All women with ovarian cancer should have the option of genetic testing, regardless of tumor histology, investigators in a retrospective, tissue-based analysis of a randomized trial concluded.
Tumors with defects in homologous recombination (HR)—BRCA1/2 or otherwise—had as much as a 9-month advantage in progression-free survival (PFS) and as much as a 33-month advantage in overall survival (OS) compared with tumors that did not have HR mutations. The survival advantage appeared across all histologic subtypes and regardless of whether patients received bevacizumab as part of randomized treatment, as reported at the Society of Gynecologic Oncology meeting in San Diego.
“Mutations affecting homologous recombination were found with all histologic subtypes of ovarian cancer,” said Barbara S. Norquist, MD, a gynecologic oncologist at the University of Washington in Seattle. “All women with ovarian cancer should be offered genetic testing. Clinical trials that focus on high-grade serous histology are missing a significant fraction of homologous recombination–deficient carcinomas.”
An invited discussant agreed with Dr Norquist’s basic conclusion about genetic testing.
“HR deficiency is common enough in epithelial ovarian cancer that genetic counseling and testing should be offered to all women with this disease,” said Kristin Zorn, MD, Director of Gynecologic Oncology at the University of Arkansas for Medical Sciences in Little Rock.
However, Dr Zorn added that “it is imperative to have adequate training to provide genetic counseling and testing, or to know how to refer to appropriate genetic professionals in your practice setting. Genetic test results can be complex and evolve over time, making genetic counseling and testing a process rather than a one-time event.”
Dr Norquist reported a retrospective analysis of Gynecologic Oncology Group 218 (GOG 218), a phase 3 randomized trial that showed that the addition of bevacizumab to paclitaxel and carboplatin significantly improved PFS in patients with advanced primary ovarian cancer. To examine the effect of HR gene mutations, investigators analyzed blood and tissue specimens from 1195 participants in the GOG 218 trial.
Investigators focused on DNA-damaging mutations in 16 genes predicted to affect HR, including BRCA1/2 and non-BRCA genes. They identified 148 patients with mutations in BRCA1, 78 with mutations in BRCA2, and 81 with mutations in other genes. Serous histology accounted for 81% of the specimens, but the frequency of HR-associated mutations did not differ among serous tumors (27%), endometrioid tumors (23.8%), clear cell tumors (21.4%), or carcinomas not otherwise specified (22%).
Patients with BRCA2 mutations had a median PFS of 21.6 months, decreasing to 16.0 months for tumors with non-BRCA mutations, 15.7 months with BRCA1 mutations, and 12.6 months for patients without HR mutations. Compared with no-mutation status, the presence of BRCA2 mutations reduced the hazard for progression or death by 48% (P <.001), non-BRCA mutations by 27% (P = .01), and BRCA1 mutations by 20% (P = .02).
Patients with no mutations had a median OS of 42.1 months. In contrast, the presence of BRCA2 mutations was associated with a median OS of 75.2 months (hazard ratio, 0.36; P <.0001), 55.3 for BRCA1 mutations (hazard ratio, 0.74; P = .01), and 56.0 months for tumors with non-BRCA mutations (hazard ratio, 0.67; P = .007).
Patients without mutations had a 29% reduction in the hazard for progression or death when treated with bevacizumab versus 5% for patients with mutations, but the difference did not achieve statistical significance in a test for interaction (P = .098).
“This is important information for patients, and the findings also suggest that mutation status should be incorporated into clinical trial design,” said Dr Norquist.