Details

Autor(en) / Beteiligte

• HENNESSY, Bryan T. J
• TIMMS, Kirsten M
• YANG LI
• JIE LI
• GONZALEZ-ANGULO, Ana Maria
• MCCUNE, Karen Smith
• MARKMAN, Maurie
• BROADDUS, Russell R
• LANCHBURY, Jerry S
• LU, Karen H
• MILLS, Gordon B
• CAREY, Mark S
• GUTIN, Alexander
• MEYER, Larissa A
• FLAKE, Darl D
• ABKEVICH, Victor
• POTTER, Jennifer
• PRUSS, Dmitry
• GLENN, Pat

Titel

Somatic Mutations in BRCA1 and BRCA2 Could Expand the Number of Patients That Benefit From Poly (ADP Ribose) Polymerase Inhibitors in Ovarian Cancer

Ist Teil von

• Journal of clinical oncology, 2010-08, Vol.28 (22), p.3570-3576

Ort / Verlag

Alexandria, VA: American Society of Clinical Oncology

Erscheinungsjahr

2010

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. 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. 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. 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.