Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer.
OBJECTIVE
The prevalence of BRCA(1/2) mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA(1/2) changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs.


METHODS
In 235 unselected ovarian cancers, BRCA(1/2) was sequenced in 235, assessed by copy number analysis in 95, and tiling arrays in 65. 113 tumors were sequenced for TP53. BRCA(1/2) transcript levels were assessed by quantitative polymerase chain reaction in 220. When available for tumors with BRCA(1/2) mutations, germline DNA was sequenced.


RESULTS
Forty-four mutations (19%) in BRCA1 (n = 31)/BRCA2 (n = 13) were detected, including one homozygous BRCA1 intragenic deletion. BRCA(1/2) mutations were particularly common (23%) in high-grade serous cancers. In 28 patients with available germline DNA, nine (42.9%) of 21 and two (28.6%) of seven BRCA1 and BRCA2 mutations were demonstrated to be somatic, respectively. Five mutations not previously identified in germline DNA were more commonly somatic than germline (four of 11 v one of 17; P = .062). There was a positive association between BRCA1 and TP53 mutations (P = .012). BRCA(1/2) mutations were associated with improved progression-free survival (PFS) after platinum-based chemotherapy in univariate (P = .032; hazard ratio [HR] = 0.65; 95% CI, 0.43 to 0.98) and multivariate (P = .019) analyses. BRCA(1/2) deficiency, defined as BRCA(1/2) mutations or expression loss (in 24 [13.3%] BRCA(1/2)-wild-type cancers), was present in 67 ovarian cancers (30%) and was also significantly associated with PFS in univariate (P = .026; HR = 0.67; 95% CI, 0.47 to 0.96) and multivariate (P = .008) analyses.


CONCLUSIONS
BRCA(1/2) somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.
Hennessy
Bryan T J
BT
Department of Gynecology Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. bryanhennessy74@gmail.com
Timms
Kirsten M
KM
Carey
Mark S
MS
Gutin
Alexander
A
Meyer
Larissa A
LA
Flake
Darl D
DD
Abkevich
Victor
V
Potter
Jennifer
J
Pruss
Dmitry
D
Glenn
Pat
P
Li
Yang
Y
Li
Jie
J
Gonzalez-Angulo
Ana Maria
AM
McCune
Karen Smith
KS
Markman
Maurie
M
Broaddus
Russell R
RR
Lanchbury
Jerry S
JS
Lu
Karen H
KH
Mills
Gordon B
GB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1