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.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
Kathryn
K
Alsop
Sian
S
Fereday
Cliff
C
Meldrum
Anna
A
deFazio
Catherine
C
Emmanuel
Joshy
J
George
Alexander
A
Dobrovic
Michael J
MJ
Birrer
Penelope M
PM
Webb
Colin
C
Stewart
Michael
M
Friedlander
Stephen
S
Fox
David
D
Bowtell
Gillian
G
Mitchell
D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001315:Australia / Q000453:epidemiology; D001943:Breast Neoplasms / Q000235:genetics; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics*; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008487:Medical History Taking; D008875:Middle Aged; D059645:Mutation Rate; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000235:genetics; D017671:Platinum Compounds / Q000008:administration & dosage; D017354:Point Mutation; D011446:Prospective Studies; D012008:Recurrence; D016896:Treatment Outcome
D017671:Platinum Compounds