These findings underscore the importance of genetic testing in all women with ovarian cancer. Clinical trials that focus only on high-grade serous histology are likely to be missing a significant fraction of homologous recombination–deficient carcinomas.
—Barbara Norquist, MD
A new study suggests that homologous recombination deficiency may have significant prognostic implications for patients with ovarian cancer, highlighting the importance of genetic testing in this population.1
According to the data, patients with ovarian cancer who have mutations in genes affecting homologous recombination had significantly longer progression-free survival and overall survival than did those with no mutations. In addition, these mutations were found in all histologic subtypes of ovarian cancer, not just high-grade serous tumors.
“This is important prognostic information for our patients,” said lead author Barbara Norquist, MD, a gynecologic oncologist at the University of Washington in Seattle. “Given how striking the effect is, mutation status should be incorporated into clinical trial design.”
As Dr. Norquist reported at the 2016 Society of Gynecologic Oncology Annual Meeting, the original study, a phase III clinical trial (GOG 218), was intended to examine the impact of adding bevacizumab (Avastin) to standard chemotherapy for advanced ovarian cancer. Patients with advanced primary ovarian cancer were randomized to one of three arms: standard chemotherapy with carboplatin/paclitaxel; chemotherapy with concurrent bevacizumab; or chemotherapy with bevacizumab and bevacizumab maintenance.
Barbara Norquist, MD
“The primary finding in this study was a difference of 3.8 months in median progression-free survival when comparing arms 1 and 3,” said Dr. Norquist. “Due to this relatively modest benefit, there’s interest in determining which patients are most likely to benefit from this treatment.”
In this new analysis, researchers sought to determine whether having mutations in DNA repair genes, called homologous recombination genes, affected the response to the combined treatment.
Of the 1,873 patients enrolled in GOG 218, Dr. Norquist and colleagues sequenced DNA from blood and/or tumors from 1,195 (63.8%) using a gene panel test. A total of 307 patients (25.6%) had a mutation in a gene predicted to affect homologous recombination. Of those with mutations, 148 (48.2%) had mutations in BRCA1, 78 (25.4%) had mutations in BRCA2, and 81 (26.5%) had mutations in one of the other homologous recombination genes.
Impact of Mutation Status on Treatment Response
Proportional hazards models were used to provide estimates of relative hazards for progression-free survival and overall survival by genotype, adjusted for clinical characteristics. As Dr. Norquist reported, all three mutation-carrier groups had significantly better progression-free and overall survival when compared with those who had no mutations.
Median progression-free survival and overall survival for women with no mutations were 12.6 and 42.1 months, respectively. For women with BRCA1 mutations, progression-free survival and overall survival were longer, at 15.7 and 55.3 months. For women with BRCA2 mutations, median progression-free survival and overall survival were even longer still, at 21.6 and 75.2 months. Finally, for patients with mutations in non-BRCA genes, median progression-free survival and overall survival were 16 and 56 months, similar to outcomes seen for those with BRCA1 mutations.
Researchers also found that these mutations were present in all histologic types of ovarian cancer, not just high-grade serous tumors. In fact, said Dr. Norquist, the mutation rate in high-grade serous tumors was not significantly different from the rate in unspecified carcinomas, endometrioid, or clear cell carcinomas. The only subtype that had a significantly lower mutation rate was low-grade serous tumors, at 11%.
“These findings underscore the importance of genetic testing in all women with ovarian cancer,” said Dr. Norquist. “Clinical trials that focus only on high-grade serous histology are likely to be missing a significant fraction of homologous recombination–deficient carcinomas.”
The relationship between mutation status and bevacizumab effect was also assessed with a test of interaction. Researchers had hypothesized that patients with ovarian cancer who had homologous recombination deficiency may derive less benefit from extended bevacizumab because of their positive response to platinum, but mutational status did not significantly modify the effect.
“If a clinician feels their patient is a candidate for bevacizumab, we don’t have sufficient evidence at this time that mutation status should impact that decision,” Dr. Norquist concluded. ■
Disclosure: Dr. Norquist reported no potential conflicts of interest.
1. Norquist BS, Brady MF, Harrell MI, et al: Mutations in homologous recombination genes and response to treatment in GOG 218: An NRG Oncology study. 2016 Society of Gynecologic Oncology Annual Meeting. Abstract 1. Presented March 19, 2016.
Kristin Zorn, MD, Associate Professor and Director of Gynecologic Oncology at the University of Arkansas for Medical Sciences, Little Rock, said that the study’s data confirm the importance of other homologous recombination genes in these defects, not just BRCA1 and BRCA2. “I think this really...