BRCA1/2 mutations and expression: Response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer

Magee Womens Hospital of UPMC, Pittsburgh, PA 15213, USA.
Gynecologic Oncology (Impact Factor: 3.77). 03/2012; 125(3):677-82. DOI: 10.1016/j.ygyno.2012.03.006
Source: PubMed

ABSTRACT Our objective was to determine the rate of BRCA1/2 deficiency in platinum-sensitive and platinum-resistant tumors from a cohort of unselect patients with advanced epithelial ovarian cancer (EOH).
BRCA1/2 mutation analysis was performed in 29 patients with platinum-sensitive EOC and 24 patients with platinum-resistant disease. Germline DNA was analyzed in mutation carriers when normal tissue was available. BRCA expression was ascertained by quantitative rt-PCR. Associations between BRCA mutation status and expression levels and parameters of platinum response were analyzed.
Fifteen of 53 (28.3%) EOC tumors had BRCA1/2 mutations. Twelve mutations were in BRCA1, while 3 involved BRCA2. Of the 12 mutation-carriers with normal tissue available for DNA analyses, 33.3% of the mutations were found to be somatic. Three mutations were novel. The majority of BRCA mutations (73%) were identified in patients with platinum-sensitive disease. In total, 38% of platinum-sensitive tumors were found to have a BRCA mutation, compared to 17% of the platinum-resistant patients. A statistical trend toward platinum-sensitive disease was seen in BRCA mutation carriers (p=0.079). Nineteen (36%) study patients had some form of BRCA deficiency, and these patients were less likely to have platinum-resistant tumors (OR=0.29; p value=0.048).
BRCA mutations occurred more frequently in platinum-sensitive EOC than platinum-resistant disease. The high overall frequency of BRCA deficiency in EOC underscores the importance of tumor profiling as therapies targeting the DNA repair pathway are being investigated.

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    • "These mutations predispose to breast and ovarian cancers ( Foulkes and Shuen , 2013 ; Kobayashi et al , 2013 ) , and are associated with increased risk of pancreatic cancer ( Fernandes et al , 1994 ; Klein et al , 2001 ; Bartsch et al , 2004 ; Grant et al , 2014 ) . In addition to a role in tumour development , BRCA1 and BRCA2 mutations are associated with sensitivity to platinum drugs and other DNA - damaging agents in ovarian cancers ( Dann et al , 2012 ; Muggia and Safra , 2014 ) , and there are anecdotal reports that this is also the case in pancreatic cancers ( Lowery et al , 2011 ; Sonnenblick et al , 2011 ) . Additional support for this comes from a recent retrospective study of 71 pancreatic cancer patients with germline BRCA1 and BRCA2 mutations that reported superior overall survival for the patients who were treated with platinum , compared with those who were not treated with platinum ( Golan et al , 2014 ) . "
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    ABSTRACT: BACKGROUND: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). METHODS: Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. RESULTS: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10�-11). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10-�5 and 10�-29), and identified breast and pancreatic cell lines with BRCA defects. CONCLUSION: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.
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