Basser Center takes aim at BRCA – Penn: Office of University Communications

Posted: November 1, 2019 at 12:41 pm

In October 1994 in the journal Science, scientists published a strong candidate underlying heritable breast cancer. Their evidence led them to mutations in the BRCA1 gene, located on a stretch of chromosome 17. A bit more than a year later, researchers traced a second suspect, BRCA2, to chromosome 13, reporting their find in Nature. Together, the transformative discoveries set off a firestorm of oncology research, andjust as significantinjected hope for the future into the lives of millions who may carry mutations in one or both genes.

Twenty-five years later, the Basser Center for BRCA within Penn Medicines Abramson Cancer Center relentlessly continues to offer up this hope, fostering advancements in science and translating them to improve lives by emphasizing outreach, prevention, early detection, treatment, and survivorship of BRCA-mutation related cancers.

The Basser Center is focused entirely on BRCA1 and BRCA2, but within that we have this broad scope of everything from basic science to clinical care to increasing awareness, says Susan Domchek, the Basser Centers executive director. So at the same time that were hoping to figure out the basic biology of why a BRCA1 mutation leads to breast cancerand theres a lot about that that we dont know yetsimultaneously we want to use the information that we already have to help people in real time.

These parallel approaches arose from the vision of Mindy and Jon Gray, Penn alums whose initial $30million gift established the Basser Center in 2012. The Centers name honors Mindy Grays sister, Faith Basser, who died from BRCA-related ovarian cancer at age 44. Including subsequent donations, the Grays have committed a total of $55 million in support of the Centers work.

True to their vision of a multi-faceted operation, in the ensuing seven years the Center has facilitated a steady clip of scientific discovery, encouraged community building around the issue of BRCA awareness, and established support systems to aid people who are considering getting tested or weighing challenging decisions about how to proceed after finding out their status.

When we talk about the lifesaving research and innovation that is happening on campus, the Basser Center is one of Penns most important initiatives, says Penn President Amy Gutmann. Its because of Mindy and Jon Grays visionary philanthropy that we can say this so proudly today.

BRCA1 and BRCA2 are named for their association with breast cancer, but mutations also increase risks of ovarian, pancreatic, and prostate cancer, among others. Everyone possesses copies of BRCA1 and BRCA2 genes; the risks arise when their sequence is altered through a genetic mutation, which can be passed from generation to generation.

In their normal form, both genes serve a protective function, creating proteins that work within complex molecular machines to repair damage to DNA. When a mutated gene gives rise to an altered version of one of these proteins, DNA damage builds up within cells, greatly increasing the risk of cancer. Women with a mutation in BRCA1 or BRCA2, for example, have up to a 75 percent chance of developing breast cancer in their lifetime, compared to a 12 percent risk in the general population; similarly, the risk of a carrier developing ovarian cancer is up to 50 percent, compared to a risk under 2 percent in the general population.

When we talk about the lifesaving research and innovation that is happening on campus, the Basser Center is one of Penns most important initiatives. Penn President Amy Gutmann

As the scientific community marks the 25th anniversary of the discovery of the BRCA genes, Basser Center scientists are notching new breakthroughs in understanding the science of heritable cancers. Roger Greenberg, director of basic science for the Basser Center, says support for fundamental laboratory science has already paid off in a number of ways.

There has been so much exchange, so many more interactions on campus because of being here, he says. This had led to grants and papers, clinical trials and philanthropy and publications. Its such an incredible impact, and theres a lot more to come.

Greenberg is a leader in studying how DNA damage repair mechanisms are affected by mutations in BRCA1 and BRCA2, and how this impaired function affects the way people respond to therapy. In recent work, his lab has begun to focus on a relatively new category of drugs called PARP inhibitors. A heartening development in the BRCA field, these agents take advantage of a vulnerability in cells with BRCA mutations, building up so much DNA damage that the cells ultimately die.

Its a very exciting field that continues to grow, says Greenberg.

His labs work has also helped unravel mysteries of how DNA damage influencesthe immune system'sresponse to cancer cells, and how PARP inhibitors themselves create immune responses.

These kinds of insights can absolutely contribute to more personalized care, Greenberg says.

An expert on cancer genetics, Katherine Nathanson, director of genetics for the Basser Center, has also seen the growing role of immunology in cancer science during her years at Penn. Nathanson, who is also deputy director of Penn Medicines Abramson Cancer Center, has contributed extensively to the fields knowledge base around cancer risks associated with particular genetic variants. In recent years, shes also brought her genetics expertise to bear in the context of new breakthroughs in understanding the role of the immune system in controlling cancer.

One thing is clear, says Nathanson. It used to be that cancer immunology and cancer genetics were very far apart. Now there is a lot of intersection and collaboration.

Nathanson was recently awarded a $3 million grant from the Gray Foundation, which is led by Mindy and Jon Gray, to probe more deeply into immune system function in BRCA mutation carriers and in those with related cancers. Those studies have the potential not only to shed more light on BRCA cancers, but on the function of the immune system in general.

Ronny Drapkin, Bassers director of gynecologic research, conducts research that straddles the lab and clinic. A dozen years ago, when Drapkin was completing his postdoctoral training and starting his own lab, he studied the tissues from women who were having prophylactic surgerymastectomies and oophorectomiesafter finding out they possessed a BRCA1 or BRCA2 mutation. His investigations revealed that many cases of ovarian cancer may in fact originate in the fallopian tubes.

That scientific observation has the potential for profound implications for patient care. In addition to be a paradigm shift in science, its also caused a shift in treatment, he says. And that was very much ushered in by the discovery of the BRCA genes 25 years ago.

The current standard of care for women with BRCA1 and BRCA2 mutations is to have their ovaries removed to reduce their cancer risk at approximately age 40. Thus, women experience what is known as surgical menopause, compressing what is normally a 5 to 7 year process into the space of a few hours. This includes experiencing all the menopause-related morbidities of heart and bone disease. Today, two multi-center clinical trials, including one enrolling patients at Penn, are investigating an alternative practice, in which a womans fallopian tubes are removed at a younger age, after child-bearing, and her ovaries are preserveduntil her 50s. These studies are extremely important to evaluate whether this approach is safe and effective.

For this disease, we dont have early detection, we dont have mammography or colonoscopy, Drapkin says. For me its been personally gratifying to see this concept progress into the clinic.

Efforts by Domchek and others in the Basser Center have led to new paradigms for treatment of BRCA-related cancers. These Penn-led studies have helped usher in three FDA approvals related to PARP inhibitor drugs: olaparib for BRCA1- and BRCA2-associated ovarian cancer and metastatic breast cancer, and rucaparib for BRCA1- and BRCA2-associated ovarian cancer. These approvals have transformed care for ovarian cancer, for which there are few other options available. And olaparib represented the first FDA-approved therapy specifically for BRCA-related breast cancer.

More recent findings spearheaded by Basser Center investigators have also suggested PARP inhibitors hold promise for treating pancreatic cancer in patients with specific genetic mutations, including in BRCA1 and BRCA2.

A major priority of the Basser Center is to take concepts not only from the lab to the clinic, but also from the clinic to the public. Since 2012, through more than 50 patient- and public-facing events, the Center has spread lifesaving messages about the importance of genetic testing to targeted communities. The Center holds an annual scientific symposium, attracting the worlds experts on inherited cancers to Penn, and a monthly seminar series to enhance the profile of this type of research more locally. The Basser Global Prize, endowed by Mindy Grays sister, Shari Potter and her husband Len Potter, awards $100,000 annually to a visionary researcher working on BRCA1 and BRCA2, while smaller grants support the work of earlier-career researchers pursuing investigations on the topic.

Thats helped nucleate expertise here at Penn, says Greenberg.

The Centers Basser Leadership Councila group of roughly 20 of the Centers strongest advocates and supportersand Young Leadership Councilwith more than 100 members across the U.S. and beyondamplify these messages so they reverberate out from Penn into communities worldwide.

The Young Leadership Council, for example, enables peer support and discussions of the issues that young people face, such as when confronting a decision about prophylactic surgeriesto reduce cancer risk.

Many of our YLC members have undergone prophylactic surgeries or are thinking about them, and they discuss the challenges of this, what that means for dating,intimacy, and family planningfor example, says Laura Ferraiolo, seniordirector of development forthe Basser Center whose team helps oversees the councils' efforts.

The group has its own, monthlye-newsletter and holds frequent events, such as a cycling fundraiser in three cities earlier this month.

Similarly, the Basser Leadership Council supports the Centers mission in a number of ways. Many of them are either affected by a mutation or have someone in their family who is, and are incredibly engaged in this work, says Beth Stearman, administrative director for the Basser Center. They are lay leaders who support us in promoting outreach events and utilize their personal and professional connections to extend our mission to people in different communities across the country.

Emphasizing the value of knowing ones BRCA status has been a through line of the Centers outreach. An emerging priority, therefore, has been to offer education on genetic testing to primary care physicians, many of whom, Domchek explains, are uncertain of when to recommend testing, and for which patients.

My last name is Domchek, its ethnically ambiguous, she explains. Ive not been asked if Im of Ashkenazi Jewish ancestry and that is a known risk factor for BRCA mutations. Why is that? Were trying to do a lot more provider outreach so physicians are educated and comfortable with these issues.

Roughly one out of 40 people with Ashkenazi Jewish ancestry have a mutation in BRCA1 or BRCA2. The Basser Center has accordingly devoted significant energy into reaching that community. A poster campaign to promote the importance of genetic testing reached 1,500 synagogues in the Centers early years, and efforts through the Basser Leadership Council and Young Leadership Counciland an emerging Parents Leadership Community aimed at issues involved in raising families as a carriercontinue those and related efforts.

Meanwhile, efforts are ramping up in the Center to continue spreading access to genetic counseling and testing across other at-risk populations.

In a New York Times op-ed published earlier this month, attorney and writer Erika Stallings noted that Mathew Knowles, Beyoncs father, had been diagnosed with breast cancer and possessed a genetic mutation in the BRCA2 gene that dramatically increased his cancer risk. Domchek is serving as Knowless oncologist, and recently appeared with him on The Dr. Oz Show, calling attention to the risk that menshare from inherited mutations.

Several years ago, Stallings, a founding co-chair of the Basser Centers Young Leadership Council, discovered that she, too, had a BRCA2 mutation, and took action to lower her risk by undergoing a double mastectomy.

While BRCA mutations are more common in people with Ashkenazi Jewish heritage, its also true that BRCA1 and BRCA2 mutations occur in people of any background, male or female, at a rate of roughly 1 in 300. Black men and women like Knowles and Stallings are no exception. And neither are Latinx individuals, like former White House aide and founder of the Well Woman Coalition Alejandra Campoverdi, a BRCA2 mutation carrier who has partnered with the Basser Center to launch LATINX & BRCA, a campaign to connect the Latinx community with resources related to BRCA-related disease.

Making its official launch at next months BasserJean Bash, a major biennial fundraising event for the Center, LATINX & BRCA has already enabled the translation of many of Bassers educational materials into Spanish, including a list of Spanish-speaking genetic counselors. The Center is planning to spin off a similar effort focusing on the African-American community next year, also working through the Penn Center for Community Health Workers to better connect with people in the Philadelphia area and across the nation.

As momentum around the importance of genetic testing builds, the Basser Center is working to meet the need for responsible genetic counseling to contextualize the testsand supporting people in their decisions of how to act on the results. The Basser Center itself has six genetic counselors on staff, but is also trialing non-traditional ways of getting appropriate counseling to patients.

Everybody working in this space is looking for alternatives to traditional genetic counseling, says Stearman.

In one effort, the Penn Telegenetics Program, launched in 2012 by Angela Bradbury, an associate professor of medicine, medical ethics, and health policy, is using a research-based approach to allowing individuals to access genetic counselors over the phone or through two-way video conferencing. Bradbury and colleagues work has shown that offering such remote cancer genetic counseling sessions can dramatically boost patient participation in counseling. Last year Abramson Cancer Center launched a pilot effort to broadly provide telegenetic counseling services to patients and providers.

Along these lines, Domchek is helping lead the BFOR study (BRCA Founder Outreach Study) that connects at-risk individuals in the Ashkenazi Jewish community with a digital health platform that takes users through disclosures and informed consent procedures through a sophisticated interactive display. Participants can be linked with their primary care providers to receive their results.

This is different from a direct-to-consumer model where people are doing this outside the medical system, Domchek explains. Were trying to create a hybrid model where its still embedded in the medical system.

At the same time that were hoping to figure out the basic biology of why a BRCA1 mutation leads to breast cancerand theres a lot about that that we dont know yetsimultaneously we want to use the information that we already have to help people in real time. Susan Domchek, the Basser Centers executive director

Another study called Point of Care has offered genetic testing to patients already being treated for metastatic prostate and pancreatic cancer, using an 8-minute video to deliver a streamlined counseling session to this specialized population who are already all-too-familiar with the possible risks of a mutation. Yet possessing that information could guide critical treatment decisions tailored to the patients cancers genetic profiles. Testing among this population rose nine-fold after the intervention.

Were still not testing all the people who should get tested, says Domchek.

Basser leaders all stress that the Centers unique efforts wouldnt be possible without its donor-supported model.

I think people dont realize that the kind of infrastructure we have built is really hard to fund out of grants, says Nathanson. And by infrastructure, she means in large part human capacity, for recruiting patients, consenting patients, biobanking samples, getting the clinical data, putting that data in a database, maintaining the database, doing longitudinal follow-up. We cant fund our outreach, our patient awareness off of grants. Philanthropy is critical to supporting these efforts.

And theyre not lowering their sights as they look ahead.

We are continuing to grow the Center, bringing in people who have the expertise we dont currently have, says Drapkin. With our vision for the future, I see us as the epicenter for this kind of research in the world. There are few places that have the basic science, the translational and clinical science that we have. Its rare that you find expertise across the spectrum that can be applied in a way that gets to the patient. We have that here.

Susan Domchek is the Basser Professor in Oncology and executive director of the Basser Center for BRCA at the University of Pennsylvania Perelman School of Medicine.

Roger Greenberg is the J. Samuel Staub, MD Professor, director of the Penn Center for Genome Integrity, and director of basic science for the Basser Center for BRCA at Penn Medicine.

Katherine Nathanson is deputy director of the Abramson Cancer Center, the inaugural Pearl Basser Professor for BRCA-Related Research, and director of genetics for the Basser Center for BRCA at Penn Medicine.

Ronny Drapkin is the Franklin Payne Associate Professor of Pathology in Obstetrics and Gynecology, director of the Penn Ovarian Cancer Research Center, and director of gynecologic cancer research for the Basser Center for BRCA at Penn Medicine.

Beth Stearman is administrative director for the Basser Center for BRCA at Penn Medicine.

Laura Ferraiolo is senior director of development for the Basser Center for BRCA atPenn Medicine.

Homepage photo: Tianpeng Zhang, a postdoctoral researcher in Roger Greenbergs lab, takes fluorescence microscopy images to investigate how the genome is faithfully maintained as it is replicated, and how damage can arise. Zhang and other members of the lab contribute to the basic science research that supports translational discoveries in the Basser Center.

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Basser Center takes aim at BRCA - Penn: Office of University Communications

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