BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group

Abstract

Purpose: The frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design.

Patients and methods: Women with nonmucinous ovarian carcinoma (n = 1,001) enrolled onto a population-based, case-control study were screened for point mutations and large deletions in both genes. Survival outcomes and responses to multiple lines of chemotherapy were assessed.

Results: Germ-line mutations were found in 14.1% of patients overall, including 16.6% of serous cancer patients (high-gradeserous, 17.1%); [corrected] 44% had no reported family history of breast orovarian cancer.Patients carrying germ-line mutations had improved rates of progression-free and overall survival. In the relapse setting, patients carrying mutations more frequently responded to both platin- and nonplatin-based regimens than mutation-negative patients, even in patients with early relapse after primary treatment. Mutation-negative patients who responded to multiple cycles of platin-based treatment were more likely to carry somatic BRCA1/2 mutations.

Conclusion: BRCA mutation status has a major influence on survival in ovarian cancer patients and should be an additional stratification factor in clinical trials. Treatment outcomes in BRCA1/2 carriers challenge conventional definitions of platin resistance, and mutation status may be able to contribute to decision making and systemic therapy selection in the relapse setting. Our data, together with the advent of poly(ADP-ribose) polymerase inhibitor trials, supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history.

Fig 1.

Kaplan-Meier survival analysis; P values calculated using a log-rank analysis. Estimated (A) progression-free survival (P = .01) and (B) overall survival (P = .01) of women with serous tumors by mutation status: BRCA1 mutation–positive (blue); BRCA2 mutation–positive (gray); BRCA1/2 mutation–positive (combined; gold); wild type (black). Death as a result of disease (n = 371); patients who died as a result of nondisease-related causes were censored (n = 40). Estimated (C) progression-free survival (P < .001) and (D) overall survival (P < .001) of women with serous BRCA1/2 mutation–positive tumors by amount of residual disease after primary surgery: nil macroscopic disease (red); ≤ 1 cm (gold); > 1 cm (blue). Death as a result of disease (n = 57); patients who died as a result of nondisease-related causes were censored (n = 4). Estimated (E) progression-free survival (P < .001) and (F) overall survival (P < .001) of women with serous tumors by both mutation status and amount of residual disease: BRCA1/2 mutation–positive with nil macroscopic disease (red); BRCA1/2 mutation–positive with ≤ 1 cm residual disease (gold); BRCA1/2 mutation–positive with > 1 cm macroscopic disease (dark blue); BRCA1/2 wild-type with nil residual disease (light blue); BRCA1/2 wild-type with ≤ 1 cm residual disease (gray); BRCA1/2 wild-type with > 1 cm macroscopic disease (dark gold). Death as a result of disease, n = 348; patients who had died as a result of nondisease-related causes were censored (n = 35).

Fig 2.

Response to treatment at first progression. Treatment response was based on a 50% decrease in CA-125, maintained for 28 days, as described in the Patients and Methods section. Patients with a sequence variant of unclassified significance were excluded from this analysis. (A) Mutation-positive and (B) mutation-negative patients are divided into those whose disease progressed within 6 months of the end of treatment (dark gray segment) and those whose disease progressed more than 6 months after primary treatment (light gray segment). Response to second line for (C and D) platin-based and (E and F) nonplatin-based treatments in patients with more than 6 months to first progression after primary platinum treatment (n = 333). Response to second line for (G and H) platin-based and (I and J) nonplatin-based treatments in patients whose disease progressed within 6 months of the end of primary platinum treatment (n = 168).

Fig 3.

Time to first progression or death was plotted by mutation position along either the BRCA1 or BRCA2 gene, or by mutation type. Progression is only plotted for patients whose disease progressed by the censoring date; time to death was only plotted for those patients who died as a result of disease-related causes before the censoring date. The line represents the median. Thirty-five of the mutation-positive patients (24.8%) had remained progression free at the time of data censoring for this study. (A) Time to first progression in patients with a BRCA1 mutation who were optimally debulked (nil or ≤ 1 cm residual disease; gold plus symbols) or suboptimally debulked (blue) at time of primary surgery. (B) Time to death in BRCA1 mutation–positive cases who were optimally (gold) or suboptimally (blue) debulked at time of primary surgery. Deaths as a result of disease-related causes (n = 45; plotted); deaths as a result of nondisease-related causes (n = 3; not plotted). (C) Time to first progression in patients with a BRCA2 mutation who were optimally (gold) or suboptimally (blue) debulked at time of primary surgery. (D) Time to death in BRCA2 mutation–positive women who were optimally (gold) or suboptimally (blue) debulked at time of primary surgery. Deaths as a result of disease-related causes (n = 26; plotted); deaths as a result of nondisease-related causes (n = 2; not plotted). (E) Time to first progression by mutation type. A deletion or insertion was considered multiple base if at least two base pairs were involved. (F) Time to death by mutation type. Deaths as a result of disease-related causes (n = 71; plotted); deaths as a result of nondisease-related causes (n = 5; not plotted). A deletion or insertion was considered multiple base if at least two base pairs were involved. HGVS, Human Genome Variation Society.