Science. Communication. Community.
Why BRCA is sometimes a misnomer—and the quest to find its Achilles’ Heel.
by Jessica McDonald
In a touching and cogent op-ed in the New York Times on Tuesday, Angelina Jolie—the actress who rose to prominence as the buxom gun-toting adventurer Lara Croft—disclosed she had recently removed both of her breasts. And for good reason. After losing her mother to ovarian cancer, Jolie had genetic testing done that revealed she was a carrier for a mutation in BRCA1, which like the BRCA2 gene, codes for a protein that helps prevent DNA damage. A variety of mutations in either of the BRCA genes result in defective proteins that no longer protect DNA, increasing the chance that cells will pick up mutations in other genes that will allow them to grow uncontrollably. Doctors estimated Jolie’s risk of breast cancer to be 87% (at the upper end of typical estimates, even for carriers), so she decided to have a preventive mastectomy.
As advanced as our diagnostics and nipple-saving surgical techniques may be, the fact that the most effective option for many women with BRCA mutations (either as a prophylactic or therapeutic measure) is cutting off body parts means there’s still a huge treatment gap. And contrary to the name (BRCA stands for breast cancer), BRCA mutations have increasingly been linked to cancers other than breast and ovarian. In a study published earlier this month, researchers found that BRCA-carrier men with prostate cancer died an average of seven years earlier than those without the mutations. A 2012 study reported that women with BRCA mutations were twice as likely to develop pancreatic cancer as non-carriers. BRCA mutations are still far more likely to impact the breasts or ovaries (lifetime risk of 54-87% versus under 8% for the pancreas), but pancreatic cancer is one of the most deadly cancers—and there’s no prophylactic recourse—so this increased risk isn’t trivial.
Nevertheless, practically and statistically, Angelina Jolie is right to focus on her most at-risk organs. But BRCA’s role in other tissues forces scientists to think in terms of the shared genetic defects that instigate and feed tumors rather than simply the tissue of origin. [For more on this conceptual revolution, see Gina Kolata’s article from Monday. Of course for BRCA, it’s also equally informative to think about what might make the breasts and ovaries particularly susceptible—hint: hormones.] Such an approach can lead to treatments that attack at the ‘root’ of tumors—for example, blocking critical growth receptors that trigger certain cells to multiply uncontrollably.
In the case of BRCA-related cancers, there’s no obvious way to fix the fact that critical DNA repair proteins are defective and more mistakes will occur as cells copy their DNA and replicate. But if you make DNA repair even worse, cells will reach a point where they can’t continue and they’ll abort. This fighting fire-with-fire strategy is the idea behind a relatively new class of drugs known as PARP (poly ADP-ribose polymerase) inhibitors. PARP-1 is another DNA repair protein that acts in a different pathway than the BRCA proteins, but importantly, serves as a backup when BRCA is defective. If PARP is also prevented from functioning, cells die. Because cells are fine as long as BRCA can step in to promote repair when PARP is blocked, PARP inhibitors generally don’t affect normal cells, and can selectively target the tumor cells without BRCA function.
In 2010, phase II clinical trials for PARP inhibitor treatment of BRCA-related breast and ovarian cancer were published in the Lancet, with remarkable success. About 40% of breast and 30% of ovarian cancer tumors responded to the treatment, with relatively minor side effects. But then in 2011 a different PARP inhibitor at the phase III stage did not prove to extend lifespans for the specific breast cancer patients in the study.
One of the latest clinical trials on BRCA-related cancers tested a PARP inhibitor on prostate and pancreatic patients in addition to breast and ovarian. Researchers in Israel and at the University of Pennsylvania (among others) found about 20% of prostate cancers and 50% of pancreatic cancers improved with treatment. The full results of the trial will be presented in June at the American Society of Clinical Oncology meeting.
There has even been the thought that PARP inhibition could be used preventatively, with at-risk patients going on spurts of the medication. But for now, it’s unclear if PARP inhibitors will live up to their initial promise—and if they will receive the financial backing from pharmaceutical companies to see them through development, since BRCA-related cancers are rare and will never be blockbuster sellers. For breast and ovarian cancer, at least, surgery remains an important and effective strategy for women who want to be proactive about their BRCA mutations.