Silver Linings for BRCA Mutation Carriers

By Rabab Charafeddine, PhD

When I started listening to the BRCA Foundation’s Positive Perspectives podcast series and reading about BRCA mutations and cancer, I was overwhelmed with emotions. On one hand, the facts and statistics are daunting and worrisome; three in five women with BRCA mutations will develop breast cancer in their lifetime, compared to one in eight for the general population. On the other hand, the personal stories of BRCA previvors and cancer survivors are both inspiring and heartbreaking. But through my continued listening to some of the interviews with healthcare professionals, I realized BRCA research is gaining a strong momentum which has helped change how scientists and clinicians view and treat cancers, generally. The second week of 2018 was particularly exciting and insightful for me and the BRCA community. A back-to-back large breast cancer study and FDA breast cancer drug approval totally changed how I look at a BRCA mutation— from an evil cancer instigator to a useful cancer marker.

Conducted by scientists and clinicians at the University of Southampton in the UK, the recent Prospective Outcomes in Sporadic versus Hereditary breast cancer (POSH) study is the largest of its kind. The study followed 2,733 women, all of whom were between the ages of 18 and 40, for a period of 10 years following their diagnosis of young-onset breast cancer. One in eight of the patients was identified as a BRCA mutation carrier (BRCA-positive) by genetic testing during the study. To truly compare BRCA-positive and BRCA-negative (non-carriers) patients, POSH adjusted for differences in Body Mass Index, ethnicity, type of treatment received, and other variables.

Based on a comparison between the overall survival of BRCA-positive and BRCA-negative patients, POSH reached two noteworthy conclusions: 1) there was no significant difference in overall survival between BRCA-positive and BRCA-negative patients; and 2) overall survival in patients with triple-negative tumors, a particularly aggressive form of breast cancer, was slightly better for BRCA positive patients two years after diagnosis (95% vs. 91%). This rate, however, leveled off at the five- and 10-year marks. Even though mutations in BRCA genes may increase a woman’s risk of developing breast cancer early in life, the findings suggest her cancer won’t be more life-threatening than that of a BRCA-negative woman. When it comes to triple-negative tumors, a BRCA-positive woman has a better chance at short- term survival since her tumor appears to be more sensitive to treatment. Interestingly, this early survival advantage POSH observed in triple-negative patients is supported by another study that found BRCA-positive triple-negative tumors to be more sensitive to chemotherapy and visible to attacks by immune cells. The POSH findings might not seem very encouraging at first; after all, these patients still have to deal with a life altering diagnosis and treatment, but the findings can change how we view BRCA-positive prognostic implications.

Currently, it is recommended that young-onset breast cancer patients with BRCA mutations undergo bilateral mastectomies right after their therapies to reduce the risk of developing other primary tumors. The POSH results, however, imply this immediacy in undergoing mastectomies does not enhance survival in the short term. Since survival rates are high in the first two years, patients can take some much needed time to recover physically and psychologically before undertaking this serious surgery. This isn’t to say there aren’t benefits to prophylactic mastectomies; POSH and others reported a long-term survival advantage in people who have had these surgeries.

POSH was also insightful to read because it gives some glimpses of how hard it is to recruit patients and conduct these types of studies— it took eight years to recruit all of the patients and 10 years to follow up with them. In fact, POSH is ongoing and we can hopefully expect more findings in the future. How BRCA diagnosis and treatment has changed in the last 10 to 18 years is also apparent.

To begin with, genetic testing for the BRCA mutation was not as prevalent or accessible; half of the BRCA-positive patients did not know they were carriers before the study. Treatments were not as customizable and cancers were not treated according to their BRCA background; BRCA-positive cancers were treated with similar types of nonspecific chemotherapy regimens to BRCA-negative cancers. Platinum-based drugs, for example, which have since been shown to have better efficacy on BRCA-positive tumors, were used on 13 patients, only one of whom was BRCA-positive. Since recruitment ended in 2008, POSH also missed the advent of PAPR inhibitors, which were first approved in 2014. This trailblazing class of BRCA-positive targeted drugs has since tremendously improved outcomes for BRCA-positive patients and presents a major stride in changing the way we look at cancer.

Historically, clinical trials have mainly focused and customized drugs based on the cancer’s organ of origin. After all, breast and ovarian cancers are not similar— or are they? Well, in the case of BRCA-positive cancers they, indeed, are. This is evidenced by the FDA approval of PARP inhibitors to treat BRCA-positive breast cancers. PARP inhibitors were originally developed and approved to treat BRCA-positive ovarian cancers but a recent clinical trial revealed they also work well on BRCA-positive breast cancers. Mechanistically, PARP inhibitors target DNA repair factor PARP1 that works similarly to functional BRCA. When the BRCA protein malfunctions (the gene is mutated) and PARP1 is inhibited, cancer cells can no longer repair their extremely damaged DNA and die, as a result. Thus, using PARP inhibitors should theoretically work on all types of BRCA-positive cancers. This historic approval, cements BRCA as a genetic marker that has helped pioneer the shift in paradigm in which cancers are defined, diagnosed, and therapeutically targeted, according to their unique genetic profile and not just the type of tissue from which they come. In other words, research is suggesting that we move away from conversations about and treatments of cancers based on organ of origin and toward a conversation about the type of cancer. A BRCA-positive breast cancer, for example, may have more in common with a BRCA-positive ovarian cancer than with a BRCA-negative breast cancer.

These two advances in our understanding and treatment of BRCA-positive cancers offer an unofficial timeline of how far we’ve come in the last 10 years. BRCA researchers and clinicians now better understand the fundamental and clinical characteristics of BRCA-positive tumors. They are also trying to harvest the therapeutic power of BRCA mutations and utilize them to fire back at BRCA-positive misbehaved cells. These cells, it seems, have a clear target on their backs and it’s only a matter of time till we shoot them in the bull’s eye.

Please note the information addressed in this blog post should not in any way replace a conversation with your doctor. It is simply intended to bring new research to the attention of the public.