Finding the Family Link
Research initiatives target hereditary cancers
The discovery of the correlation between mutations in the genes called Breast Cancer 1 (BRCA 1) and Breast Cancer 2 (BRCA 2) and hereditary breast, ovarian, pancreatic, and prostate cancers has given this generation hope that one day their children may be able to prevent cancer.
More than a decade ago researchers identified that BRCA 1 and BRCA 2 genes, when changed or mutated, increase the risk of certain cancers. Since this discovery, much effort has been directed towards investigating fundamental questions about hereditary cancer risk and the role of BRCA mutations. And while the answers to these and other related questions may lead to better early detection methods and treatments, our understanding of the roles these mutations play is still in its infancy.
Thanks to a $1 million commitment from the David S. and Karen A. Shapira Foundation, a new program at the University of Pittsburgh Cancer Institute (UPCI) and Magee-Womens Hospital of UPMC is addressing these key questions. The gift is structured as a matching grant to raise an additional $1.5 million from individuals and foundations. UPMC is matching these gifts on a dollar-for-dollar basis, for an overall goal of $5 million. 
The Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program, named to honor the parents of David Shapira, chairman, president, and chief executive officer of Giant Eagle, Inc., is focused on advancing the understanding, prevention, early detection, and treatment of BRCA mutation-associated malignancies.
“The program is one of the most focused of its kind,” said Ronald Herberman, MD, Director Emeritus of UPCI and UPMC Cancer Centers. “The more we learn about these mutations, the better chance we have to target high-risk people and to find innovative ways to reduce their cancer risk.” Research projects in the program include:
- a comprehensive registry and specimen bank to facilitate BRCA 1- and BRCA 2-related research
- proteomics research into the discovery of breast cancer biomarkers
- a multi-marker approach for a blood test for early detection of breast or ovarian cancer in BRCA-mutation-positive women
- cancer-risk prediction in daughters of BRCA 1- or BRCA 2-mutation carriers to identify opportunities for prevention
- prediction of breast cancer risk among individual BRCA 1-or BRCA 2-mutation carriers
- risk analysis and risk reduction targets based on gene-environmental interactions
At the heart of the program is the establishment of a comprehensive registry and specimen bank that will serve as a powerful resource for a wide range of studies by providing investigators with ongoing access to clinical samples, as well as demographic, pedigree, and genetics data for BRCA-mutation carriers and non-carriers.
Kristin K. Zorn, MD, an expert in gynecologic oncology at Magee, is collaborating on the development and management of the registry and specimen bank with Darcy Thull, MS, CGC, of the UPMC Cancer Genetics Program.
“Over the last decade there has been a real recognition, both nationally and internationally, of the importance of specimen banking. But the problem is doing it effectively,” says Dr. Zorn. “It is very expensive to harness all the resources to collect specimens and bank them appropriately. We are fortunate to have donors who recognize the importance of the basic work of building the registry and continuing specimen banking.”
Screening and early detectionAnother goal of the program is to develop a reliable, preclinical blood test to detect cancer in high-risk women. Women who test positive for a BRCA mutation are at the highest risk for breast cancer. A blood test could help to identify cancer earlier, leading to more effective treatments and better long-term survival. “
Currently the best tool we have to screen women is mammography, which does not always identify small lesions,” says William Bigbee, PhD, co-leader of the program’s breast cancer biomarkers discovery project. “Early-stage breast cancer is often difficult to identify using mammography alone, particularly in pre-menopausal women with dense breast tissue.”
Dr. Bigbee and his colleague, Thomas Conrads, PhD, who are co-directors of the Clinical Proteomics Facility at UPCI, hope to identify and validate serum-based biomarkers, a characteristic indicating the presence of disease process, using state-of-the-art proteomic technologies to further improve breast cancer screening, early detection, and diagnosis.
The ultimate goal is to use this information to create a molecular blood test to complement existing clinical screening methods, such as mammography, that will assist radiologists and oncologists in determining whether or not suspect lesions are precancerous or cancerous.
Who is at risk?Individuals with a BRCA mutation are not only at risk for breast cancer. Male and female BRCA mutation carriers also have an increased risk of ovarian, prostate, and pancreatic cancers. The High-Risk Clinic at Magee counsels and treats women and men with a strong family history of these cancers. Information gathered at the clinic will be used to build the registry and specimen bank.
Although most breast cancers occur in women who do not have a strong family history of the disease, about 10 percent are linked to a genetic predisposition. In the United States, it is estimated that somewhere between one out of 345 to 1,000 individuals carries a BRCA mutation, and for individuals of Ashkenazi Jewish decent, the number is approximately one in 40 individuals. Pittsburgh has a relatively large Ashkenazi Jewish population. “
The BRCA-Associated Cancer Research Program brings together innovative researchers with physicians who clinically treat patients with these types of cancers, giving us the opportunity to not only treat the patients and help them to manage their risk, but to learn from them so we hopefully find better answers for their children,” says Dr. Zorn.
To be or not to be (tested)…
It’s been nearly ten years since Titina Ott received the news that a relative tested positive for a BRCA mutation. Her father’s cousin decided to have the genetic testing done after losing her mother to breast cancer and finding a lump of her own. For Titina’s cousin it was an easy decision to be tested. The cousin decided that she needed to share this information with her relatives, so that they too could make the decision to be evaluated by a genetic counselor. The decision was not as easy for Titina.
She discussed getting tested with her family and eventually decided not to be tested. “I found out about my family’s risk when I was in my early 30s. At the time I was concentrating on my career and wasn’t really thinking about health issues,” says Titina.
The reality of Titina’s own cancer risk hit home when her best friend from college was diagnosed with Stage III colon cancer. Her friend’s mother had passed away from complications of Stage IV colon cancer, prompting her friend to get tested for colon cancer and ultimately saving her life. This was a wake-up call for Titina.
She now takes her risk very seriously. As a patient at the High Risk Clinic at Magee-Womens Hospital of UPMC, she gets regular breast MRIs and sees an oncologist once a year. She credits the clinic with giving her more awareness and education about being in a high-risk group. She also has become passionate about encouraging women to take an active role in their health.
“I am 100 percent more proactive in my life knowing I am part of a high-risk group,” says Titina. “You only have one life to live. Education has helped me to make better choices that potentially may prevent cancer. I want to empower other high-risk women to take advantage of as many opportunities as possible to decrease their risk as well.”
Image of BRCA 2 gene courtesy of RCSB Protein Data Bank.Yang, H., Jeffrey, P.D., Miller, J., Kinnucan, E., Sun, Y., Thoma, N.H., Zheng, N., Chen, P.L., Lee, W.H., Pavletich, N.P.(2002) BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297: 1837-1848.