BRCA Mutations Linked to Longer Survival in Ovarian Cancer

Barbara S. Norquist, MD

Patients with advanced ovarian cancer harboring mutations in homologous recombination (HR) genes, including BRCA1/2, had improved survival versus patients without HR mutations, according to a mutational analysis of the phase III GOG 218 study presented at the 2016 Society of Gynecologic Oncology (SGO) Annual Meeting.¹

In the primary GOG 218 analysis, add-on bevacizumab (Avastin) followed by maintenance bevacizumab improved progression-free survival (PFS) by 3.8 months versus chemotherapy alone in the frontline setting for patients with stage III/IV ovarian cancer.²

The analysis presented at SGO showed that among patients with BRCA1, BRCA2, and non-BRCA HR mutations, respectively, the reduction in the risk of death, regardless of the treatment received, was 26%, 64%, and 33%, compared with patients without HR mutations. The risk of disease progression was decreased by 20%, 48%, and 27%, respectively. The findings also demonstrated that HR mutations did not mitigate the benefit of adding bevacizumab to standard care.

“All 3 mutation-carrier groups had significantly better progression-free and overall survival when compared to those with no mutations,” said lead author Barbara S. Norquist, MD, a gynecologic oncologist at the University of Washington, who presented the results at the meeting.

The double-blind, phase III GOG-0218 trial included 1873 patients with untreated stage III/IV ovarian cancer who had undergone debulking surgery. Patients were randomized to carboplatin (AUC 6) and paclitaxel (175 mg/m²) with placebo (n = 625), bevacizumab-initiation from cycle 2 through 7 (n = 625), or bevacizumab-continuation starting at cycle 2 and continuing throughout the study (n = 623). Bevacizumab was administered at 15 mg/kg every 3 weeks.

Using the BROCA-HR assay, Norquist et al sequenced germline and/or somatic DNA from 1195 women (63.8%) who participated in GOG 218. Among this subgroup, 87.7% (n = 1048) were non-Hispanic White, 81.2% (n = 971) had grade 2/3 serous disease, and 33.6% (n = 401) were treated in the bevacizumab-continuation arm.

HR defects were defined as damaging mutations in BRCA1, BRCA2, BRIP1, PALB2, RAD51D, RAD51C, ATM, SLX4, NBN, BLM, BARD1, CHEK2, MRE11A, RBBP8, XRCC2, and ATR. The researchers identified germline or somatic BRCA1, BRCA2, or non-BRCA HR mutations in 12.4% (n = 148), 6.5% (n = 78), and 6.8% (n = 81), of patients, respectively. No HR mutations were detected in 74.3% (n = 888) of the population.

For the most part, histology was not predictive of mutation status; however, patients with low-grade serous carcinoma (n = 46) had a significantly lower mutation rate of 10.9% versus 27.0% in patients with high-grade serous histology (n = 971; odds ratio, 0.33; 95% CI, 0.1-0.8; P = .02).

In the primary GOG-0218 analysis, the median PFS with bevacizumab-continuation was 14.1 months compared with 10.3 months with chemotherapy alone (HR, 0.717; 95% CI, 0.625-0.824; P <.001). The bevacizumab-initiation arm did not demonstrate a statistical difference compared with placebo (HR, 0.908; P = .16). A significant difference in overall survival (OS) was not observed between the arms.

Using proportional hazard models, Norquist et al estimated the hazard ratios for OS and PFS for the HR mutation subgroups versus the non-mutation population. The models adjusted for treatment, stage, residual disease, and performance status.

The median OS was 55.3 months (HR, 0.74; 95% CI, 0.59-0.94; P = .01), 75.2 months (HR, 0.36; 95% CI, 0.25-0.53; P <.0001), and 56.0 months (HR, 0.67; 95% CI, 0.49-0.90; P = .007) in the BRCA1, BRCA2, and non-BRCA HR mutation subgroups, respectively, compared with 42.1 months in the group without HR mutations.

The median PFS was 15.7 months (HR, 0.80; 95% CI, 0.67-0.97; P = .02), 21.6 months (HR, 0.52; 95% CI, 0.40-0.67; P <.0001), and 16.0 months (HR, 0.73; 95% CI, 0.57-0.94; P = .01) in the BRCA1, BRCA2, and non-BRCA HR mutation subgroups, respectively, compared with 12.6 months in the group without HR mutations.

When combining the 3 groups of patients with HR mutations and comparing them with the non-HR mutation population, bevacizumab provided a similar improvement in PFS, regardless of mutation status.

In the non-HR mutation group, the median PFS was 15.7 months in the bevacizumab-continuation arm (n = 281) versus 10.6 months with chemotherapy alone (n = 300), representing a 5.1-month PFS benefit (HR, 0.71; 95% CI, 0.60-0.85; P = .0001).

Among the combined group of patients with HR mutations, the median PFS was 19.6 months in the bevacizumab-continuation arm (n = 120) versus 15.4 months with chemotherapy alone (n = 108), representing a 4.2-month PFS benefit (HR, 0.95; 95%, 0.71 —1.26; nonsignificant).

Norquist said a test of interaction confirms that mutation status did not significantly modify the effect of extended bevacizumab on PFS (0.95/0.71 = 1.33; 95% CI, 0.95-1.85; P = .098).

Summarizing the findings she presented, Norquist remarked, “This is important prognostic information for patients and highlights the importance of knowing genetic status in clinical trials in ovarian cancer.”

References:

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. Presented at: 2016 SGO Annual Meeting. March 19-22, 2016. San Diego, CA. Abstract 1.
2. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011; 365:2473-2483.

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