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New perspective on maintenance therapies for platinum- sensitive recurrent ovarian cancer in women with germline and somatic mutations in BRCA1 and BRCA2 genes.

ABSTRACT: Ovarian cancer (OC) is the seventh most common cancer in women. Although women diagnosed with OC are usually treated frontline with platinum-based chemotherapy, most of them relapse once treatment is halted. Therefore, maintenance therapies have been developed to secure the response and delay further chemotherapy. There are two established maintenance therapies for women affected by platinum-sensitive recurrent OC: bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, and olaparib, an inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARPi). Loss-of-function mutations in genes in the homologous recombination pathway, especially BRCA1 and BRCA2, predict higher rates of platinum sensitivity, better overall survival (OS), and better response to PARPi in women with OC. Among patients with platinum-sensitive recurrent OC, a BRCA mutation is the first genetically defined predictive marker for targeted therapy, since these patients are most likely to benefit from treatment with a PARPi, such as olaparib. In patients with platinum-sensitive recurrent OC without a BRCA mutation, bevacizumab currently seems to be the best maintenance option. Women with OC are progressively more routinely screened for germline BRCA mutations, and the implication of somatic BRCA mutations is increasingly being recognized in OC. Therefore, the recommendations should be updated to reflect the importance of both types of mutations. Together, these data highlight the fact that treatment of recurrent OC can be optimized using genomic contributions to individualize therapy and to improve treatment response.

SUBMITTER: Vergote I

PROVIDER: S-EPMC5172572 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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New perspective on maintenance therapies for platinum- sensitive recurrent ovarian cancer in women with germline and somatic mutations in BRCA1 and BRCA2 genes.

Vergote I I Bours V V Blaumeiser B B Baurain J-F JF

Facts, views & vision in ObGyn 20160901 3

Ovarian cancer (OC) is the seventh most common cancer in women. Although women diagnosed with OC are usually treated frontline with platinum-based chemotherapy, most of them relapse once treatment is halted. Therefore, maintenance therapies have been developed to secure the response and delay further chemotherapy. There are two established maintenance therapies for women affected by platinum-sensitive recurrent OC: bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growt ...[more]

PMID: 28003870

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Project description:BackgroundApproximately 3/4 of ovarian cancers are diagnosed in advanced stages, with the high-grade epithelial ovarian carcinoma (EOC) accounting for 90% of the cases. EOC present high genomic instability and somatic loss-of-function variants in genes associated with homologous recombination mutational repair pathway (HR), such as BRCA1 and BRCA2, and in TP53. The identification of germline variants in HR genes in EOC is relevant for treatment of platinum resistant tumors and relapsed tumors with therapies based in synthetic lethality such as PARP inhibitors. Patients with somatic variants in HR genes may also benefit from these therapies. In this work was analyzed the frequency of somatic variants in BRCA1, BRCA2, and TP53 in an EOC cohort of Brazilian patients, estimating the proportion of variants in tumoral tissue and their association with progression-free survival and overall survival.MethodsThe study was conducted with paired blood/tumor samples from 56 patients. Germline and tumoral sequences of BRCA1, BRCA2, and TP53 were obtained by massive parallel sequencing. The HaplotypeCaller method was used for calling germline variants, and somatic variants were called with Mutect2.ResultsA total of 26 germline variants were found, and seven patients presented germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2. The analysis of tumoral tissue identified 52 somatic variants in 41 patients, being 43 somatic variants affecting or likely affecting protein functionality. Survival analyses showed that tumor staging was associated with overall survival (OS), while the presence of somatic mutation in TP53 was not associated with OS or progression-free survival.ConclusionFrequency of pathogenic or likely pathogenic germline variants in BRCA1 and BRCA2 (12.5%) was lower in comparison with other studies. TP53 was the most altered gene in tumors, with 62.5% presenting likely non-functional or non-functional somatic variants, while eight 14.2% presented likely non-functional or non-functional somatic variants in BRCA1 or BRCA2.

Dataset Information

New perspective on maintenance therapies for platinum- sensitive recurrent ovarian cancer in women with germline and somatic mutations in BRCA1 and BRCA2 genes.

Publications

New perspective on maintenance therapies for platinum- sensitive recurrent ovarian cancer in women with germline and somatic mutations in BRCA1 and BRCA2 genes.

Similar Datasets

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