AT THE ANNUAL MEETING ON WOMEN’S CANCER
SAN DIEGO (FRONTLINE MEDICAL NEWS) – Women with advanced ovarian cancer who possess a mutation in a homologous recombination DNA repair gene have impressively longer progression-free and overall survival in response to therapy than those who don’t, Dr. Barbara S. Norquist reported at the annual meeting of the Society of Gynecologic Oncology.
What’s more, these mutations are common in women with ovarian cancer. Of 1,195 patients with advanced ovarian cancer enrolled in the phase III Gynecology Oncology Group 218 trial, fully 25.7% – or 1 in 4 patients – had a mutation in BRCA1, BRCA2, or one of 14 other homologous recombination DNA repair genes included in the BROCA-HR gene panel test, according to Dr. Norquist, a gynecologic oncologist at the University of Washington, Seattle.
Defects in these genes were associated with improved survival in GOG 218. The most impressive gain in overall survival was seen in women with a BRCA2 mutation: their median overall survival was 33.1 months longer than in patients with no mutations.
In a multivariate analysis adjusted for treatment, stage, residual disease, and performance status, the likelihood of disease progression was reduced by 20% in patients with a BRCA1 mutation compared to women with no mutations, by 48% in patients with a BRCA2 mutation, and by 27% in those with non-BRCA HR mutations. The risk of death was reduced by 26% in patients with a BRCA1 mutation, by 64% in those with a BRCA2 mutation, and by 33% in those with other HR mutations, according to Dr. Norquist.
Mutation status proved unrelated to patient age, histologic tumor type, or family history. That’s a key finding, she stressed. The clinical implication is that all women with any type of ovarian cancer should undergo genetic testing for mutations in homologous recombination genes.
Forty-eight percent of women in the homologous recombination (HR) gene mutation-positive cohort had a damaging mutation in BRCA1, 25% in BRCA2, and 27% in one of the 14 other HR genes included in the BROCA-HR gene test panel. The BROCA-HR gene test panel was developed by University of Washington physicians and is commercially available through the university’s department of laboratory medicine. Dr. Norquist noted, however, that these 16 genes are included in most gene panel tests.
Testing only for BRCA1/2 mutations, while less expensive than testing for the full set of 16 HR genes, would have missed 27% of patients who had one of the other mutations linked to improved prognosis, she observed.
The GOG 218 study was a randomized, placebo-controlled trial designed to evaluate the impact of adding extended bevacizumab to first-line chemotherapy for advanced ovarian cancer. The main finding was that bevacizumab modestly improved progression-free survival by about 3 months (N Engl J Med. 2011 Dec 29;365(26):2473-83). Dr. Norquist’s secondary analysis of the GOG 218 dataset looked at whether HR mutation status could be used to identify a patient subset who would get a more robust benefit from bevacizumab; it did not.
“How I would interpret this clinically is that 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,” she said.
Dr. Norquist was honored with the Society of Gynecologic Oncology annual President’s Award, bestowed for the study presented at the meeting which is judged to have the biggest direct effect on the care of women with gynecologic cancer.
Discussant Dr. Kristin Zorn was strongly supportive of the award going to Dr. Norquist.
“I think what this amounts to is a change in the standard of care for ovarian cancer. If you care for ovarian cancer patients, it’s 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,” according to Dr. Zorn of the University of Arkansas for Medical Sciences in Little Rock.
She endorsed Dr. Norquist’s call for genetic screening for HR deficiency in all patients with ovarian, fallopian tube, or primary peritoneal cancer regardless of tumor histology, family history of cancer, or ethnicity. Dr. Zorn noted that stance has been an underappreciated element in National Comprehensive Cancer Network guidelines since 2011.
“That knowledge of HR mutation status has such an impact for that patient and her family,” Dr. Zorn stressed.
Based upon other evidence, she added, it’s quite possible that the true proportion of ovarian cancer patients with HR deficiency could be as high as 50%, rather than the 26% figure Dr. Norquist reported in her GOG 218 analysis. That’s because for many participants in GOG 218, DNA was available from either germline or somatic samples, but not both.
The new understanding of the importance of HR deficiency has important implications for the design of clinical trials. At present many trials of potential new treatments for ovarian cancer restrict enrollment to patients with high-grade serous disease. It’s now clear that such restrictions exclude many patients who could benefit from drugs with activity in the setting of HR deficiency, Dr. Zorn said.
Homologous recombination deficiency increases tumor sensitivity to a variety of medications, including platinum, pegylated liposomal doxorubicin, antiangiogenic agents, and PARP inhibitors, she added.
The 16 HR genes Dr. Norquist scrutinized in GOG 218 are BRCA1/2, BRIP1, PALB2, RAD51C, RAD51D, ATM, ATR, NBN, SLX4, BARD1, BLM, CHEK2, RBBP8, MRE11A, and XRCC2. These genes lie along what has come to be called the Fanconi Anemia/BRCA homologous recombination pathway.
