Defining Variations in Survival of BRCA1 and BRCA2 Mutation Carriers

In the second half of the 20th century, women with a family history of breast cancer were treated with bilateral mastectomies. Among 639 such women in 1 study, the median length of survival after surgery was 14 years. Using their sisters as control participants, there was a large survival difference between women who underwent bilateral mastectomies and those who did not.¹ By the 1990s, after the identification of hereditary breast cancer genes BRCA1 and BRCA2, an understanding began to emerge about the elevated lifetime risks of ovarian and breast cancers for women carrying deleterious mutations of the BRCA1 or BRCA2 genes.^{2 - 3} The effects of these discoveries moved quickly and helped define the extent of genetic heterogeneity and the penetrance of the 17q and 13q tumor suppressor gene regions.

In this issue of JAMA, the article by Yang et al⁴ highlights several new findings. Using data from The Cancer Genome Atlas (TCGA) research network,⁵ the investigators assessed the association of BRCA1 and BRCA2 mutations with overall survival and chemotherapy response in women with ovarian cancer. The investigators cataloged molecular alterations that may influence therapy for ovarian cancer based on the specific mutation present, which favored longer survival in patients with BRCA2 mutation than in those with BRCA1 mutation or hypermethylation. After sequencing tumor DNA from genomic exons, BRCA2 mutations were associated with an increased number of acquired mutations of genes, although the types of mutation (eg, nonsense vs missense) were not delineated nor was there an increase in the detection of tumor protein p53 (TP53) mutations.

Among 316 women with high-grade serous ovarian cancers, 219 had wild-type BRCA, 35 had BRCA1 mutations, 27 had BRCA2 mutations, 33 had BRCA1 methylation, and 2 had both BRCA1 and BRCA2 mutations. Founder mutations observed in 12 BRCA1 individuals (185/187delAG and 5382/5385insC) have been extensively noted among Ashkenazi Jewish individuals. Of 29 patients with BRCA2-tumor mutations, 20 also had germline BRCA2 mutations, including 5 that were 6174delT and the remainder that were somatically acquired.

The investigators found significant differences in survival and response to chemotherapy according to BRCA mutation status. Among the women in these cohorts, 225 had ovarian cancers that were sensitive to treatment, and 36 had tumors that were treatment resistant (and 55 were missing primary treatment outcomes). Of 192 patients eligible for drug (platinum)-free survival analysis, data were available for 163 patients (and missing from 29). Survival among patients with BRCA2 mutations was increased compared with those having BRCA1 mutations, suggesting that their cancers were more resistant to platinum-based treatment. The 5-year survival of BRCA2 mutation carriers was significantly longer than that of patients with wild-type BRCA (61% vs 25%), whereas the 5-year survival of patients with mutations or methylation of the BRCA1 gene was not significantly different from that of wild-type BRCA cases (44% and 24% vs 25%, respectively).

The discrepancy between response and survival among BRCA1 and BRCA2 mutation carriers should encourage attention to the differences in treatment between the 2 groups, particularly among women with ovarian cancer. Moreover, these findings should raise the issue that the nature of the deficit in DNA repair detected due to BRCA2 mutation is not equivalent to the deficit due to BRCA1 mutation or hypermethylation. Further refinement in the understanding of the differences in the DNA repair deficits due to BRCA1 vs BRCA2 mutations could lead to therapy that is better targeted.

Because this is an observational study, there are some limitations to the results. For instance, information was missing for 15% of women for analysis of the primary treatment outcomes and for 15% of women for the platinum drug-free survival analysis. This amount of missing data is not unusual in an epidemiologic study. In addition, the study is relatively small and there may have been other measured and unmeasured prognostic factors that differed between the groups of patients with different BRCA1/2 status.

The study by Yang et al⁴ provides a major advance in the understanding of the use of new treatments for ovarian cancer among patients with BRCA mutations by demonstrating a difference in the response among patients with BRCA1 and BRCA2 mutations diagnosed with ovarian cancer. Newer studies may support the use of poly (ADP-ribose) polymerase inhibitors for the treatment of such patients.⁶ Early studies among women with advanced breast cancer suggest some improvement—especially with platinum-based therapy and the use of neoadjuvant chemotherapy.⁷ The next step would be to enroll these patients in randomized clinical trials to test whether BRCA1 or BRCA2 mutation carriers respond differently with regard to ovarian cancer, as Yang et al⁴ suggest.

In addition, a careful family history taking, especially of close relatives, is a critical part of identifying men and women at risk and may lead more physicians to consider genetic testing in higher-risk patients.⁸ Such histories can also identify women who will require screening with annual or semiannual mammography and magnetic resonance imaging as well as preventive use of tamoxifen or aromatase inhibitors. Other preventive medications such as oral contraceptives also can reduce the risk of ovarian cancer.⁹ For patients at high risk of breast and ovarian cancer due to BRCA1 or BRCA2 mutations, prophylactic oophorectomy also may lower the risk of developing breast cancer if performed prior to age 50 years.^{10 - 11} If patients in this category develop metastatic cancer, they can receive surgery and more tailored chemotherapy treatments, which for ovarian cancer may include platinum and polymerase inhibitors.⁷

For these high-risk patients, the large health care costs for procedures such as annual magnetic resonance imaging, prophylactic surgeries, chemotherapy, hormonal therapy, and studies of newer preventive medications cannot be ignored.⁹ These costs must be weighed against the costs of treating terminally ill patients and the expense of improving their survival and reducing quality-adjusted time lost. Comparing alternative costs and benefits related to prognosis and therapy may help to develop the methods and science for cancer prevention, control, and treatment at an early and more curable phase.^{12 - 13}