Mutations in the BRCA2 gene appear to confer better survival in women who have ovarian cancer, according to a report in the Oct. 12 issue of JAMA.
The BRCA2 mutations appear to improve survival by enhancing sensitivity to platinum-based chemotherapy, thus improving treatment response, said Da Yang, Ph.D., of the department of pathology at the University of Texas M.D. Anderson Cancer Center, Houston, and associates.
BRCA1 mutations showed no such effects, they noted.
Women with either BRCA1 or BRCA2 mutations are known to be at increased risk of developing ovarian cancer, but the findings regarding their outcomes after the malignancy is diagnosed are conflicting. Some studies have reported favorable clinical courses, while others have shown the opposite. Most of these studies have pooled the results on BRCA1 and BRCA2 carriers together.
Dr. Yang and colleagues assessed possible associations between each genetic mutation separately and survival. They used the Cancer Genome Atlas (TCGA) database, which included genomic and clinical data on 316 high-grade serous ovarian cancer patients. All tumors were stage III or IV.
Most of the study subjects (86%) were non-Ashkenazi Jewish white women; 7% were Ashkenazi Jewish, 3% were African American, and 3% were Asian. All were treated with platinum-based adjuvant chemotherapy, and 94% also received a taxane.
A total of 29 women (9.2%) carried BRCA2 mutations, 37 (11.7%) BRCA1 mutations, and 219 had BRCA wild-type mutations.
The 5-year survival was 61% for BRCA2 carriers, significantly higher than the 25% 5-year survival seen in wild-type BRCA cases. In contrast, there was no significant difference in survival between BRCA1 carriers (44%) and wild-type BRCA cases, the investigators said (JAMA 2011;306:1557-65).
In further analysis of treatment response, BRCA2 mutations were associated with significantly improved chemotherapy response and longer platinum-free durations than were BRCA1 mutations and wild-type BRCA.
In addition, "BRCA2-mutated cases, but not BRCA1-mutated cases, exhibited a ‘mutator phenotype’ that contained significantly more mutations as determined from whole-exome mutation data. These findings suggest that the different associations between survival and BRCA1 and BRCA2 deficiencies likely result from patients’ distinct responses to platinum-based treatment, which may be caused by the differing nature of the dysfunction of these two genes," the researchers said.
"Functionally, both BRCA1 and BRCA2 have been reported to play key roles in DNA damage repair, but they appear to have distinct but complementary functions," they added.
This study population "represents the most comprehensive data composition (both genomic and clinical) assembled" to date. However, the cohort was still "relatively small, and our findings should be further validated" in additional studies, Dr. Yang and associates said.
This study was supported by the National Institutes of Health, the Blanton-Davis Ovarian Cancer Research Program, and an Ovarian Cancer SPORE grant. No financial conflicts of interest were reported.