Advancements in BRCA research are revolutionizing women’s health. The genetic test has even gained notoriety outside the healthcare community, as celebrities like Angelina Jolie openly discuss preemptive mastectomy and hysterectomy after testing positive for BRCA mutations. Just how much will this blood test change the face of healthcare, and what should general practitioners know about BRCA testing?
Identifying Those at Risk
First, the facts: According to the National Institutes of Health, 12 percent of women in the general population will develop breast cancer sometime during their lives, and 1.3 percent will develop ovarian cancer. By contrast, 55 to 65 percent of women who inherit a harmful BRCA1 mutation and around 45 percent of women who inherit a BRCA2 mutation will develop breast cancer by age 70. In addition, 39 percent of women with BRCA1 mutation and 11 to 17 percent of women with BRCA2 mutation will develop ovarian cancer by age 70.
BRCA & Ovarian Cancer
Marta Ann Crispens, MD, associate professor and gynecological oncologist at Vanderbilt-Ingram Cancer Center, said BRCA testing is recommended for all women diagnosed with ovarian cancer – the disease that killed Jolie’s mother. “We’ve been testing these patients for BRCA 1 and 2 for several years, as breast cancer is very common among patients with ovarian cancer,” Crispens said.
Michael Milam, MD, a board-certified gynecologic oncologist with Saint Thomas Health, said the absence of a screening test for ovarian cancer means most cases are found in an advanced stage. “The interesting thing about ovarian cancer is that its risk of having a genetic mutation is approximately 20 percent, which is a lot higher and a separate topic than breast cancer,” Milam said. “The idea of identifying people at risk before they develop the disease is the Holy Grail.”
BRCA & Breast Cancer
Mutations affect both men and women and often are associated with breast, pancreatic, ovarian and prostate cancers. BRCA mutational status also becomes important for those with an early stage cancer such as breast cancer, where knowledge of their status and high risk of subsequent cancers might influence surgical decisions.
Misconceptions about BRCA still exist, even in the medical community.
“Many people believe that if someone in their family has breast cancer, they must have BRCA,” said Erika Hamilton, MD, associate director of the Breast Cancer and Gynecologic Cancer Research Program at Sarah Cannon Research Institute. “But statistics tell us that only 5-10 percent of cases are due to BRCA 1 or 2. The rest of the cases are because breast cancer is just so common, and we need to educate people about that.”
Genetic Testing: What Providers Need to Know
Knowing who - and how - to screen is the biggest struggle surrounding BRCA testing. The screening process starts with a thorough family history, often gathered by a general practitioner. Milam said patients could be their own best advocates by providing a thorough family history up front, especially since today’s office visits are often rushed. Patients with a diagnosis of ovarian cancer are always screened. Those under the age of 50 with a history of cancer, or those with multiple family members with breast or ovarian cancer also are strong candidates for BRCA testing.
The next step, said all three specialists, is often marred by the medical community at large. While any provider can order the blood test (which typically is covered by insurance for those at-risk patients), patients often don’t receive adequate genetic counseling to help them grasp the potential emotional, physical and familial impact of BRCA testing. “It’s not just, ‘Here’s a blood test,’ but practitioners need to really understand how it impacts patients and potentially their families,” Milam cautioned. “One of the biggest changes over the last few years is that we used to just test for certain mutations, but today’s expanded testing can add to the confusion. That part’s complicated to patients, and we need to emphasize the need for more support with genetic counseling.”
Crispens also cautioned that genetic testing should never be done outside of genetic counseling. Counselors help patients understand implications, know how to talk to families, obtain medical records, clarify risks and interpret tests.
“Get counseling first and then get testing,” Crispens stressed. “A positive test is fairly straightforward, but a negative test may mean there’s no established gene in the family and may not be truly negative. Genetic testing isn’t definitive in that sense. If there’s no established gene but a strong family history and you test negative, there may be a gene you didn’t inherit, or a gene we don’t know how to test for.”
A third possibility is a variant of an insignificant gene appearing on a test. “Polymorphism is normally no big deal, but if it results in a protein that doesn’t function, that’s a mutation,” Crispens said. “These genes can have mutations in multiple sites. Sometimes there’s not enough people with a gene at that site to know whether a change there is associated with cancer or not, and we can’t know whether it’s a mutation or a variant of uncertain insignificance.” Over time, researchers can track these changes and reclassify them as benign or mutations depending on how many patients demonstrate that pattern.
“Interpreting these tests is relatively complex, and genetic testing isn’t just a ‘yes’ or ‘no’ answer,” said Crispens, who often sees referrals who lack a real understanding of what their tests mean. “Testing has changed so much, and it really is hard to keep up with. There are a lot of subtleties, but if you don’t fully understand it or know how to manage it, that’s a problem. If you’re a generalist, will you follow-up every year about a genetic insignificance? Those are important things to think about when ordering BRCA testing.”
Options After Testing
According to Hamilton, BRCA-linked cancers behave differently and are driven by cellular signaling. Preventative strategies including medications and surgical options (such as mastectomies and oophorectomy) reduce a woman’s risk of developing cancers.
“We also now have a FDA-approved PARP inhibitor (olaparib) for heavily pre-treated ovarian cancer so knowing an ovarian cancer patient’s BRCA status may open them up for commercially available treatments,” Hamilton said of the new drug class, which received accelerated approval December 2014. However, she said the jury’s still out on the best settings for PARP inhibitors.
“There are a variety of clinical trials using PARP inhibitors and certain classes of chemotherapy (platinums) aimed at improving our standard-of-care treatments for patients whose cancers may be driven by a mutation in BRCA 1 or 2,” she said. “We know there are many patients who would benefit from them, and we still need to find out who the best candidates are and in which cases they work best as a single agent or combined with other therapies. There are still a lot of questions.”
What are BRCA1 and BRCA2?
BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of the cell’s genetic material. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.
Specific inherited mutations in BRCA1 and BRCA2 increase the risk of female breast and ovarian cancers, and they have been associated with increased risks of several additional types of cancer. A harmful BRCA1 or BRCA2 mutation can be inherited from a person’s mother or father. Each child of a parent who carries a mutation in one of these genes has a 50 percent chance (or 1 chance in 2) of inheriting the mutation. The effects of mutations in BRCA1 and BRCA2 are seen even when a person’s second copy of the gene is normal.
Source: National Institutes of Health
Sarah Cannon Research Institute currently has three trials available for patients with BRCA mutations and metastatic beast cancer, one trial for early stage triple negative patients with or without BRCA mutations combining platinum chemotherapy with a PARP inhibitor, two trials for BRCA-related ovarian cancer, and a final trial for patients with platinum sensitive ovarian cancer as a maintenance strategy to prevent disease recurrence.
For more information visit sarahcannon.com/clinical-trials.
RELATED LINKS:
Vanderbilt-Ingram Cancer Center: www.vicc.org
Tennessee Oncology: www.tnoncology.com
Sarah Cannon Cancer Center: www.sarahcannon.com
Saint Thomas Health: www.sths.com
Cancer.gov BRCA Fact Sheet: http://www.cancer.gov/cancertopics/causes-prevention/genetics/brca-fact-sheet
