BRCA1/2 mutations and expression: Response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer
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.
[Show abstract] [Hide abstract]
- "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 ) . "
ABSTRACT: Germline mutations of the BRCA tumour suppressors have been associated with increased risk of pancreatic cancer. Clinical evidence suggests that these patients may be more sensitive to treatment with cisplatin. As the frequency of germline BRCA mutations is low, definitive experimental data to support the clinical observations are still missing. We tested gemcitabine and cisplatin sensitivity of four BRCA1 and BRCA2 mutant and three BRCA1 and BRCA2 wild-type (WT) patient-derived pancreatic cancer xenografts. We observed treatment sensitivity to gemcitabine and cisplatin in the BRCA WT and mutant models. The BRCA1 and BRCA2 mutant xenografts were significantly more sensitive to cisplatin although these models also showed sensitivity to gemcitabine. The BRCA1 and BRCA2 WT models showed sensitivity to gemcitabine but not cisplatin. Treatment sensitivity in the xenograft models closely resembled treatment response in the corresponding patients. We have characterised a panel of xenografts derived from pancreatic cancer patients carrying germline BRCA mutations, and shown that their genetic features resemble the patient donor. Our results support further clinical testing of treatment regimens combining gemcitabine and platinum drugs in this patient population, as well as preclinical research aiming to identify mechanisms of cisplatin resistance in BRCA mutant pancreatic cancers.British Journal of Cancer advance online publication, 16 July 2015; doi:10.1038/bjc.2015.220 www.bjcancer.com.British Journal of Cancer 07/2015; 113(3). DOI:10.1038/bjc.2015.220 · 4.84 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: A key function of BRCA1 and BRCA2 is the participation in dsDNAbreak repair via homologous recombination. BRCA1 and BRCA2 mutations, which occur in most hereditary ovarian cancers (OCs) and approximately 10% of all OC cases, are associated with defects in homologous recombination and genomic instability, a phenotype termed 'BRCAness'. The clinical effects of BRCA1 and BRCA2 mutations have commonly been analyzed together; however, it is becoming increasingly apparent that these mutations do not have the same effects in OC. Recently, three major reports highlighted the unequal clinical characteristics of OCs with BRCA1 and BRCA2 mutations. All studies demonstrated that BRCA2-mutated patients are associated with better survival and therapeutic response than BRCA1-mutated and wild-type patients with serous OC. The differing prognostic effects of the BRCA2 and BRCA1 mutations is likely due to differing roles of BRCA1 and BRCA2 in homologous recombination repair and a stronger association between the BRCA2 mutation and a hypermutator phenotype. These new findings have potentially important implications for clinical management of patients with serous OC.Pharmacogenomics 10/2012; 13(13):1523-35. DOI:10.2217/pgs.12.137 · 3.22 Impact Factor
- [Show abstract] [Hide abstract]
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.British Journal of Cancer 10/2012; 107(10-Advance Online Publication). DOI:10.1038/bjc.2012.451 · 4.84 Impact Factor