TY - JOUR
T1 - Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer
AU - Hennessy, Bryan T.J.
AU - Timms, Kirsten M.
AU - Carey, Mark S.
AU - Gutin, Alexander
AU - Meyer, Larissa A.
AU - Flake, Darl D.
AU - Abkevich, Victor
AU - Potter, Jennifer
AU - Pruss, Dmitry
AU - Glenn, Pat
AU - Li, Yang
AU - Li, Jie
AU - Gonzalez-Angulo, Ana Maria
AU - McCune, Karen Smith
AU - Markman, Maurie
AU - Broaddus, Russell
AU - Lanchbury, Jerry S.
AU - Lu, Karen H.
AU - Mills, Gordon B
PY - 2010/8/1
Y1 - 2010/8/1
N2 - Purpose: The prevalence of BRCA1/2 mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA1/2 changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs. Patients and Methods: In 235 unselected ovarian cancers, BRCA1/2 was sequenced in 235, assessed by copy number analysis in 95, and tiling arrays in 65. 113 tumors were sequenced for TP53. BRCA1/2 transcript levels were assessed by quantitative polymerase chain reaction in 220. When available for tumors with BRCA1/2 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. BRCA1/2 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). BRCA1/2 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. BRCA1/2 deficiency, defined as BRCA1/2 mutations or expression loss (in 24 [13.3%] BRCA1/2-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. Conclusion: BRCA1/2 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.
AB - Purpose: The prevalence of BRCA1/2 mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA1/2 changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs. Patients and Methods: In 235 unselected ovarian cancers, BRCA1/2 was sequenced in 235, assessed by copy number analysis in 95, and tiling arrays in 65. 113 tumors were sequenced for TP53. BRCA1/2 transcript levels were assessed by quantitative polymerase chain reaction in 220. When available for tumors with BRCA1/2 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. BRCA1/2 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). BRCA1/2 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. BRCA1/2 deficiency, defined as BRCA1/2 mutations or expression loss (in 24 [13.3%] BRCA1/2-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. Conclusion: BRCA1/2 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.
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U2 - 10.1200/JCO.2009.27.2997
DO - 10.1200/JCO.2009.27.2997
M3 - Article
C2 - 20606085
AN - SCOPUS:77955886707
SN - 0732-183X
VL - 28
SP - 3570
EP - 3576
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 22
ER -