go to a value of undetectable, 0 [ng/mL]. There are certain definitions, because we use ultrasensitive assays, etc. For the most part, we want to see that at what an equivalent value is of 0 [ng/mL]. At our institution, that is less than 0.02, or less than 0.001 [ng/mL], which I have seen depending on the assay. If after surgery that level rises to a value of 0.2 [ng/mL], I think everyone would agree this is a common definition that would be considered a recurrence. There has been some evolution, especially for men with higher-risk disease, that if youre using an ultrasensitive assay and you are seeing consecutive rises of that PSA before theyre actually getting to a value of 0.2 [ng/mL], most people would agree that thats a recurrence as well. There is some devil in the details there, but certainly, I think if youre going to walk away with this, the value of 0.2 [ng/mL] after a surgery would be considered a recurrence.

For radiation, it becomes a little trickier because we still have the prostate gland thats in situ, and there is some benign tissue there, so there is for many patients, a level of PSA that exists. Your PSA will get down to some lowest value, or that nadir value. There have been various definitions that have been used throughout the years. I typically use whats referred to as the Phoenix definition, which is a value of 2 ng/mL greater than their lowest value. Again, if you see consecutive rises at least a month apart, consistently rising more than would be expected, I also have some suspicion there that earlier intervention or recurrence may be warranted.

Raoul S. Concepcion, MD, FACS: Judd, we know that in the surgical patient, that nadir happens quickly, usually within 6 months, if its going to get to the level that Brian was discussing. What about with the radiation? When do you start to say, OK, Im at 6 months, Im at 12 months, or Im at 18 months? When do you feel comfortable? Ithink as Brian pointed out, its not going to go to less than .001 or less than .02 [ng/mL]. What does that time frame look like in the radiation patient?

Judd W. Moul, MD: Thats a great question. In the classic teaching, in the era before androgen deprivation therapy [ADT] was used with radiation, the radiation therapy itself would sometimes take up to 18 months to clear the prostate cancer. Therefore, weve been always taught that you need to sometimes wait up to 18 months if its a patient whos just receiving radiation, and you wouldnt necessarily want to do a biopsy. You also have a PSA bounce phenomenon that sometimes can occur. Now, all the high-risk patients and many of the intermediate-risk patients are also receiving ADT with the radiotherapy. With the ADT, their PSA should go down generally more quickly, especially if youre using an antagonist like Degarelix, or now the new oral option, relugolix. In general, the PSA typically nadirs, I see it nadir usually within 3 to 6 months in men who are getting hormone therapy with radiation.

The only additional point that I would make is that sometimes in guys who had low-risk or intermediate-risk disease and had a modern-era radical prostatectomy [RP] with aggressive nerve sparing, bladder neck sparing, and urethra sparing, we see low levels of PSA that are not cancer-related. Therefore, I agree with Brian that in the high-risk patients, you can jump on a PSA recurrence quickly, but I would caution the oncologists in our audience tonight that you must look at the RP pathology. Moreover, if it was not so bad pathology, and if the guy has a PSA of 0.13, or even 0.2 [ng/mL] a couple of years out, I tend to follow those patients because there is this phenomenon of benign glands at the margin. We know from the Mayo Clinics series and our work at Duke [Cancer Center], that honestly, sometimes up to 30% of patients can have this in long-term follow-up, a little bit of PSA in the system thats not cancer-related.

Transcript edited for clarity.

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EP. 3: Defining PSA Nadir After Definitive Therapy in Prostate Cancer - Urology Times

[Full text] A Review of Modifiable Risk Factors in Young Women for the Prevention | BCTT – Dove Medical Press


Globally, breast cancer (BC) is currently the most common cancer diagnosed in women below the age of 40, accounting for 244,000 cases per year.1 It is also the second highest cause of cancer-related mortality in women aged 039 worldwide with 44,800 deaths per year.1 Women under the age of 45 account for 11% of all BC diagnoses in the United States (US)2 and 9% in the United Kingdom (UK).3 Furthermore, there has been a 16% increase in the incidence of BC in women aged 2549 years since the 1990s.3

Geographically, the cumulative risk of developing BC varies between countries: the highest cumulative risk for women aged less than 40 years is seen in Italy and France (0.9%), and lowest in India (0.26%) with the UK and US having a moderate level of risk (0.77% and 0.61%, respectively).1

Most young women are not eligible for asymptomatic breast screening and therefore present to clinicians with either personal breast symptoms or family-related concerns. Although young women with breast cancer have a higher frequency of underlying pathogenic mutations in high penetrance breast cancer susceptibility genes (CSGs) than older women, the vast majority of young breast cancer patients are not found to have a germline CSG mutation.4 Therefore, modifiable risk factors for breast cancer should also receive attention in this age group.

Clinicianpatient interactions during a breast clinic consultation may provide unique opportunities to educate patients about modifiable cancer risk factors,: so-called teachable moments5 These opportunities occur regardless of whether or not the patient receives a cancer diagnosis6 and consultations pertaining to potential cancer diagnoses are regarded as underused moments for the provision of encouraging cancer risk-reducing behaviours.7 When employing these moments to encourage behaviours that can reduce BC risk, the advice given should be based on a comprehensive understanding of the current evidence on modifiable lifestyle risk factors and how younger patients can most effectively influence their risk of disease.

This review presents current understanding of factors in young women associated with the development of primary BC, the direction of risk and the magnitude of effect. Whilst previous publications in this area have focussed on life-style associated risk factors, this article also includes a discussion of the categorisation of risk factors and the inclusion of reproductive and iatrogenic factors as well as those factors that can be most influenced by an individuals behaviour. The interaction between modifiable and genetic factors is also considered.

An electronic literature review using PubMed (NLM) was performed. Search terms included young or early onset, and breast cancer and modifiable risk. All identified articles published in English language between 1960 and 2020 were assessed for suitability. Abstracts and reports from meetings not published in peer-reviewed journals were excluded. Additional references known to the authors or cited within reference lists of relevant papers were also investigated. Articles were excluded from this review if they contained solely post-menopausal data or if they contained data for risk factors that were non-modifiable such as age, sex and past history of breast cancer or proliferative breast disease, apart from genetic risk factors which were included. The last search was performed in October 2020.

The European consensus treatment guidelines for BC in young women define young as aged 40 years or below8 partially based on the observation that women in this age group have poorer BC outcomes than older age groups.9 However, most epidemiological studies of BC risk, including the World Cancer Research Fund (WCRF) continuous update project, stratify patients according to menopausal status (pre- or post-menopausal).10 Although in some datasets this categorisation is based on biological indicators of ovarian function, age ranges of 050 or 055 years are frequently used as surrogate indicators of premenopausal status. It is therefore evident that premenopausal groups will contain data for young women (40 years), but will additionally include variable numbers of older women dependant on the data source. The biological differences in BC between age groups exist on a continuum so that a specific age threshold, such as below 40 years, alludes to trends in BC biology as opposed to definitive unique differences.1113

Many factors have been implicated as factors that influence BC risk in a younger female population,14 with variable effect sizes as well as variable degrees of modifiability.

Some factors associated with BC development are clearly inherent risk factors whereby an individuals choices cannot influence the risk factor, such as the germline genome or pre-natal development. Other risk factors are potentially modifiable such as: physical activity, body weight/habitus, alcohol consumption, which are influenced by personal choice.15

Some factors discussed in this review are more nuanced. For example, increased parity appears to decrease risk of developing BC but problems such as infertility may confound ones degree of personal choice over this factor. Iatrogenic risk factors are similarly more limited in terms of self-adjustment. These factors are referred to here as less modifiable.

Women below the age of 40 with BC are more likely to die from the disease than older women.9,16,17 This can be explained in part by the biological characteristics of tumours in this cohort.

BCs in young women have a higher frequency of more aggressive phenotypes than older women. Young patients are more likely to present with more advanced disease stage with larger tumour size, lymph node involvement, and less differentiated tumours.1821 Tumour biology also reflects more aggressive disease in younger women with increased frequency of oestrogen receptor (ER) negative and triple negative tumours,11 and increased Ki-67 expression than in those over the age of 50 years.20,21

Women under 40 years at first breast cancer diagnosis have a higher frequency of a family history of BC and a higher chance of an underlying pathogenic mutation in a BC susceptibility gene than women diagnosed with breast cancer aged over 40 years.22 BRCA gene mutations (either BRCA1 or BRCA2) are found in approximately 12% of BC patients aged <40 years.4 TP53 germline mutations are found in 5% of diagnoses of BC aged 35 years23 and PALB2 mutations in approximately 1% in early-onset BC.24 Mutation penetrance seems to be higher in younger than older women for some breast cancer susceptibility genes (CSGs); the relative risk of developing BC was 89 in PALB2 mutation carriers below 40 years compared to 58 in women over 40 years.25

American studies have reported some notable racial variations in breast cancer age of onset, with black women experiencing significantly higher breast cancer incidence before the age of 40 years and lower incidence after age 50 compared with white women of the same ages.26 Differences in breast cancer incidence rates between most racial/ethnic groups have been largely explained by risk factor distribution except in African Americans27 where the higher incidence in the younger age group is not yet fully explained. Population-based studies in the UK have concluded that the younger age of Black Caribbean and Black African breast cancer patients in South East England reflects the younger age of these populations, rather than an increased risk of disease at younger ages28. Several non-age selected studies have reported increased incidence of adverse biological features in black women compared to white women. The POSH prospective study of 2915 breast cancer patients aged <41 years has confirmed this finding in young onset breast cancer with higher median tumour diameter and higher frequency of ER/PR/HER2-negative tumours in Blacks (26.1%) than Whites (18.6%, P=0.04).29

In the past, there had been a general acceptance that physical activity has no effect on premenopausal BC risk following large-scale prospective cohort studies such as Rockhill et al (104 468 participants) which reported no association.30 However, more recent data seem to contradict these findings. Since 2013, three independent meta-analyses3133 investigating the effect of physical activity on premenopausal BC have concurred that physical activity significantly reduces the risk of premenopausal BC development. Physical activity led to a 23% reduction in BC cases (RR 0.77; 95% CI 0.720.84) when comparing women in the highest versus the lowest categories of amounts and types of physical activity in a meta-analysis of 6 studies (2258 cases).31 Hardefeldt et als 2018 meta-analysis of 48 cohort studies found that physical activitys ignificantly reduced overall risk (OR 0.79, 95% CI 0.730.87)32 and finally Chen et al in 2019 reported an overall relative risk of 0.83 (95% CI 0.790.87) over 14,968 cases, of developing premenopausal BC associated with physical activity.33 Therefore, it seems there is a recent body of evidence suggesting that physical activity may be key in reducing premenopausal BC risk.

Although evidence in premenopausal women is limited, it indicates a significant downward trend between increasing intensity (in metabolic equivalent task hours per week) and/or longer duration (hours per week) of physical activity in relation to BC risk.34 For studies considering combined pre- and post-menopausal BC risk, for which there are significantly more data, the intensity of the exercise played a modest role in reducing risk. Engaging in higher-intensity activities (activity that causes you to sweat, ie, running and competitive sports) had a slightly greater risk reduction (OR 0.73; 95% CI 0.650.81; P<0.001) than in those who did low-intensity activities (such as walking and gardening) (OR, 0.79; 95% CI, 0.720.86; P<0.001).32 A meta-analysis of 11 studies reporting amount of exercise and 11 studies reporting metabolic equivalent task hours per week (MET-h/week) demonstrated a significant dose-response relationship (p<0.0001) between increasing intensity and/or duration of exercise per week and reductions in BC risk.35 This method for reducing risk is especially important for a younger population, who tend to have an increased capacity for exercise; considering engaging in higher intensity exercises may be an effective way of significantly reducing their BC risk.

Chen et als pooled analysis reported that overall relative risk reductions are associated with all types of physical activity (recreational, occupational and non-occupational) and the differences in risk between types of activity were modest. It remains unclear whether recreational physical activity specifically reduces risk in young women any more than occupational.36,37

It seems that physiological differences between pre- and post-menopause alter the effect of body mass index (BMI) on risk of developing BC.38 Younger adult women have a modest inverse correlation for BC risk with increasing BMI, according to many studies and meta-analyses (Table 1).3946 This is contrary to the positive correlation between BMI and BC risk in post-menopausal women.

Table 1 Summary and Details of Meta-Analyses Investigating the Relationship Between BMI and Relative Risk (RR) of Developing Premenopausal BC

This relationship is comprehensively summarised in Renehan et als meta-analysis of 20 prospective cohort studies, which reported that for every 5kg/m2 increase in BMI there was a significant decrease in relative risk of developing premenopausal BC (RR 0.92; 95% CI 0.880.97), highlighting a dose-response effect of BMI on premenopausal BC.39 The mechanism underpinning this effect is unclear and evidence limited, although it has been suggested that obesity causes ovarian suppression leading to decreasing levels of circulating oestradiol.47

BMI however is simply a marker of overall adiposity at a population level and does not inform us about the distribution of weight in the body in an individual. Waist-to-hip ratio (WHR) describes a pattern of adiposity (comparison of abdominal to gluteal fat), and increases in WHR are associated with increased risk of premenopausal BC. This was explored in a meta-analysis by Amadou et al42 that used 9 case-control and 3 cohort studies to demonstrate a significant dose-response premenopausal BC relative risk increase of 1.08 (95% CI 1.011.16) per 0.1 unit increase in WHR, despite acknowledging that BMI was still associated with a significant dose-response decreased relative risk of premenopausal BC per 5kg/m2 increase (RR 0.95;95% CI 0.940.97).42 This suggests that although increases in BMI (as a marker of general adiposity) decrease risk, central adiposity (deposited around the abdomen) is associated with increased risk of premenopausal BC.

Furthermore, although a higher BMI is protective in premenopausal women, the magnitude of risk reduction in premenopausal BC is less than the increased BC risk witnessed post-menopause.39 Many studies agree that weight change during adulthood increases the risk of BC at an older age (post-menopausal).4851 Although true that a higher BMI can reduce BC risk in premenopausal women, the cumulative risk of developing BC across a persons lifetime will be increased in those with a high BMI.38 Obesity is also associated with increased risk of other malignancies and other serious health issues. Therefore, gaining weight should not be recommended as a suitable method to reduce BC risk long term. Interestingly, in the Carolina Breast Study, higher adult body mass index was inversely associated with premenopausal breast cancer for Whites but not for Blacks;52 Higher waist/hip ratio, adjusted for body mass index, increased risk for both black and white premenopausal women.53

Swanson et al investigated the effect of alcohol consumption in young women (<45 years) in 1997, and found that those who drank more than 14 alcoholic drinks per week had the highest risk of developing BC (RR 1.73, 95% CI 1.22.6) compared with non-drinkers.54

Since then, many studies have investigated the effect of alcohol consumption on BC and most have found that alcohol increases risk of BC in young or premenopausal women.5557

In their evaluation of evidence in 2018, the WCRF concluded that there was strong probable evidence that alcohol consumption increases the risk of premenopausal BC. A pooled multivariate analysis of 3730 cases of premenopausal women found that a 10g per day increment of alcohol consumption was associated with a BC RR of 1.03 (95% CI: 0.991.08), thus supporting the idea that a dose-response effect exists between alcohol and risk of premenopausal BC.58 This supports the WCRF meta-analysis which found statistically significant evidence of dose-response relationship between alcohol and premenopausal BC risk, whereby an increase of 10g of ethanol per day led to a 5% increased risk of developing BC in premenopausal women.10

Type of alcohol beverage also appears to be significant when considering premenopausal BC risk. The WCRFs 2018 report concluded that consuming 10g of ethanol per day as beer had a RR of 1.32 (95% CI: 1.061.64) whereas from wine this was less (RR 1.17, 95% CI: 0.791.73) and from spirits the lowest (RR 1.10, 95% CI: 0.921.30).10

The impact of active smoking on BC risk in young women has been unclear since it was first discussed by MacMahon in 1982.5961 The Collaborative Group on Hormonal Factors in BCs meta-analysis showed that the effect of smoking on BC risk is confounded by its known association with alcohol.61,62 However, most research concurs that if there is a risk associated with smoking, that it is more influential in premenopausal (than post-menopausal) BC risk.6365 Women who commence smoking at a young age seem to have a higher lifetime BC risk than those who take up smoking in later life. A cohort study of 1815 women with invasive BC found that the hazard ratio for all ever smokers (compared to never smokers) was 1.14 (95% CI 1.031.25; p=0.010) rising to 1.24 (95% CI 1.081.43; p=0.002) for starting smoking at ages <17 years.66

Interestingly, passive smoking may be a greater risk factor for BC than active smoking. It has been postulated that active smoking is associated with an anti-oestrogenic effect which may to some extent counteract exposure to smoking-related carcinogens. Passive smoking does not benefit from the anti-oestrogenic effect but results in continued exposure to carcinogenic compounds (ie, N-nitrosamines, benzenes, carbon monoxide and carbon dioxide) which persist in side stream smoke and therefore, a relatively increased risk of breast oncogenesis.64,67,68 A meta-analysis including 14 studies of smoking and premenopausal BC risk found that passive smoking was associated with an increased risk (pooled RR 1.68, 95% CI 1.882.12) increasing to a pooled summary risk estimate of 2.19 (95% CI 1.682.84) when the analysis was limited to the 5 studies with more complete exposure data.63

Individual studies place emphasis on genetic susceptibility and how this, compounded with exposure to secondary smoke, greatly increases BC risk64,69 For example, one study found that passive smoke exposure increased premenopausal BC risk in PARP1 or ESR1 genetically susceptible individuals (OR 1.54 95% CI 1.142.07).69

Long-term rotating night shift work in young adulthood is particularly associated with increased risk of ever developing BC according to an analysis of two large-scale prospective cohort studies (n=9541 total invasive BCs) in the United States: The Nurses Health study (NHS) and Nurses Health study II (NHS-II).70 This analysis found that in the NHS, women who had done 30 years or more of shift work did not have a higher risk of breast cancer (HR 0.95; 95% CI 0.771.17) compared with those who had never done shift work. However, participants of the NHS-II, who were a younger cohort (by approximately 20 years) than those in NHS had a significantly higher risk of breast cancer with 20 years or more of shift work (HR=2.15, 95% CI 1.233.73), and a significantly higher risk for women with 20 years or more of cumulative shift work (HR=1.40; 95% CI 1.001.97) compared to those who had never done shift work.70 This conclusion is supported by a Spanish case-control study (OR 1.08; 95% CI 0.981.79)71 which found that night shift work was a higher risk factor in premenopausal than post-menopausal BC.

Shernhammer et al found that there was a non-significant increase in premenopausal BC relative risk with number of years on rotating night shift work, and that the risk of developing premenopausal breast cancer appeared to increase with increasing years on a rotating night shift (Never worked a night shift age adjusted RR: 1.0; 114 years RR 1.23, 95% CI 0.981.56); 15 years RR: 1.30, 95% CI 0.752.26).72

A recent pooled analysis by Coridina-Duverger et al73 using studies from 5 different western countries: Australia, Canada, France, Germany and Spain found that there was a pooled odds ratio of developing premenopausal BC of 1.26 (95% CI 1.061.51) associated with having ever worked a night shift for 3 or more hours between midnight and 5am. This risk increased to 2.55 (95% CI 1.036.30) for those who had been working the most night shifts per week (3 or more per week) and for a longer period of time (>10 years).

Working at night causes disruptions in circadian rhythm, whereby the light-at-night causes a suppression of pineal gland production of the hormone melatonin.74 Pre-clinical trials suggest that melatonin exerts tumour-suppressive effects through a variety of mechanisms, including modulation of the oestrogen pathway, producing an anti-oestrogenic effect. Therefore, it is hypothesised that the absence of melatonin can lead to breast tumour growth.75

Globally in 2020, the highest incidence rates for premenopausal BC occur in high human development index (HDI) regions (such as Western Europe, Australia and New Zealand and North America), however low human development index regions (such as North and West Africa) had higher new cases and mortality with premenopausal BC in proportion to those of higher income.76

There is a lack of data for the impact of SES within a young US population. However, Akinyemiju et al77 looked at SES across different ethnicities in a US population and found that combined early and late BC risk increased with increasing socioeconomic status. This shows concordance with current understanding of this relationship whereby women of higher socioeconomic status are at the highest risk of developing BC but have better survival outcomes from their diagnoses than lower-income areas in the US.78

An analysis of data from the Wisconsin longitudinal study (4275 women) found that having a higher socioeconomic status (SES) in early life/childhood and being born of a mother of a higher educational level increased BC incidence.79 The underlying reasons may be that higher SES individuals tend to be older at the age of their first pregnancy and have decreased parity compared with lower SES.79,80

The evidence suggests that physical activity reduces the risk of premenopausal and early onset breast cancer with a dose-dependent effect and for all types of activity and so should be recommended. In contrast, although there is a slight risk reduction seen for premenopausal breast cancer with increased BMI this is offset both by the larger increased risk for post-menopausal breast cancer and the more general and cardiovascular risks of obesity and so maintaining a healthy weight, BMI and body composition should be recommended. Alcohol is perhaps one of the more easily modifiable risk factors and there is a dose-dependent relationship with breast cancer risk so should be reduced wherever possible. The effects of smoking may be confounded by alcohol intake but should be avoided regardless due to the overall harm to health beyond that of breast cancer alone. Socioeconomic status and shift working patterns are less easily modifiable and are perhaps more easily addressed at a public health and population rather than individual level.

Within high-income countries, there has been a shift in reproductive behaviours, favouring fewer children per household and at a later stage in a womans reproductive timeframe. Simultaneously, there has been an increased uptake in the use of exogenous hormonal medications, in the form of the oral contraceptive pill (OCP), intrauterine hormonal devices and menopausal hormone therapy (MHT), as cultural shifts have occurred within society.81 Epidemiological evidence associates both exogenous and endogenous hormone exposure with an increased risk of BC82 with exogenous hormone use being amenable to risk modification. There are two types of oestrogen (conjugated equine oestrogen and oestradiol) and four types of progestogen (norethisterone acetate, levonorgestrel, medroxyprogesterone, and dydrogesterone) commonly prescribed in the UK.83

In 2018, the OCP was the main method for contraception for 28% of women in the UK and was the most common method used by women aged between 15 and 49 years.84

In 1996, a large collaborative dataset confirmed the association of an increased risk of BC with OCP use. This analysis compared OCP use in 53,297 women with BC and 100,239 women without a BC diagnosis and concluded an overall relative risk (RR) of BC in OCP users of 1.24 (95% CI 1.151.33).85 On stopping the OCP the modest increased risk disappeared after 10 years (RR 1.01 95% CI 0.961.05). In real terms, this equates to one additional BC case with OCP use among 20,000 women aged 2025 years using this form of contraception.82 For women with a higher background risk, such as strong family history or high risk genetic mutation carriers, the data are limited but suggest the same effect in BC risk as for the overall population.82 A more recent Danish paper has shown that the duration of contraceptive pill use to be important, with 13 years use associated with the highest increase of relative risk at 18% compared to a 5% RR increase for five years use.86 Mrch et al calculated an overall BC risk with users of any hormonal contraceptive to be one extra BC case for every 7690 women using hormonal contraception for 1 year. Long-term hormonal contraceptive use has not been found to be associated with increased total cancer risk however.87 As the overall population risk for BC in women in their 20s is low, the absolute risk for BC with OCP use is therefore small (1:20,000). In an older cohort of women (over 35 years old), with increased overall risk including family history, the additional increased RR with age with the OCP use is an important consideration. Long-term follow-up data on women using the OCP have shown a considerable protection against cancer of the ovary (RR= 0.67), endometrium (RR= 0.66), or colorectum (RR= 0.81).88 Physicians need to establish a risk-benefit ratio on an individual basis to enable a joint decision between the physician and patient on the use of hormonal contraception. For example, patients with BRCA1 mutations will be at potentially increased risk of BC with OCP use, versus a protective effect for ovarian cancer risk should they not be planning a risk-reducing oophorectomy.89

An increased risk has also been noted with the progestin-only intrauterine system (levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena)) compared to women who had not used hormonal contraceptives (RR 1.21; 95% CI 1.11 to 1.33).86

The use of a LNG-IUS is often informed by the need to control heavy menstrual bleeding and avoidance of gynaecological procedures. A recent systematic review and meta-analysis on LNG-IUS users concluded an overall increased risk of BC for all users (odds ratio OR = 1.16; 95% CI 1.061.28) with an increased risk in women over 50 years (OR = 1.52 (95% CI 1.341.72)).90 A riskbenefit discussion between gynaecologist and patient, taking into account personal BC risk factors, is recommended prior to commencement of this long-term hormonal treatment.

Premature menopause before the age of 40 (in the absence of treatment for cancer) is rare affecting 1% of women.91 However, the adverse impact of menopausal symptoms on quality of life in women with premature menopause is well documented and exogenous hormonal replacement therapy (HRT; or menopausal hormonal therapy MHT) is frequently recommended for their relief and also sometimes for bone protection purposes. There are predominately two main forms of preparations: unopposed oestrogen therapy and combined oestrogen and progestin preparations.82

A large meta-analysis of worldwide epidemiological evidence for type and timing of MHT and BC risk was published in the Lancet in 2019.92 This study did include women aged 3039 but there were insufficient data to analyse the impact on breast cancer risk associated with use of MHT for <5 years in this age group. Current use of MHT for 515 years starting between ages of 3039 was not overall found to be associated with a statistically significant increased risk (RR 1.07; 95% CI 0.881.31) associated with a RR of 1.07 (95% CI 0.881.31).

The UK National Institute for health and Care Excellence (NICE) guidelines for patients with a familial BC risk recommend tailoring of MHT to individual needs and seeking alternatives to MHT where possible. MHT should generally be prescribed at the lowest dose required to control symptoms and for as short a duration as possible.89 However, when women with no personal history of breast cancer have either a BRCA1 or BRCA2 mutation or a family history of breast cancer and they have had a bilateral salpingo-oophorectomy before their natural menopause, they can be offered either combined HRT if their uterus remains or oestrogen-only HRT if their uterus has been removed, up until the time they would have expected natural menopause (average age for natural menopause is 5152 years).89

Women who decide to have children later in life may undergo fertility techniques for oocyte harvesting, oocyte cryopreservation and embryo transfer techniques and fertilisation (In vitro fertilisation (IVF)). Follicle-stimulating hormone (FSH) injections are often used daily for 2 weeks to stimulate follicle development and assist harvesting. No association has been reported between use of fertility preservation techniques and BC development,82 including for BRCA 1/2 mutation carriers. IVF exposure was not associated with risk of BC (HR: 0.79, 95% CI: 0.461.36).93 A recent systematic review has highlighted however there is limited evidence on the association between IVF and premenopausal breast cancer risk.94

The age at which a woman gives birth to a child has been shown to influence her BC risk.81 Arguably, timing of pregnancy and child-bearing is not always planned, however a woman with an increased BC risk may wish to actively start a family earlier to reduce her BC risk. The age at first pregnancy is especially important, with parity under 20 years of age associated with the longest term risk reduction of 50% compared to nulliparous women.95 Having a child over 35 years of age conferred an increased BC risk compared to a nulliparous woman.96 Recent data suggest that the age of first pregnancy and parity affects the risk of specific BC subtype development, with young age of first pregnancy and parity being associated with a reduction in luminal oestrogen receptor positive BCs but not other subtypes.97

Post-partum there is a transient observed increase in BC risk which is attributed to the post-partum involution process within the breast.81 It is hypothesised that the breast remodelling following lactational changes takes up to ten years on average and the increased risk may be due to immune microenvironment changes.81 The reduction in BC risk following this period may be due to a reduction in ER sensitive epithelial cells within the breast.98 Compared to nulliparous women, parous women have an increased BC risk peaking 5 years after birth before decreasing up to 34 years later (HR, 1.80 [95% CI, 1.63 to 1.99]) and 0.77 (CI, 0.67 to 0.88, respectively).99

Data from the 19932001 Carolina Breast Cancer Study which included 1505 African-American and 1809 White women identified some important racial differences in breast cancer risk factors amongst younger women (aged 2049). Multiparity was associated with increased risk of breast cancer among younger African-American women (for three or four pregnancies: adjusted odds ratio (OR) = 1.5, 95% confidence interval (CI): 0.9, 2.6; for five or more pregnancies: OR = 1.4, 95% CI: 0.6, 3.1) but not among younger White women (for three or four pregnancies: OR = 0.7, 95% CI: 0.4, 1.2; for five or more pregnancies: OR = 0.8, 95% CI: 0.2, 3.0). The relationship with age at first full-term pregnancy and nulliparity also varied by race.100 Thus, the higher incidence of breast cancer among younger African-American women may result from both higher prevalence of risk factors and higher relative risks associated with these.

Breastfeeding has been shown to reduce a womans risk of BC.101 The mechanism of risk reduction is not clear; however, for every 12 months of breast feeding, the RR reduction is 4% for all women with an increased RR reduction of 5.1% for premenopausal BC.81,102

Interestingly, the protective effect of breast feeding is not limited to only hormone receptor positive breast cancer subtypes.103 A reduction in risk has also been demonstrated in hormone receptor negative breast cancers which are more common in younger women.104

The World Health Organisation recommends at least six months of breast feeding post-partum prior to weaning for a protective effect.105 Young mothers should be supported to breastfeed to reduce their BC risk in addition to promoted benefits to the developing baby.

Anti-oestrogen medications may be offered in specialist clinics to women with high and moderate personal risk for BC.106 These medications are referred to as chemoprevention however risk-reducing medication is a more favourable term to encourage uptake.81

In premenopausal women, use of tamoxifen for 5 years reduced BC risk by 33% and the reduction persisted for at least 15 years after cessation of the anti-hormonal medication.107,108 Of note, there was no benefit shown for overall BC mortality with this treatment. They may be a useful option for women with high to moderate risk of BC who wish to reduce their risk as an alternative or bridge to risk-reducing surgery.106 Caveats to the use of tamoxifen are an increased risk of venous thromboembolism and endometrial cancer (risk 4:1000). A short trial of tamoxifen for six to eight weeks may feel more acceptable to a patient prior to a five-year course to test for medication induced side effects.81 Although raloxifene and aromatase inhibitors have been shown to reduce breast cancer occurrence in high risk post-menopausal women, these drugs are not recommended in premenopausal women.89 Non-hormonal forms of chemoprophylaxis for breast cancer remain under investigation. Several meta-analyses of observational studies have reported reduced risk of breast cancer in aspirin users compared to non-users.109,110 However, in their sub-group analysis, Cao et al found a significant risk reduction of breast cancer associated with aspirin use in postmenopausal women (RR=0.89, 95% CI: 0.830.96, P=.002), but not in premenopausal women (RR=0.88, 95% CI: 0.721.08, P=.223).110

In younger women less than the age of 35 the absolute increased breast cancer risk with the combined oral contraceptive is very small and so this can be prescribed with appropriate information. Between the age of 35 and 50 women with a breast cancer family history should be aware that the increased breast cancer risk increases with age as their absolute familial breast cancer risk increases and this should be weighed within the overall risks and benefits of the combined oral contraceptive. For those with BRCA1 or BRCA2 gene alterations considering the combined oral contraceptive the situation is more complex and specialist genetic service input may be beneficial to judge the competing impacts of increased breast cancer risk against reduced ovarian cancer risk within the specific circumstances of the individual.111 For those with an early menopause no increased risk is seen with HRT up to the natural age of menopause for a general population, but in those with increased familial risk more specialist input may again be helpful.

Worldwide it is estimated that over 1.8 million breast augmentation procedures are performed annually, of which 2.8% are in those aged 18 years or younger, 53.9% in those aged 1934 and 35.0% in those aged 3550. The UK independent review group on Silicone Gel Breast Implants concluded that BC incidence is not raised in women with breast implants,112 however, in those with cosmetic breast augmentation breast cancer diagnosis appears to occur at a later stage and possibly impacts negatively on survival.113 More recently an association has been identified between silicone breast implants and a form of non-Hodgkin lymphoma known as Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). This typically occurs 710 years following implantation,114 and so given the demographics of cosmetic breast augmentation surgery will be relevant to younger women considering such surgery. The MHRA estimates that the incidence of the BIA-ALCL is 1 per 20,000 implants sold,115 and since cosmetic augmentation is usually a bilateral procedure, the rate may be 1 per 10,000 in women undergoing cosmetic implant breast augmentation.

It has been recognised since the 1980s that treatment for Hodgkins Lymphoma (HL) is associated with a subsequent increased risk of BC amongst other secondary malignancies, with an increasing risk over time for over three decades after HL diagnosis. A recent study of 200945 survivors of teenage and young adult cancer survivors reporting cumulative risk of BC of 0.3%, 1.3%, 3.8%, 6.7%, 10.8% and 14.4% at 10, 15, 20, 25, 30 and 35 years after HL diagnosis.116 Risk of BC in HL survivors is closely associated with use of mantle irradiation with both total dose and field size/site of irradiation influencing risk levels.117 A significantly lower risk of BC has been reported among patients who received supradiaphragmatic field radiotherapy not including the axilla than among those who received complete mantle-field radiotherapy (HR, 0.37; 95% CI 0.19 to 0.72).118 Recognition of these risk factors led to adoption of potentially less toxic treatment regimes in the late 1980s incorporating smaller and less intense radiation fields. However, recent cohort studies comparing second malignancy rates in patients treated for HL during different time periods have not indicated the anticipated fall in treatment-related BC rates with newer treatment regimens.118,119 It is postulated that this is due to the simultaneous adoption of less toxic chemotherapy regimens with a lower incidence of premature menopause with associated reduction in oestrogen exposure.

Age at time of HL diagnosis is an important modifier of risk. Studies of childhood cancer survivors however indicate that radiation treatment at age 10 16 years carries more risk than treatment at age <10 (RR 1.9).117 In the teenage and young adult (TYA) population RR is significantly higher for those treated for HL at age <19 than those treated at 2029 years with no increased BC risk for HL patients diagnosed at 30 years.120

For women who received radiotherapy for HL between the ages of 1029, current UK guidelines recommend that breast screening in the form of an annual magnetic resonance imaging (MRI) scan should start 8 years after radiotherapy to breast tissue or at age 25 or 30 (whichever occurs later). Women treated between the ages of 3039 should commence annual breast MRIs at age 30.121

Female HL patients with a family history of BC are significantly more likely to develop BC, compared to HL patients with no history of BC among relatives.119,122 However, there is currently no evidence that there is a role for mutations in the known high penetrance BC susceptibility genes TP53, BRCA1, BRCA2, and ATM as a cause of subsequent cancer risk in HL survivors.123

Some studies report that there are important interactions between an individuals genetics (their background risk) with lifestyle risk factors that can alter the effect size or direction of risk. Niehoff et al demonstrated that recreational physical activity does not reduce risk in premenopausal women with a family history of BC,124 contrary to the effect seen in young women without familial history.

Tryggvadottir et al125 investigated the changes in risk of developing any BC associated with BRCA2 mutations in an Icelandic population, reporting that there was a four-fold increase of incidence of BC in BRCA2 mutation carriers in 2000 (compared to 1920), ultimately concluding that BRCA2 mutation penetrance has increased with time. This work concluded that this increase in penetrance was proportional to increases in the Icelandic population of modifiable BC risk factors which have increased over time. Additionally, a case-control study by Jernstrm et al showed that young women (below age 40 years) who carried BRCA1 and BRCA2 mutations would be at higher risk of developing BC with increasing number of pregnancies. Therefore, the direction of a partially modifiable risk factor such as parity is dependent on whether they have wild type or mutant BRCA1 and 2 genes.126 Tobacco smoking in BRCA1 and 2 mutation carriers increases risk of developing BC by 17% compared to mutant non-smokers, and women with the highest pack years (4.39.8) having a 33% increase of BC (HR=1.33 9% CI 1.021.75).127 More research is needed the investigate the interactions between genetic effects and other factors.

Counselling and health education for premenopausal women with a family history of BC is complex. Communicating DNA-based disease risk estimates for conditions where risk could be reduced by behaviour change produced no significant effects on smoking, diet, physical activity or alcohol use behaviours.128 An interview study of premenopausal women with a family history of BC who were overweight/obese found that they had feelings of guilt and anxiety when unable to lose weight. Therefore, credible rationales for weight loss that address these feelings of anxiety and doubt are required to reduce this significant risk factor in this high risk population, as well as appropriate support.129 In a feasibility study of 79 overweight premenopausal women at increased risk of breast cancer, 55% of those enrolled in a 12-month diet and exercise weight loss programme (n = 40) achieved target weight loss of 5% baseline weight, compared to 15% of those receiving usual care in the form of a healthy lifestyle advice leaflet.130

BC is the most common cancer diagnosis in women aged under 40 and associated with poorer survival outcomes than in older women. As incidence of young onset BC increases globally there is an urgent need to address risk factors that are modifiable by individual behaviour change.

Overall risk is however determined by both modifiable and non-modifiable risk factors and the most significant non-modifiable risk factor is often familial risk. Health care professionals should therefore assess BC inherent and familial risk through a careful medical and family history and aim to discuss modifiable factors in relation to this background risk. Modifiable risk factors (Table 2) including physical activity and alcohol habits should be considered whenever presented with a teachable moment applicable to breast health. Discussions regarding personal risks and benefits should also accompany conversations regarding reproductive health and hormonal preparations, and take into consideration other modifiable risks and the background individual non-modifiable and iatrogenic BC risk factors. Increasing understanding of the interactions between genomic and modifiable factors will be vital in providing individualised advice to young women who wish to minimise their personal BC risk.

Table 2 Summary of the Key Evidence Regarding Specific Risk Factors in Relation to the Risk of Developing Breast Cancer at a Premenopausal Age/Stage

Prof. Ramsey I Cutress reports non-financial support from SECA, outside the submitted work. Dr Ellen R Copson reports grants, personal fees from World Cancer Research Fund, non-financial support from SECA, personal fees from AstraZeneca, personal fees from Roche, personal fees from Lilly, personal fees from Pfizer, personal feesfrom Nanostring, personal fees from Novartis, outside the submitted work. Prof. Cutress and Dr Copson report research funding from World Cancer Research Fund (WCRF UK) as part of the WCRF International grant programme . The authors report no other conflicts of interest in this work.

1. Global Cancer Observatory (GLOBOCAN). Global cancer observatory. Cancer Today- International Agency for Research on Cancer: World Health Organisation; 2018. Available from: Accessed November 3, 2020.

2. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute. U.S. Cancer Statistics Working Group. U.S. cancer statistics data visualizations tool; June, 2020. Available from: Accessed November 3, 2020.

3. Cancer Research UK. Breast cancer statistics UK: cancer research UK; 2016. Available from: Accessed November 3, 2020.

4. Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19(2):169180. doi:10.1016/S1470-2045(17)30891-4

5. Lawson PJ, Flocke SA. Teachable moments for health behavior change: a concept analysis. Patient Educ Couns. 2009;76(1):2530. doi:10.1016/j.pec.2008.11.002

6. Senore C, Giordano L, Bellisario C, Di Stefano F, Segnan N. Population based cancer screening programmes as a teachable moment for primary prevention interventions. A review of the literature. Front Oncol. 2012;2:45. doi:10.3389/fonc.2012.00045

7. Gritz ER, Fingeret MC, Vidrine DJ, Lazev AB, Mehta NV, Reece GP. Successes and failures of the teachable moment. Cancer. 2006;106(1):1727. doi:10.1002/cncr.21598

8. Paluch-Shimon S, Cardoso F, Partridge AH, et al. ESO-ESMO 4th international consensus guidelines for breast cancer in young women (BCY4). Ann Oncol. 2020;31(6):674696. doi:10.1016/j.annonc.2020.03.284

9. Gnerlich JL, Deshpande AD, Jeffe DB, Sweet A, White N, Margenthaler JA. Elevated breast cancer mortality in women younger than age 40 years compared with older women is attributed to poorer survival in early-stage disease. J Am Coll Surg. 2009;208(3):341347. doi:10.1016/j.jamcollsurg.2008.12.001

10. World Cancer Research Fund. Diet, nutrition, physical activity and breast cancer: a global perspective. World Cancer Research Fund/American Institute for Cancer Research; 2017 (Revised 2018). Available from: Accessed November 3, 2020.

11. Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. JNCI. 2014;106(5):dju055dju. doi:10.1093/jnci/dju055

12. Thomas GA, Leonard RCF. How age affects the biology of breast cancer. Clin Oncol. 2009;21(2):8185. doi:10.1016/j.clon.2008.11.006

13. Narod SA. Breast cancer in young women. Nat Rev Clin Oncol. 2012;9(8):460470. doi:10.1038/nrclinonc.2012.102

14. Anders CK, Johnson R, Litton J, Phillips M, Bleyer A. Breast cancer before age 40 years. Semin Oncol. 2009;36(3):237249. doi:10.1053/j.seminoncol.2009.03.001

15. Maas P, Barrdahl M, Joshi AD, et al. Breast cancer risk from modifiable and nonmodifiable risk factors among white women in the United States. JAMA Oncol. 2016;2(10):12951302. doi:10.1001/jamaoncol.2016.1025

16. Brandt J, Garne JP, Tengrup I, Manjer J. Age at diagnosis in relation to survival following breast cancer: a cohort study. World J Surg Oncol. 2015;13(1):33. doi:10.1186/s12957-014-0429-x

17. Collins LC, Marotti JD, Gelber S, et al. Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat. 2012;131(3):10611066. doi:10.1007/s10549-011-1872-9

18. Lee H-B, Han W. Unique features of young age breast cancer and its management. J Breast Cancer. 2014;17(4):301. doi:10.4048/jbc.2014.17.4.301

19. Seidler S, Huber D. Breast cancer in young women: implications for clinical practice. Rev Med Suisse. 2020;16(695):11061113.

20. Morrison DH, Rahardja D, King E, Peng Y, Sarode VR. Tumour biomarker expression relative to age and molecular subtypes of invasive breast cancer. Br J Cancer. 2012;107(2):382387. doi:10.1038/bjc.2012.219

21. Walker R, Lees E, Webb M, Dearing S. Breast carcinomas occurring in young women (<35 years) are different. Br J Cancer. 1996;74(11):17961800. doi:10.1038/bjc.1996.632

22. Lynch HT, Watson P, Conway T, Fitzsimmons ML, Lynch J. Breast cancer family history as a risk factor for early onset breast cancer. Breast Cancer Res Treat. 1988;11(3):263267. doi:10.1007/BF01807285

23. Lee DS, Yoon S-Y, Looi LM, et al. Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. Breast Cancer Res. 2012;14(2):R66. doi:10.1186/bcr3172

24. Gmez-Flores-Ramos L, lvarez-gmez RM, Villarreal-Garza C, Wegman-Ostrosky T, Mohar A. Breast cancer genetics in young women: what do we know? Mutat Res. 2017;774:3345. doi:10.1016/j.mrrev.2017.08.001

25. Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497506. doi:10.1056/NEJMoa1400382

26. Joslyn SA, Foote ML, Nasseri K, Coughlin SS, Howe HL. Racial and ethnic disparities in breast cancer rates by age: NAACCR breast cancer project. Breast Cancer Res Treat. 2005;92(2):97105. doi:10.1007/s10549-005-2112-y

27. Chlebowski RT, Chen Z, Anderson GL, et al. Ethnicity and breast cancer: factors influencing differences in incidence and outcome. J Natl Cancer Inst. 2005;97(6):439448. doi:10.1093/jnci/dji064

28. Jack RH, Davies EA, Mller H. Breast cancer and age in black and white women in South East England. Int J Cancer. 2012;130(5):12271229. doi:10.1002/ijc.26088

29. Copson E, Maishman T, Gerty S, et al. Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study. Br J Cancer. 2014;110(1):230241. doi:10.1038/bjc.2013.650

30. Rockhill B, Willett WC, Hunter DJ, et al. Physical activity and breast cancer risk in a cohort of young women. J Natl Cancer Inst. 1998;90(15):11551160. doi:10.1093/jnci/90.15.1155

31. Wu Y, Zhang D, Kang S. Physical activity and risk of breast cancer: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2013;137(3):869882. doi:10.1007/s10549-012-2396-7

32. Hardefeldt PJ, Penninkilampi R, Edirimanne S, Eslick GD. Physical activity and weight loss reduce the risk of breast cancer: a meta-analysis of 139 prospective and retrospective studies. Clin Breast Cancer. 2018;18(4):e601e12. doi:10.1016/j.clbc.2017.10.010

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[Full text] A Review of Modifiable Risk Factors in Young Women for the Prevention | BCTT - Dove Medical Press

[Full text] Prognostic value of TP53 mutation location in breast cancer | CMAR – Dove Medical Press


As a tumor suppressor and DNA binding transcription factor, TP53 is actively involved in the regulation of the cell cycle, apoptosis, and genomic stability.1,2 TP53 is one of the most frequently mutated genes in human cancers, including breast cancer,3 and numerous studies have reported it as a biomarker for predicting an aggressive and metastatic phenotype in breast cancer.47 Most of these studies used first-generation sequencing or automated DNA extraction from formalin-fixed and paraffin-embedded tissue (FFPE). However, real-time (RT)-PCR results and first-generation sequencing could not be used to detect all TP53 mutations to further investigate TP53 status more accurately and reliably.

TP53 is located on chromosome 17p13.1 and contains 11 exons and 10 introns. Most TP53 mutations map to exons 58, which encodes the DNA binding domain (DBD), and most are missense mutations.810 Hotspot codons 175, 213, 245, 248, 273, and 282 account for at least 2% of all mutations within the DBD.2 Patients with acute myeloid leukemia carrying TP53 mutations in the DBD had a worse prognosis than those with wild-type TP53.11 Furthermore, another clinical trial showed that truncating mutations in the DBD had a significant independent prognostic value in breast cancer, being associated with increased recurrence compared with patients with non-modified p53 proteins.12

Early studies using first-generation sequencing or automated DNA extraction from FFPE found that TP53 mutations were associated with poor prognosis in hormone receptor-positive (HR+) breast cancer patients.1315 Moreover, in an HR+ cohort, TP53 signaling was enriched in resistant tumors (38% in the aromatase inhibitor-resistant group vs 17% in the sensitive group) such that HR+ tumors with TP53 mutations were mostly aromatase inhibitor-resistant.5 No significant result was obtained from human epidermal growth factor receptor 2 positive (HER2+) or triple-negative breast cancer (TNBC) cohorts.16 Other studies found that TP53 mutations were associated with tumor recurrence and apoptosis, which were more common in HER2-positive and TNBC cohorts.17,18

While the significance of TP53 mutations has been shown by RT-PCR and first-generation sequencing, most clinical laboratories do not use next-generation sequencing (NGS) to determine the p53 mutational status because of high costs and complex interpretation. Therefore, it is difficult to understand the clinical applications of TP53.19 In the present study, we collected peripheral blood samples from Chinese patients with freshly diagnosed metastatic breast cancer (MBC) and examined the whole exons and introns of TP53 by NGS to further investigate the relationship between TP53 mutations, prognosis, and therapy.

From January 2013 to March 2020, patients past first-line treatment and those for whom blood samples were not available were excluded, leaving a total of 194 at the stage of first-line treatment at the Department of Breast Oncology, Peking University Cancer Hospital. Of these, 187 consented with enrollment and had complete clinic-pathological information (Figure 1).

Figure 1 Flowchart of patient inclusion.

We defined estrogen receptor (ER), progesterone receptor (PR), and HER2 status according to recommended guidelines,20,21 which identified three subtypes: the HER2+ cohort, HR+/HER2- cohort, and TNBC cohort.

HR+/HER2- patients who accepted adjuvant endocrine therapy were divided into two groups: endocrine-resistant patients were defined as patients relapsing during adjuvant endocrine therapy, or <12 months after its completion. Endocrine-sensitive patients were defined as patients relapsing 12 months after completing adjuvant endocrine therapy in the early breast cancer stage.22

Peripheral blood samples before first-line therapy were collected in EDTA Vacutainer tubes and centrifuged at 2000 g for 10 min at 4C. The supernatant was then removed, and each sample of 3 mL plasma was stored at 80C.

Circulating free (cf)DNA was extracted using a QIAamp Circulating Nucleic Acid Kit (QIAamp, Venlo, the Netherlands) from EDTA and citrate anticoagulant plasma. The average volume of plasma used for extraction was 2.6 mL (range, 0.73.9 mL). The quantity and quality of the purified cfDNA were checked using a Qubit 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) and Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA, USA). For samples with severe genomic contamination from peripheral blood cells, size selection was performed to remove large genomic fragments with AMPure XP beads (Beckman Coulter, Brea, CA, USA). Samples with a total yield <5 ng were considered inadequate for NGS and were removed from any further sequencing methods.

cfDNA was end-repaired before the dA-tailing process, and then ligated with proprietary UMI adapters. The library yield was measured after PCR amplification using a Qubit and Bioanalyzer 2100. Samples yielding >700 ng proceeded to the hybridization step. Library capture was conducted using biotin-labeled DNA probes (Thermo Fisher Scientific). In brief, the library was hybridized using PredicineCARE panel (Huidu Shanghai Medical Sciences, Inc.) overnight and captured on Dynabeads M-270 Streptavidin (Thermo Fisher Scientific).23,24 Unbound fragments were washed away, and the enriched fragments were amplified via PCR. For library preparation, the purified product was checked using Bioanalyzer 2100 and loaded into the HiSeq X Ten system (Illumina, San Diego, CA, USA) for NGS with paired-end 150 bp sequencing kits.

Consensus binary alignment map (BAM) files were derived by merging paired-end reads that originated from the same molecules (based on mapping location and unique molecular identifiers) as single-strand fragments. Single-strand fragments from the same double-strand DNA molecules were merged to be double-stranded for suppressing sequencing and PCR errors during this process. NGS quality-checking was performed by examining the percentage of targeted regions with >1500x unique consensus coverage. Samples with <80% regions having >1500x unique coverage were deemed to be QC failed and excluded. Candidate variants, consisting of point mutations, small insertions and deletions, were identified using Huidu proprietary bioinformatics pipeline. Candidate variants with low base quality, mapping scores, and other quality metrics were filtered. Candidate variants in repeat regions were also excluded.

A variant identified in cfDNA was considered to be a candidate somatic mutation-based if all of the following pre-defined criteria were present. These criteria were 1) the presence of at least 4 distinct paired reads in the mutation in the plasma; 2) the number of distinct paired reads containing a particular mutation in the plasma is at least 0.1% of the total distinct read pairs (if the nucleotide change and amino acid change are identical to an alteration observed in 20 cancer cases reported in the COSMIC database or previously reported as a cancer hotspot []) or the number of distinct paired reads containing a particular mutation in the plasma was at least 0.25% of the total distinct read pairs (if the nucleotide change and amino acid change are not a frequent alteration in COSMIC database or reported as a cancer hotspot previously); 3) the variant is not present in public databases of common germline variants, including 1000 genomes, ExAC, gnomAD, and KAVIAR, with population allele frequency >0.5%; 4) the variant is not present in matched PBMC samples (unpublished data, manuscript in preparation).

Candidate somatic mutations were further filtered based on gene annotation to identify those occurring in protein-coding regions. Intronic and silent changes were excluded, and mutations resulting in missense mutations, nonsense mutations, frameshifts, or splice site alterations were retained. Mutations annotated as benign or likely benign in ClinVar database were also filtered.

Clinical outcome was evaluated as disease-free survival (DFS) and overall survival (OS). Disease-free survival (DFS) was defined as the interval between surgery and time of recurrence for relapsed patients so that patients with stage IV were not included. OS was defined as the time from diagnosis to the date of death or last follow-up. According to Response Evaluation Criteria in Solid Tumors version 1.1 guidelines,25 we evaluated the response assessment by a computed tomography scan or magnetic resonance imaging every 612 weeks or as the patients condition deteriorated.

SPSS software version 20 was used to analyze the TP53 status and categorical patient characteristics. DFS and OS were estimated by the KaplanMeier method and comparisons between groups were conducted by the log rank test. P values <0.05 were considered significant. For multivariable analysis, Cox proportional hazards method was used to evaluate clinical outcome. The association between the TP53 status and clinical characteristics was examined using the Chi-square test.

Of 187 patients, 79 carried TP53 mutations and 108 had wild-type TP53. Detailed baseline clinical information of all patients is shown in Table 1. The median age in the TP53 mutated group was 48 years (range: 2769 years old) versus 46 years of age in the TP53 wild-type group (range: 2680 years old) (P = 0.702). We also found that 73.4% (58/79) of TP53-mutated patients and 86.1% (93/108) of TP53 wild-type patients were HER2 negative (P=0.030).

Table 1 Baseline Clinical Characteristics of TP53 Wild-Type and -Mutated Metastatic Breast Cancer Patients (n=187)

In univariate analysis of DFS (Table 2), HER2 status (P=0.024) and HR status (P=0.000) were significant predictors in TP53 wild-type patients and TP53-mutated patients, respectively, and Ki67 status was also a significant predictor for TP53 wild-type patients (P=0.001) and TP53-mutated patients (P=0.022). After multivariable analysis of DFS (Table 2), Ki67 status (P=0.003) and HR status (P=0.000) in TP53 mutated group remained significant predictors and patients with stage III had a higher risk of relapse after surgery than stage III (p=0.030) in TP53 wild-type cohort.

A total of 87 somatic TP53 mutations were identified in the 79 TP53-mutated patients. Sixty-seven of these (77.0%) were located in exons 58, which span the DBD of the protein (Supplementary Table S1). Codons 175, 220, and 248 within the DBD were the locations of 4.6% of all mutations, respectively, which were all missense mutations (Figure 2). Of the 87 mutations, there were 46 missense mutations (43 was in DBD, 1 was in TD, 1 was in TAD, and 1 was outside the p53 protein domain) and 41 non-missense mutations (18 nonsense mutations, 3 splicing mutations, 16 frameshift mutations, 4 in-frame mutations).

We found that the median DFS of TP53-mutated patients was significantly shorter at 33.0 months (95% confidence interval [CI]=21.444.6) than that of TP53 wild-type patients at 51.0 months (95% CI=39.160.9) (hazard ratio=1.89, 95% CI=1.312.71, P=0.001) (Figure 3A). Similarly, the median OS of TP53-mutated patients was significantly shorter at 67.0 months (95% CI=44.489.6) than that of TP53 wild-type patients at 140.0 months (95% CI=119.5160.5) (hazard ratio=1.99, 95% CI=1.213.26, P=0.006) (Figure 3B).

Figure 3 Survival analyses by KaplanMeier according to TP53 status in MBC patients. (A and B) TP53 wild-type patients had a significantly better clinical outcome than TP53-mutated patients. (C and D) there were no significant differences between TP53 wild-type and -mutated patients in the HER2-positive cohort. (E and F) TP53 wild-type patients had a significantly longer median DFS and OS than TP53-mutated patients in the HR+/HER2 cohort. (G and H) TP53 wild-type patients had a significantly longer median DFS than TP53-mutated patients in the TNBC cohort.

In the HER2+ cohort (n=36, 21 of whom were TP53-mutated patients), there was no significant difference regarding TP53 status with respect to DFS (34.0 vs 21.0 months, P=0.822) (Figure 3C) or OS (91.0 vs 65.0 months, P=0.080) (Figure 3D).

In the HR+/HER2- cohort (n=113, 40 of whom were TP53-mutated patients), the median DFS of TP53 mutated patients of 44.0 months (95% CI=35.952.1) was significantly shorter than the 58.0 months (95% CI=46.269.8) of TP53 wild-type patients (hazard ratio=1.57, 95% CI=0.972.54, P=0.038) (Figure 3E). No significant difference was observed for OS (P=0.606) (Figure 3F).

In the TNBC cohort (n=38, 18 of whom were TP53-mutated patients), the median DFS of TP53-mutated patients of 16.0 months (95% CI=7.824.2) was significantly shorter than the 26.0 months (95% CI=16.635.4) of TP53 wild-type patients (hazard ratio=2.17, 95% CI=0.964.90, P=0.023) (Figure 3G). There was no significant difference regarding TP53 status with respect to OS (137.0 vs 54.0 months, P=0.117) (Figure 3H).

We next classified the 187 patients into three groups by mutation domain: TP53 mutations in the DBD, TP53 mutations in the non-DBD, and TP53 wild-type groups. The median DFS for these patients was 36.6 (95% CI=25.342.7), 22 (95% CI=16.125.9), and 51 (95% CI=39.160.9) months, respectively, while the median OS was 80 (95% CI=46.3113.7), 51 (95% CI=41.260.8), and 140 (95% CI=119.5160.5) months, respectively.

TP53 wild-type patients had a significantly better clinical outcome than those with TP53 mutations in the DBD with respect to DFS (P=0.008, Figure 4A) and OS (P=0.003, Figure 4B). Similarly, TP53 wild-type patients had a significantly better clinical outcome than those with TP53 mutations in the non-DBD with respect to DFS (P<0.001, Figure 4A) and OS (P=0.001, Figure 4B). There were no significant differences in DFS or OS between patients with TP53 mutations in the DBD compared with those in the non-DBD.

Figure 4 Survival analyses by KaplanMeier according to TP53 mutation sites in MBC patients. (A) Patients with a mutation in the non-DNA binding domain had a significantly shorter median DFS than TP53 wild-type patients and those with mutations in the DNA-binding domain. (B) Patients with a mutation in the non-DNA binding domain had shorter median OS than TP53 wild-type patients and those with mutations in the DNA-binding domain. (C) Patients with protein non-stable mutation had shortest median DFS than patients with protein stable mutation and TP53 wild-type patients. (D) Patients with protein non-stable mutation had shortest median OS than patients with protein stable mutation and TP53 wild-type patients.

Notes: Protein stable mutations would include non-truncating and non-frame altering mutations outside of the p53 tetramerization domain, and protein non-stable mutations would include all truncating and frame-altering mutations, as well as mutations in the tetramerization domain.

And then, we divided patients into three groups: TP53 wild-type group; protein stable mutations group (non-truncating and non-frame altering mutations outside of the p53 tetramerization domain); protein non-stable mutations group (all truncating and frame-altering mutations, and mutations in the tetramerization domain).

Patients with protein non-stable mutations had significantly shorter DFS (21.0 months vs 49.0 months, respectively, hazard ratio=2.82, 95% CI=1.634.87, P<0.001, Figure 4C) and OS (57.0 months vs 140.0 months, respectively, hazard ratio=4.05, 95% CI=1.958.40, P<0.001, Figure 4D) than TP53 wild-type patients. Moreover, the median DFS of protein stable mutations was 43.5 months, longer than protein non-stable mutations (hazard ratio=0.54, 95% CI=0.310.93, P=0.025, Figure 4C). There were no significant differences in DFS or OS between patients with protein stable mutations and TP53 wild type.

Furthermore, we wanted to study mutations in DBD so that we classified them into missense (n=43) and non-missense mutations (n=24, including nonsense mutations, splicing mutations, frameshift mutations and in-frame mutations). Patients with non-missense mutations in the DBD had significantly shorter DFS (20.0 months vs 51.0 months, respectively, hazard ratio=3.26, 95% CI=1.586.71, P=0.001, Figure 5A) and OS (57.0 months vs 140.0 months, respectively, hazard ratio=10.45, 95% CI=3.7928.8, P<0.001, Figure 5B) than TP53 wild-type patients. Moreover, the median OS of patients with non-missense mutations in the DBD was significantly shorter than those with missense mutations in the DBD (hazard ratio=2.45, 95% CI=1.055.09, P=0.015, Figure 5B). There were no significant differences in DFS or OS between patients with missense mutations in the DBD and wild-type TP53 patients.

Figure 5 Survival analyses by KaplanMeier according to TP53 mutation type in the DNA binding domain. (A and B) Patients with non-missense mutations in the DNA binding domain had a significantly shorter median DFS and OS than TP53 wild-type patients and those with missense mutations in the DNA binding domain.

A total of 96 patients who received adjuvant endocrine therapy were selected to evaluate the relationship between TP53 mutation status and the response to endocrine therapy. As shown in Table 3, we found that 84.7% (50/59) of patients accepted adjuvant chemotherapy in TP53 wild-type group, whereas 78.4% (29/37) of patients accepted adjuvant chemotherapy treatment in TP53 mutant patients. There was no significant difference between TP53 status and adjuvant chemotherapy (P=0.467). As well known, ESR1 mutations are associated with acquired endocrine resistance in breast cancer so that we took ESR1 mutation rate into consideration in Table 3, but there were no significant differences in ESR1 mutation rate (p=0.558) between the two groups.

Table 2 Univariate and Multivariate Cox Regression Analysis of DFS in TP53 Wild-Type and -Mutated Patients

Table 3 Clinical Characteristics of Patients Receiving Adjuvant Endocrine Therapy (n=96)

To further explore the relationship between TP53 status and treatment response, we classified patients into the adjuvant endocrine therapy-resistant group and the adjuvant endocrine therapy sensitive group. Interestingly, we found that in the adjuvant endocrine therapy sensitive group, patients with TP53 mutations had a significantly shorter DFS than TP53 wild-type patients (69.0 months vs 108.0 months, respectively, hazard ratio=3.22, 95% CI=0.7014.77, P=0.008) (Figure 6B). No significant DFS differences between TP53-mutated and TP53 wild-type patients were seen in the endocrine therapy-resistant group (34.0 months vs 40.0 months, respectively, P=0.903) (Figure 6A).

Figure 6 Survival analyses by KaplanMeier according to TP53 status in MBC receiving adjuvant endocrine therapy. (A) There was no significant difference in TP53 status in the endocrine therapy-resistant cohort. (B) TP53 wild-type patients had a significantly better clinical outcome than TP53-mutated patients in the endocrine therapy sensitive cohort.

In our study, we used NGS to detect TP53 mutations in the cfDNA, which might affect tumor temporal and spatial heterogeneity, of 187 Chinese MBC patients. Our results indicated that TP53 mutations could be used as a prognostic marker for worse outcome in MBC and for the response of adjuvant endocrine therapy.

We established genomic profiles of patients which revealed a TP53 mutation frequency of 42.2%, similar to that seen in the Guangdong Provincial Peoples Hospital cohort (45.0%) but higher than in the TCGA breast cancer cohort (30.0%).26 Another recent study on cfDNA molecular profiling in Chinese patients with MBC reported a TP53 mutation rate of 64.1% compared with 52% in Caucasian patients.27,28 These discrepancies could reflect differences between patient ethnicities, such as in the median age of breast cancer patients with TP53 mutations in our study of 48 years compared with 55.2 years in Caucasians.29

The p53 pathway was previously shown to rank top in the basal-like breast cancer subtype, but not in the HER2-enriched type; therefore, TP53 mutations were not associated with poor prognosis in the HER2-enriched group.6 In support of this, our data indicated that the TP53 mutation status was an independent predictive factor of survival especially in HR+/HER2 and TNBC cohorts, but not in the HER2-positive cohort.

Several studies have shown that the DBD is the most frequently mutated TP53 region in breast cancer. In line with this, codons 175, 220, and 248 located within the DBD were the site of many TP53 mutations in our study, of which most were missense mutations. DBD mutations were previously reported to have prognostic value,30,31 while non-missense mutations were associated with a worse outcome in MBC.32 A recent study showed that missense mutation in the DNA-binding domain had dominant-negative effects (DNE).33 There was no difference in survival between patients with dominant-negative p53 mutant tumors and those with TP53 mutations that are predicted to be non-dominant negative.34,35 In our study, TP53 missense mutations in the DBD were associated with improved survival. Further analysis showed that patients with TP53 mutations in the non-DBD had a significantly shorter DFS than those in the TP53 non-mutation cohort.36 In order to investigate the prognostic value of p53 protein further, we divided them into TP53 wild-type group; protein stable mutations group and protein non-stable mutations group. In our study, patients with protein non-stable mutations had significantly shorter DFS and OS than TP53 wild-type patients. Moreover, protein non-stable mutations included all truncating and frame-altering mutations, and mutations in the tetramerization domain so that mutations in TD had a worse clinical outcome. The reasons were that mutations in TD could either abolish or reduce binding of p53 protein to DNA and transcriptional activation, and TP53 mutation in TD domain had dominant-negative effects (DNE) that inactivate TP53 wild type in some cases.37 Other researchers also found mutations in TD domain were associated with cancer-associated development.38 Not all missense mutations cause protein accumulation, while non-missense mutations are true loss-of-function mutations. Thus, missense mutations have generally been associated with higher protein expression compared with non-missense mutations.16

Some clinical trials showed us TP53 might be the potential to be a therapeutic biomarker. Studies on the role of TP53 mutation in breast cancer response to chemotherapy are conflicting.3942 Data on the association between TP53 mutations and endocrine therapy response were also controversial.4345 When it came to the association between hormone therapy and chemotherapy, some researchers found that adding hormone therapy to chemotherapy could improve the survival for TP53 wild-type patients not for TP53 mutation patients.46,47 While in our research, 84.7% of patients in TP53 wild-type group and 78.4% patients in TP53 mutant group all accepted adjuvant chemotherapy and endocrine therapy treatment in Table 3, and the distribution of patients with adjuvant chemotherapy was balanced in two groups, which did not exert an influence on the analysis of endocrine therapy and TP53 status. In our study, we also found TP53 mutations were associated with endocrine resistance. TP53-mutated patients had a shorter DFS than TP53 wild-type patients in the adjuvant endocrine therapy sensitive group. Previously, increased expression of estrogen-related receptor (ERR) was associated with increased levels of p53 in ER-positive cases. ER and ERR share only 33% homology in their ligand-binding domains, resulting in the insensitivity of ERR to tamoxifen.48 Additionally, TP53 wild-type tumors might be more responsive to endocrine therapy because this disrupts the ERp53 interaction and reactivates p53.49

The retrospective nature of our study resulted in a number of limitations. DFS might have influenced the survival analysis, which was retrospectively calculated. Additionally, we lacked matched primary and recurrence samples for analysis. Finally, we did not analyze p53 protein expression to verify our results.

In conclusion, TP53 wild-type MBC patients showed better survival than TP53-mutated patients in HR+/HER2 and TNBC cohorts. Missense mutations in the DBD of p53 appeared to be an independent prognostic marker for short DFS, while TP53 mutations were associated with endocrine resistance. This indicates that alternative therapies for HR-positive patients with TP53 mutations should be considered. Large-scale prospective studies are needed to verify our findings.

We can provide the original data in this manuscript upon request.

The written informed consent of this research had been provided by the patients, and this study was approved by the Medical Ethics Committee of Peking University Cancer Hospital & Institute (Approval No.2016KT47) according to the Declaration of Helsinki.

We thank Sarah Williams, PhD, from Liwen Bianji, Edanz Editing China, for editing the English text of a draft of this manuscript.

There were no funding sources for this work.

Jianjun Yu and Shidong Jia are employees and stockholders of Huidu Shanghai Medical Sciences, Ltd. The authors declare that they have no other competing interests.

1. Kastenhuber ER, Lowe SW. Putting p53 in context. Cell. 2017;170(6):10621078. doi:10.1016/j.cell.2017.08.028

2. Hainaut P, Pfeifer GP. Somatic TP53 mutations in the era of genome sequencing. Cold Spring Harb Perspect Med. 2016;6(11):a026179. doi:10.1101/cshperspect.a026179

3. Stephens PJ, Tarpey PS, Davies H, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486(7403):400404. doi:10.1038/nature11017

4. Basho RK, de Melo Gagliato D, Ueno NT, et al. Clinical outcomes based on multigene profiling in metastatic breast cancer patients. Oncotarget. 2016;7(47):7636276373. doi:10.18632/oncotarget.12987

5. Ellis MJ, Ding L, Shen D, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012;486(7403):353360. doi:10.1038/nature11143

6. Ren J, Wang B, Li J. Integrating proteomic and phosphoproteomic data for pathway analysis in breast cancer. BMC Syst Biol. 2018;12(Suppl S8):130. doi:10.1186/s12918-018-0646-y

7. Koak A, Heselmeyer-Haddad K, Lischka A, et al. High levels of chromosomal copy number alterations and TP53 mutations correlate with poor outcome in younger breast cancer patients. Am J Pathol. 2020;190(8):16431656. doi:10.1016/j.ajpath.2020.04.015

8. Wang D, Kon N, Lasso G, et al. Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. Nature. 2016;538(7623):118122. doi:10.1038/nature19759

9. Sullivan KD, Galbraith MD, Andrysik Z, et al. Mechanisms of transcriptional regulation by p53. Cell Death Differ. 2018;25(1):133143. doi:10.1038/cdd.2017.174

10. Marchenko ND, Hanel W, Li D, et al. Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-alpha3 binding. Cell Death Differ. 2010;17(2):255267. doi:10.1038/cdd.2009.173

11. Parry TE. Mutagenic mechanisms in leukemia and cancer: a new concept cytosine lack could be as mutagenic as cytosine deamination. Leuk Res. 2006;30(9):10791083. doi:10.1016/j.leukres.2005.12.019

12. Fernndez-Cuesta L, Oakman C, Falagan-Lotsch P, et al. Prognostic and predictive value of TP53mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 0298 Phase III trial. Breast Cancer Res. 2012;14(3):R70. doi:10.1186/bcr3179

13. Meric-Bernstam F, Zheng X, Shariati M, et al. Survival outcomes by TP53 mutation status in metastatic breast cancer. JCO Precis Oncol. 2018;2:15. doi:10.1200/PO.17.00245

14. Lopez G, Costanza J, Colleoni M, et al. Molecular insights into the classification of luminal breast cancers: the genomic heterogeneity of progesterone-negative tumors. Int J Mol Sci. 2019;20(3):510. doi:10.3390/ijms20030510

15. Silwal-Pandit L, Vollan HKM, Chin S-F, et al. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res. 2014;20(13):35693580. doi:10.1158/1078-0432.CCR-13-2943

16. Darb-Esfahani S, Denkert C, Stenzinger A, et al. Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy. Oncotarget. 2016;7(42):6768667698. doi:10.18632/oncotarget.11891

17. Luo Y, Huang W, Zhang H, et al. Prognostic significance of CD117 expression and TP53 missense mutations in triple-negative breast cancer. Oncol Lett. 2018;15(5):61616170. doi:10.3892/ol.2018.8104

18. Pileczki V, Pop L, Braicu C, et al. Double gene siRNA knockdown of mutant p53 and TNF induces apoptosis in triple-negative breast cancer cells. Onco Targets Ther. 2016;9:69216933. doi:10.2147/OTT.S110719

19. Li J-P, Zhang X-M, Zhang Z, et al. Association of p53 expression with poor prognosis in patients with triple-negative breast invasive ductal carcinoma. Medicine. 2019;98(18):e15449. doi:10.1097/MD.0000000000015449

20. Wolff AC, Hammond MEH, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med. 2014;138(2):241256. doi:10.5858/arpa.2013-0953-SA

21. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):27842795. doi:10.1200/JCO.2009.25.6529

22. Brando M, Maurer C, Ziegelmann PK, et al. Endocrine therapy-based treatments in hormone receptor-positive/HER2-negative advanced breast cancer: systematic review and network meta-analysis. ESMO Open. 2020;5(4):e000842. doi:10.1136/esmoopen-2020-000842

23. Newman AM, Lovejoy AF, Klass DM, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016;34(5):547555. doi:10.1038/nbt.3520

24. Cibulskis K, Lawrence MS, Carter SL, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31(3):213219. doi:10.1038/nbt.2514

25. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228247. doi:10.1016/j.ejca.2008.10.026

26. Zhang G, Wang Y, Chen B, et al. Characterization of frequently mutated cancer genes in Chinese breast tumors: a comparison of Chinese and TCGA cohorts. Ann Transl Med. 2019;7(8):179. doi:10.21037/atm.2019.04.23

27. Rossi G, Mu Z, Rademaker AW, et al. Cell-free DNA and circulating tumor cells: comprehensive liquid biopsy analysis in advanced breast cancer. Clin Cancer Res. 2018;24(3):560568. doi:10.1158/1078-0432.CCR-17-2092

28. Tao Z, Li T, Feng Z, et al. Characterizations of cancer gene mutations in Chinese metastatic breast cancer patients. Front Oncol. 2020;10:1023. doi:10.3389/fonc.2020.01023

29. Warner ET, Tamimi RM, Hughes ME, et al. Racial and ethnic differences in breast cancer survival: mediating effect of tumor characteristics and sociodemographic and treatment factors. J Clin Oncol. 2015;33(20):22542261. doi:10.1200/JCO.2014.57.1349

30. Olivier M, Langer A, Carrieri P, et al. The clinical value of somatic TP53 gene mutations in 1794 patients with breast cancer. Clin Cancer Res. 2006;12(4):11571167. doi:10.1158/1078-0432.CCR-05-1029

31. Liu Y, Xu F, Wang Y, et al. Mutations in exon 8 of TP53 are associated with shorter survival in patients with advanced lung cancer. Oncol Lett. 2019;18(3):31593169. doi:10.3892/ol.2019.10625

32. Petitjean A, Achatz MIW, Borresen-Dale AL, et al. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene. 2007;26(15):21572165. doi:10.1038/sj.onc.1210302

33. Boettcher S, Miller PG, Sharma R, et al. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science. 2019;365(6453):599604. doi:10.1126/science.aax3649

34. Shahbandi A, Jackson JG. Analysis across multiple tumor types provides no evidence that mutant p53 exerts dominant negative activity. NPJ Precis Oncol. 2019;3(1):1. doi:10.1038/s41698-018-0074-x

35. Giacomelli AO, Yang X, Lintner RE, et al. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat Genet. 2018;50(10):13811387. doi:10.1038/s41588-018-0204-y

36. Terada K, Yamaguchi H, Ueki T, et al. Full-length mutation search of the TP53 gene in acute myeloid leukemia has increased significance as a prognostic factor. Ann Hematol. 2018;97(1):5161. doi:10.1007/s00277-017-3143-2

37. Gencel-Augusto J, Lozano G. p53 tetramerization: at the center of the dominant-negative effect of mutant p53. Genes Dev. 2020;34(1718):11281146. doi:10.1101/gad.340976.120

38. Muscolini M, Montagni E, Caristi S, et al. Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain. Cell Cycle. 2009;8(20):33963405. doi:10.4161/cc.8.20.9910

39. Jackson JG, Pant V, Li Q, et al. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell. 2012;21(6):793806. doi:10.1016/j.ccr.2012.04.027

40. Bertheau P, Turpin E, Rickman DS, et al. Exquisite sensitivity of TP53 mutant and basal breast cancers to a dose-dense epirubicincyclophosphamide regimen. PLoS Med. 2007;4(3):e90. doi:10.1371/journal.pmed.0040090

41. Bertheau P, EspiƩ M, Turpin E, et al. TP53 status and response to chemotherapy in breast cancer. Pathobiology. 2008;75(2):132139. doi:10.1159/000123851

42. Bonnefoi H, Piccart M, Bogaerts J, et al. TP53 status for prediction of sensitivity to taxane versus non-taxane neoadjuvant chemotherapy in breast cancer (EORTC 10994/BIG 1-00): a randomised Phase 3 trial. Lancet Oncol. 2011;12(6):527539. doi:10.1016/S1470-2045(11)70094-8

43. Kai K, Nishimura R, Arima N, et al. p53 expression status is a significant molecular marker in predicting the time to endocrine therapy failure in recurrent breast cancer: a cohort study. Int J Clin Oncol. 2006;11(6):426433. doi:10.1007/s10147-006-0601-6

44. Yamashita H, Toyama T, Nishio M, et al. p53 protein accumulation predicts resistance to endocrine therapy and decreased post-relapse survival in metastatic breast cancer. Breast Cancer Res. 2006;8(4):R48. doi:10.1186/bcr1536

45. Bailey ST, Shin H, Westerling T, et al. Estrogen receptor prevents p53-dependent apoptosis in breast cancer. Proc Natl Acad Sci U S A. 2012;109(44):1806018065. doi:10.1073/pnas.1018858109

46. Ungerleider NA, Rao SG, Shahbandi A, et al. Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment. Breast Cancer Res. 2018;20(1):115. doi:10.1186/s13058-018-1044-5

47. Shahbandi A, Nguyen HD, Jackson JG. TP53 mutations and outcomes in breast cancer: reading beyond the headlines. Trends Cancer. 2020;6(2):98110. doi:10.1016/j.trecan.2020.01.007

48. Thewes V, Simon R, Schroeter P, et al. Reprogramming of the ERR and ER target gene landscape triggers tamoxifen resistance in breast cancer. Cancer Res. 2015;75(4):720731. doi:10.1158/0008-5472.CAN-14-0652

49. Konduri SD, Medisetty R, Liu W, et al. Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation. Proc Natl Acad Sci U S A. 2010;107(34):1508115086. doi:10.1073/pnas.1009575107

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Shower vs grower: What is the difference and does it really matter? – Medical News Today

How much a penis extends in length while erect varies from person to person. It may also change over time and with age. However, there is no evidence to suggest this affects an individuals health or sex life.

A shower or grower refers to how much a penis expands in length when erect compared with its flaccid state.

This article explores the science behind the terms, how common they are, and whether being a shower or a grower has any significant impact on health and sex life.

According to the popular colloquialism, a shower is a person with a penis that does not expand relatively significantly in length when it becomes erect.

In contrast, a grower is a person with a penis that grows relatively significantly longer when erect.

The erectile tissue of the penis comprises:

All of these allow the penis to become erect.

However, with age, the penis can lose tissue elasticity, which may affect how it stretches.

People may also experience inflammation and less blood flow to the penis as they age, which can affect erection.

A 2018 study involving 274 males found that age played a role in whether participants were a grower or a shower.

The researchers defined a grower as having a flaccid to erect penile length increase of 4 centimeters (cm) or more, while an increase of less than 4 cm indicated that a person was a shower.

All of the participants had previously undergone penile duplex ultrasound (PDDU) for erectile dysfunction.

Researchers measured flaccid penile length and gave participants a vasodilation drug before measuring erect penile length.

Growers had an average length change of 5.3 cm, while showers had an average length change of 3.1 cm. The mean age of the growers was 47.5 years, compared with an average of 55.9 years in the showers.

The research also reported that 37% of males who fell into the grower category were single, compared with 23% in the showers category, although this may also relate to age.

Growers also had a lower dose of the vasodilation drug.

There were no differences in the showers or growers regarding:

The study notes that confirming these findings requires more research, including larger scale, multicultural, and multinational studies.

The research did find an age difference between growers and showers. According to the International Society for Sexual Medicine, the way the penis changes as people age may account for this age differentiation.

The 2018 study found that out of 274 participants, 73 males (26%) were growers, while 205 males (74%) were showers, according to the researchers criteria on flaccid to erect penis length.

This suggests that showers may be more common, but there is not enough evidence to reflect the whole population.

Further studies are needed to confirm the findings.

People may be able to tell if they are a shower or grower without any tests.

If people have a penis that does not significantly change size between a flaccid and erect state, they may be a shower.

In contrast, if an individuals penis size changes drastically between a flaccid and erect state, they may be a grower.

People can measure their penis when flaccid, from the base to the tip. They can then take the same measurement when their penis is erect.

If the difference between the two measurements is greater than 4 cm, people meet the definition of a grower.

However, if the difference is less than 4 cm, people meet the definition of a shower.

The 2018 study found that age was the main factor in whether people were a grower or a shower, which suggests that people may change between a grower and a shower as they age.

When people age, collagen and elastic fibers in the penis decrease, which may affect whether they are a shower or grower.

Other penis changes can also happen as people age. Testosterone levels start to decline after a person reaches 40 years of age, which can cause the penis to shrink slowly.

Health conditions that impair blood flow can also affect penis color and erection.

According to the Kinsey Institute, flaccid penis size is not a reliable indicator for its erect size.

Generally, shorter flaccid penile lengths enlarge by a greater percentage than longer flaccid penile lengths.

The 2018 study found that growers had a larger erect penis size, measuring 15.5 cm compared with 13.1 cm in the showers group.

There is no research to suggest whether being a shower or a grower impacts a persons sex life.

However, concerns about penis appearance may affect sexual activity.

A 2016 survey looked at genital dissatisfaction in 4,198 males aged 1865 years and living in the United States.

Participants reported the lowest satisfaction with flaccid penile length, with 27% reporting dissatisfaction. Different demographics had no bearing on survey answers.

Those who reported dissatisfaction with their genitals reported less sexual activity, including less vaginal sex and less receptive oral sex.

If a person has concerns that their penis appearance is affecting their self-esteem, confidence, or sex life, people may find it helpful to talk with their partner or healthcare professional.

Being a shower or a grower refers to the change in penis length from a flaccid to erect state.

If people have a penis that increases significantly in length from a flaccid to erect state, they may be a grower. If there is no significant change, they may be a shower.

Some research suggests being a shower or a grower relates to age. Therefore a persons category may change over time.

However, there is no evidence to suggest that being a shower or grower affects their health or sex life.

Shower vs grower: What is the difference and does it really matter? - Medical News Today

Positive decision from SMC on Takeda’s breast cancer treatment – Pharmafield

The Scottish Medicines Consortium (SMC) has accepted Takedas PROSTAP SR DCS & PROSTAP 3 DCS (leuprorelin acetate) for use in patients with early breast cancer and advanced breast cancer.1,2,*,

Leuprorelin acetate belongs to a family of drugs called gonadotrophin-releasing hormone (GnRH) agonists which is used as adjuvant treatment in combination with tamoxifen or an aromatase inhibitor for endocrine responsive early-stage breast cancer and in advanced breast cancer suitable for hormone manipulation. In patients with breast cancer cells that have oestrogen receptors (ER) about 70% of cases of breast cancer3 it is important to lower the levels of oestrogen in the body to stop the cancer cells from growing.

Leuprorelin acetate works by suppressing the release of luteinising hormone (LH) and follicle stimulating hormone (FSH) and offers an additional treatment choice as its dosing regimen means that suitable patients with early-stage breast cancer require four clinic visits a year, up to 13 visits a year as with other GnRH agonists licenced for breast cancer.

GnRH agonists are an important part of treatment for women with oestrogen receptor positive breast cancer. In patients with early breast cancer, the combination of (GnRH) agonists with the peripheral oestrogen antagonist, tamoxifen results in a significant benefit in recurrence-free survival and overall survival, while the regime in those with advanced breast cancer has been shown to prolong progression-free survival.4

Dr Roger Henderson, GP in Dumfries and Galloway, said: As a GP I find that being able to use PROSTAP 3 DCS in women with early breast cancer helps to reduce both the number of times a woman with early breast cancer needs to visit the hospital and the stress associated with these, while maintaining efficacy of treatment.




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Positive decision from SMC on Takeda's breast cancer treatment - Pharmafield

Could metabo-oncology be the treatment modality of the future? – Drug Target Review

Jim Shanahan from SynDevRx explains why metabo-oncology treatment modalities could be the answer to a rise in metabolic disorders and cancers.

The global pandemic of metabolic disorders such as obesity and diabetes combined with an ageing population is leading to an upcoming tsunami of cancers, according to Jim Shanahan, Co-Founder, Vice President of Business Development and Director of SynDevRx.

Some cancers, such as breast, colon, liver, prostate and certain parts of lung, are sensitive to dysregulated metabolic hormones. In an interview with Drug Target Reviews Victoria Rees, Shanahan highlighted that metabolic hormone signalling pathways could be exploited to treat these cancers, including with SynDevRxs lead molecule, SDX-7320.

Shanahan began by explaining that the metabolic hormones insulin, leptin and adiponectin are the three primary signalling molecules that work through well understood cancer signalling pathways. Insulin primarily signals through the PI3K/AKT/mTOR pathway, leptin through the MAPK and JAK2-STAT3 pathways, while adiponectin is an agonist of the cyclic adenosine monophosphate pathway (cAMP) and protects against the phosphorylation and activation of notch signalling.

While these pathways have been thoroughly researched and described in many peer-reviewed research papers, Shanahan emphasised that how these externalities affect cancer growth and outcomes have been underappreciated.

Cancer looks for external signals that indicate there is sufficient energy for the cell to replicate. That is where the PI3K/AKT/mTOR pathway, the JAK-STAT pathway and other pathways come in, he said, as aberrant signalling by dysregulated hormones stimulates these pathways.

Having developed a lead molecule to fulfil this unmet need for oncology and metabolic disorders, Shanahan explained that SDX-7320 is in the fumagillin class of methionine aminopeptidase 2 (MetAP2) inhibitors. He explained that fumagillin is a naturally occurring biomass from the fungus named Aspergillus fumigatus Fresenius.

This was discovered by accident in the lab of Dr Judah Folkman in the mid-1980s a researcher named Dr Don Ingber had a contamination in one of his angiogenesis experiments that lead to the discovery. When he returned to the lab after the weekend, he found that there was a part of the dish that was clear of blood vessels. He was then able to isolate fumagillin and realised this could be a potential drug.

Working with Takeda in the 1990s, they developed a drug called TNP-470 that went into the clinic as an anticancer agent and demonstrated promising antitumour efficacy. However, while this drug was successful against late-stage tumours across a variety of different solid tumour types, it crossed the blood-brain barrier and induced central neural toxicity.

After several years, Takeda returned the technology to Dr Folkmans lab and the researchers investigated how to change its physical characteristics while maintaining its activity. One strategy they explored was conjugating the drug to a high molecular weight polymer backbone. By attaching TNP-470 to a polymer, the researchers developed a molecule called caplostatin.

Shanahan said that around this time, SynDevRx were exploring ways to improve the risk associated with drug development. Their aim was to identify drug classes that had been explored clinically and had proven human activity but had side effects that could be addressed.

Meeting with Dr Folkman, they began to work on the molecule. Shanahan said that SynDevRx brought in a polymer chemist and spent several years developing a new compound that is their current lead molecule.

the focus on metabo-oncology as a new and complimentary treatment modality could be critical to the improvements in patient outcomes

While the discovery of fumagillin and its potent antiangiogenic effects were reported in the early 1990s, Shanahan said that its mechanism of action was not elucidated until the late 1990s by researchers at MIT. He explained that this fumagillin drug class inhibits the metalloprotease class enzyme MetAP2, also known as protein 67 (p67), referring to its molecular weight.

Shanahan explained that there are two known methionine aminopeptidase isoforms, identified as MetAP1 and MetAP2. Both carry out code translational functions, meaning the enzymes sit on the ribosome and cleave the initiator methionine concurrent with protein synthesis and in preparation for post-translation modifications.

He said that MetAP2 has six identified exclusive AP2 substrates. These are: thioredoxin-1 (TRX-1); cyclophilin A (CypA); GAPDH; eukaryotic elongation factor-2 (eEF2); Rab37; and SH3BGRL.

The fumagillin drug class inhibits methionine aminopeptidase activity. When it is administered, it binds irreversibly to the histidine 231 pocket of MetAP2 and prevents the removal of methionine. Where MetAP1 will remove methionine for most other molecules, the exclusive MetAP2 substrates do not undergo the removal of their methionine; this has some interesting downstream effects, said Shanahan.

By inhibiting MetAP2, the methionine on these proteins is retained and therefore post-translational modifications that would add different fatty acids do not occur. The proteins do not fold properly, causing some to be ubiquitinated, while others are relocated to a different part of the cytosol because of changes to their solubility. Shanahan explained that these cause a cascade effect and have a downstream impact, including on the metabolic hormone signalling pathways.

By inhibiting MetAP2, you affect these six proteins then by impacting these six proteins, you get this pleiotropic set of effects, from very potent antiangiogenic effects, to changes to the cell signalling, to really potent effects on metabolic and lipid processing, said Shanahan.

We see this as a prime modality for treatment in combination with other modalities, highlighted Shanahan. He said that the researchers have so far completed Phase I clinical trials in solid tumours, which included a dose escalation to determine the maximum tolerated dose and schedule for Phase II and subsequent clinical phases.

We have demonstrated pre-clinically that by coming at the tumours with a multimodal attack, we can have a profound effect. Over the last five to 10 years, it has now been demonstrated through the immune system that external factors have a large impact on the fate of the cancer and the patient. With the increase in obesity and diabetes and rise of tumours sensitive to systemic metabolic dysfunction, Shanahan said that the focus on metabo-oncology as a new and complimentary treatment modality could be critical to the improvements in patient outcomes.

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Could metabo-oncology be the treatment modality of the future? - Drug Target Review

Men’s health: What is the best anti-ageing treatment? Q&A – Eastern Daily Press

A new clinic has launched in Norwich to focus on mens health, including male hormone replacement therapy, anti-aging treatments and erectile dysfunction.

Dr Gary Horn, consultant plastic surgeon and mens health expert, answers some of the questions he is most frequently asked:

Q: What are the benefits of attending a specialist mens clinic?

We are able to focus on mens health as a whole as we have a more comprehensive understanding of how the whole body is working and how we can make it better. If someone comes to me for liposuction, for example, I can ask them about why they think they have so much fat and find out more about their diet and look into their hormone levels. Some products work better for men or for women they are two different types of patient and need specific advice and treatment.

A patient of Dr Gary Horn, pre-reshaping operation and post-operation.- Credit: Dr Gary F. Horn

Q: What is the main cause of erectile dysfunction?

There are different causes. I look into lifestyle, weight and whether someone smokes, for example. As well as conducting a physical examination, I might end up ordering blood tests and checking testosterone levels. The problem might be neurological or vascular, where vessels in the penis have become smaller. This is often is the first sign of having a more general cardiovascular problem, which could go on to affect the heart or other vessels in the body. I may therefore need to refer this person to a cardiologist. Erectile dysfunction can also follow prostate surgery, or it can be a psychological issue.

Q: How can I improve my erectile dysfunction?

There was a time when Viagra was one of our only options, but now we can also treat erectile dysfunction with low-intensity shock waves and that can be used alone or combined with injections of stem cells which is becoming quite popular.

Q: Is male hormone therapy safe?

Yes, absolutely. But you dont give it without carrying out certain checks. It starts with a questionnaire; then a physical examination and then, of course, there is a blood test to assess different things, including testosterone levels, which can then be managed with oral or injectable applications.

Dr Gary Horn, consultant plastic surgeon and mens health expert. - Credit: Dr Gary F. Horn

Q: What are the signs that I might need hormone replacement therapy?

Feeling tired all the time; not being able to complete different activities or do sport; having problems concentrating and not being able to finish tasks can all be signs that you may need hormone replacement therapy. There can be sleeping issues, a reduction in libido or problems maintaining a proper erection. The majority of men requiring hormone replacement therapy will be over 50 but anyone from 20 to 80 can have an assessment.

Q: What is the best anti-aging treatment for men?

Apart from hormone replacement therapy and the other supplements that go along with it, peptides etc, as a plastic surgeon I can offer non-surgical treatments such as facial injections, including fillers and botox, and maybe different types of cream to maintain and restore texture of the skin. On the surgical side, I can offer eyelid surgery, facelifts, rhinoplasty and hair transplants.

Q: What other treatments do you offer?

I have a reshaping clinic for men. Apart from looking at exercise and diet, I also offer surgery such as scar revision or laser liposuction and high definition liposuction for people who want to look more athletic. I can carry out tummy tucks and body lifts, when patients have had massive weight loss and can offer implants, ranging from pectoral implants to calf, buttock and bicep implants.

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Men's health: What is the best anti-ageing treatment? Q&A - Eastern Daily Press

Perceptions and experiences of women with premature ovarian insufficiency about sexual health and reproductive health – BMC Blogs Network

In this study, 16 women with POI, aged from 27 to 46years old, and a POI duration of 125years were interviewed. The age range of women at the time of POI and definitive diagnosis was 13 to 40years. Among the participants, three women had remarried, two of whom had divorced after diagnosis POI due to infertility. The level of education of women was from primary to doctorate. The cause of the POI was mainly unknown, but in 2 participants, POI occurred after cancer treatment and a participant afflicted to POI following an autoimmune disease. The Other demographic characteristics of the participants are presented in Table 1.

After content analysis of the interviews with a focus on the perception and experience of women with POI of reproductive-sexual health, four categories emerged (endangerment of women's health, psychological agitation, disruption of social life disturbance in sexual life), explained as follows.

The results showed that all participants were concerned about the effects of decreased ovarian function and changes in hormone levels on their future health.

This main category consists of four subcategories (irregular menstruation, emergence of menopausal symptoms, infertility, signs of early aging) as follows:

Menstrual cycle changes (irregular menstrual cycle, primary amenorrhea or sudden cessation of menstrual bleeding) are one of the first suspicious signs of POI in women that resulted mostly to consult a physician.

One of the participants, who had POI for 8years, said:

The first time my period became irregular, I went to the doctor and she told me that I should take hormone therapy. Before that, I had regular periods, but after 2-3years, I did not have regular periods, and the doctor said there was a possibility of premature ovarian insufficiency (p. 9, 43 y).

Another participant who had regular periods for 27years, stated:

Suddenly, I did not have another period. I went to the doctor. I had an ultrasound and found that I no longer had an ovum (p. 3, 46 y).

A number of participants did not experience menstruation at puberty and had primary amenorrhea, or spotted only once.

One participant that had a spontaneous POI, said:

I did not menstruate at all from the beginning, like my sister (p. 1, 30 y).

Following changes in hormone levels, participants experienced some degree of menopausal complications.

One of the participants who had POI following treatment of cancer, said:

Dry uterus bothers me a lot, especially during sex (p. 10, 46 y).

Another participant who had POI for 10years, stated:

It was very hard at first. In particular, flushing much annoyed me (p. 11, 44 y).

The other participant had POI with an autoimmune disease origin and had one live child with successful spontaneous pregnancy, said:

Premature ovarian insufficiency reduced libido (p. 8, 35 y).

This issue was the main concern of most participants and one of the main complaints of participants with POI was infertility.

A participant who had underwent chemotherapy for cancer treatment in 2008 and had lost her fertility for 11years, said:

I did not know before, but when I inclined to have a baby, I later realized that POI result to infertility (p.2, 4 y).

Another woman who had divorced due to have a 17-year-old history of infertility and remarried, stated:

When I did ultrasound check for infertility, the report showed that my ovaries are very small like as ovaries in menopause women (p.12, 43 y).

Due to decreased levels of estrogen in afflicted women, some of them reported conditions like loss of beauty, wrinkling of the skin and decreased feeling of youth.

One participant, who had been suffering from premature ovarian failure since the age of 22 and for 10years, said:

My first concern was this: I was no longer beautiful (p.16, 34 y).

The other participant that is pregnant currently with donated egg, said:

Eventually you f1eel the changes in your body. For example, you notice wrinkles on your skin (p.9, 43 y).

One participant that had POI for 13years, stated:

Although I am 37years old, I do not feel young I feel aging and I am old (p.13, 38 y).

POI occur in women is less than 40years old, while the normal age of menopause in women is 4555years. Hence the acceptance of POI for participants was accompanied with psychological reactions.

This main category consists of three subcategories [anxiety reaction, mood reaction, agitation in the selection of childbearing] as following:

Participants experienced an onslaught of negative emotions after being diagnosed with POI by a physician, including feelings of despair, depression, a sense of aging, and shock from menopause.

A participant who had POI since the beginning of her marriage and for 5years said:

When it told me to get menopause, I tried for traditional medicine but, due to that was not successful, I was disappointed (p.7, 37 y).

Another participant expressed:

At that time, when I realized my problem, I became depressed and thought that I was the only one. It had a great effect on my mood (p.1, 30 y).

A participant told in despair:

Because I dont have children, I be early menopause, that is, I got oldThese are other signs of aging (p.4, 46 y).

Another participant, who had POI since the age of 22 and had been struggling with it for 12years, said:

I really didnt expect such a thing at all. I was planning to have a planned pregnancy. But the exact opposite happened. The shock was so great it was the biggest shock of my life I have ever experienced (p.16, 34 y).

Popular reactions in afflicted women with POI were included: feeling of uncertainty of future conditions, fear of disease outcome, feeling eternal problems [eternal infertility] negative effect on mood and weakness of the nerves.

One of the participants expressed with surprise and confusion:

I have no idea about the future. I'm very confused. I dont know what will happen to me (p.4, 42 y).

Also part of the conversation with a participant was as follows:

I think more about the fact that this [pregnancy] may never have happened to me (p.14, 27 y).

Another participant said:

Premature ovarian insufficiency makes me angry quickly. I'll get mad soon (p.10, 46 y).

A participant told:

I am worried that I will not have any problems after the age of 40. I am afraid of the consequences of this disease (p.2, 34 y).

Considering that the options available to solve the problem of infertility in women with POI are currently limited and unfortunately there is no definitive treatment for female infertility in these women and the issue of cell therapy is being researched on animal models and do not use so far on humans, the only options offered to couples are the use of donated egg and adoption. Nevertheless, some participants opposed to accept them. If a participant commented on the issue of donated egg as follow:

I think to myself about the baby Because the egg is not mine, I am afraid I will not feel like a mother when she was born. Also she continue:

I must convince myself about this pregnancy and deal with it (p.15, 43 y).

Spiritual aspects of donated egg were important for some participants.

A participant was concerned about this, saying,

I do not care if I conceive with the donated egg, but its religious issue is important to me. It bothers me a little (p.1, 30y).

Moreover, it was important for a number of participants to know that the donor be a familiar person.

A participant stated:

I'm happy to have an ovum from my sister rather than a stranger (p.2, 34 y).

Most participants expressed POI has disrupted the social aspects of their lives. Social isolation, having privacy, unconscious jealousy and seeking support are four subcategories that related to this main category and be explain as follows:

Patients stated that they were reluctant to be in public because of impatience, a tendency to be alone, and to become nervous about social relationships.

A participant said:

I'm not bored totally. I like to be at home, to be alone (p.13, 38y).

Most afflicted women tended to maintain their privacy for fear of being judged by others, the importance of hiding the problem of infertility and believing in the privacy of the subject.

Some of the statements of the participants are as follows:

It is important for us that the donated egg is kept secret. Because if I get a donated egg, I will not be my own child and I will not judge (p.6, 34 y).

This is a personal matter and has nothing to do with anyone (p.13, 38 y).

Some participants expressed a reluctance to associate with families that have children and they are jealous of pregnancies in others or seeing children.

If a participant that had POI for 26years, said:

I was upset when I saw that others had children and became pregnant. Because I have a problem getting pregnant myself (p.12, 43 y).

This issue was the most important item that as a motivation factor helped afflicted women not only to accept complicated condition but also to pursue infertility treatment seriously. According to participants, the support of husbands, family and friends helped to increase hope and reduce psychological threat to women. In the meantime, the supportive role of the husbands was very prominent for women, as one of the participants that had POI for 18years, said:

I am most supported by my husband. If he did not help me, I wouldn't be able to control the situation and control myself. He encourages me to continue my treatment and does not let me Disappointed. (p.5, 30 y).

Another participant stated:

My sister, like me, had an early menopause. He tells me you are young now. Get treated sooner. You get the result. She is very hopeful and encourages me (p.7, 37 y).

In most patients, POI had a negative effect on the couple's sexual relationship.

Due to changes in hormone levels, women experienced sexual function disorders such as dyspareunia, reduced libido, and anorgasmia. These factors caused women to worry about the stability of their married life and the instability in marriage that they formed two subcategories from three.

In contrast, a number of other patients reported that POI had no effect on their sexuality.

The third subcategory was the ambivalence sensations that all of them explained as follows:

The disease had a negative effect on sexual intercourse and sexual pleasure of affected women and on the other hand, sexual intercourse was important for the husband. As a result, a number of participants were concerned about the stability of married life.

A participant stated:

Before my problem, I had sexual desire, but now I do not have it at all, and this causes us to have sex more often with fights, and it has disrupted our relationship (p.10, 46 y).

Beside to decreased sexual satisfaction in couple, infertility also, leaded to some women felt insecure and worried about divorce. A few others threated to divorce from the spouse's family, and some be feared from their husband remarriage.

A participant said:

From the beginning of my marriage, I was stressed until now because I did not have children. My concern is to have children and that our marriage will fall apart (p.1, 30 y).

Another participant stated:

Now my mother-in-law can easily divorce me. She says either bring a child or we will divorce you (p.4, 42 y).

The cessation of menstrual bleeding on the one hand created negative feelings for the participants and caused a kind of psychological pressure on them, but on the other hand had different effects on the participants spouses such as sexual satisfaction and helping to improve sexuality. Moreover, in the context of Iran religiously, having sex during a woman's period is against the Sharia, some patients even said that their partners were delighted with stopping in their menstruation to have sex freely. Therefore, these conditions caused women had been had a dual feeling about the negative impact of POI on their sexuality.

One of the participants said:

My husband says how good I am. I am comfortable without a condom. No man is happier than me (p.5, 31y).

Another participant, who has been suffering from POI since the age of 22 and for 12years, said:

We are trying to cope with and we are trying to control and improve the condition ourselves. For example, we use lubricant for dyspareunia (p.16, 34 y).

Or another participant said:

My husband thought POI meant we could no longer have sex. But when he saw that we had no problem with sex, he said it didn't matter. The important thing is that we can have sex without any limitation (p.11, 44 y).

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Perceptions and experiences of women with premature ovarian insufficiency about sexual health and reproductive health - BMC Blogs Network

How multi-disciplinary treatment of cancer is giving hope to patients – The Standard

Dr Miriam Mutebi, Consultant Breast Cancer Surgeon.

What started as a lump in her left breast early last year would mark the beginning of Sylvia Sandagis fight for survival against cancer.

The 40-year-old was having a bath when she noticed the swelling. And there was some pain.

I thought Id probably been hit by something. I went to hospital and an ultrasound was done. The doctor said blood was not flowing in the lump and recommended a biopsy, Sandagi says.

Five days later, the biopsy results were out and the swelling was found to be cancerous. I remember that day, on August 31. I didnt want to believe what Id just heard. But I didnt cry. All I could think of was when I would start treatment and who would take care of my daughter should I get weak, especially because her father does not live in Kenya."

The mother of one is among patients under the care of various clinicians at Aga Khan University Hospitals Multidisciplinary Breast Cancer Clinic, which is touted as the hope for those in need of cancer treatment.

Sandagi says an oncologist referred her to Aga Khan where she was admitted to the centre and started her treatment. What I love about multidisciplinary clinic is a patient is not attended to by one doctor, or one medical professional," she says.

I found several experts when I came. That is when I learnt my cancer was in Stage Four. They told me the rate of survival for breast cancer is high. The doctors said the drugs they would give me were effective and that I would survive.

Horror stories

Sandagi is currently taking the drugs which will also ensure her oestrogen levels are reduced as breast cancer feeds on it. After six months, the doctors will decide whether she will need chemotherapy or radiotherapy.

Many patients have interpreted Stage Four cancer to mean death. However, Sandagi says the treatment she has been receiving has reduced the pain and shes living a near-normal life.

What people share about cancer are more of horror stories. It is true I have cancer and it is in Stage Four. But there is no pain. Im not bedridden. The only time I remember I have cancer is when someone mentions it or when Im taking my medicine, Sandagi says.

She has never told her eight-year-old daughter she is suffering from cancer because of the stigma attached to the disease by some communities.

All that I told her was Im unwell and that Ill be going to the hospital more often. I fear talking to her about cancer because when she tells people about it, the horror stories they will tell her will scare her. Shell think Im dying. I dont want that to happen, she says. I will fight. I dont want to die. I want to see my daughter grow up.

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Aga Khan launched the Multidisciplinary Breast Cancer Clinic to improve treatment. At any given time, a patient is able to be attended to by a breast surgeon, a medical and a radiation oncologist in one sitting.

It takes a village to care for a cancer patient. But here, we have decided to bring the village to the patient with our multi-disciplinary treatment, says Dr Mansoor Saleh, the founding chair of the Department of Hematology-Oncology at Aga Khan University.

He adds: Here, we have a breast cancer surgeon, a pathologist who helps with diagnosis, a radiologist who helps with imaging, a medical oncologist who does chemotherapy, and a radiation oncologist who gives radiation therapy, all in one place, at the same time. This enables the patient to get a unanimous report. When each doctor attends to a patient by themselves, they work in silence and the patient may not get the full picture.

Dr Miriam Mutebi, a breast surgical oncologist at Aga Khan, notes there are many types of breast cancers with the distinguishing factor being either hormone-positive breast cancers or hormone-negative breast cancers.

Think of a breast cancer cell as having three little spikes or receptors on its surface. These receptors act like doors to the cell and can influence how the cancer cell behaves. Different hormones act like keys that sit in the doors to the cell causing activity to increase or reduce, Dr Mutebi says.

The receptors we see on the surface of a breast cancer cell are ER-estrogen receptor, PR-progesterone receptor and HER-2 receptor (a special molecule on the cell). Its the presence or absence of these three doors or receptors that determines the type of breast cancer one has.

Mutebi says this is important information that must be established before treatment starts as it has implications on how the cancers behave and determines the treatment options.

The most common are the hormone-positive breast cancers (ER positive, PR positive) that account for between 60-70 per cent of cancers. When we say a breast cancer is hormone-positive, we mean female hormones in the body will act as keys to these cancer doors and encourage the cancer to grow.

"Therefore, as part of treatment after surgery, chemotherapy or radiotherapy, a patient may need medicine for five to ten years to minimise chances of the cancer recurring.

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How multi-disciplinary treatment of cancer is giving hope to patients - The Standard