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Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.

ABSTRACT: PURPOSE:To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. EXPERIMENTAL DESIGN:We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. RESULTS:The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality. CONCLUSIONS:BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.

SUBMITTER: Candido-dos-Reis FJ

PROVIDER: S-EPMC4338615 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.

Candido-dos-Reis Francisco J FJ Song Honglin H Goode Ellen L EL Cunningham Julie M JM Fridley Brooke L BL Larson Melissa C MC Alsop Kathryn K Dicks Ed E Harrington Patricia P Ramus Susan J SJ de Fazio Anna A Mitchell Gillian G Fereday Sian S Bolton Kelly L KL Gourley Charlie C Michie Caroline C Karlan Beth B Lester Jenny J Walsh Christine C Cass Ilana I Olsson Håkan H Gore Martin M Benitez Javier J JJ Garcia Maria J MJ Andrulis Irene I Mulligan Anna Marie AM Glendon Gord G Blanco Ignacio I Lazaro Conxi C Whittemore Alice S AS McGuire Valerie V Sieh Weiva W Montagna Marco M Alducci Elisa E Sadetzki Siegal S Chetrit Angela A Kwong Ava A Kjaer Susanne K SK Jensen Allan A Høgdall Estrid E Neuhausen Susan S Nussbaum Robert R Daly Mary M Greene Mark H MH Mai Phuong L PL Loud Jennifer T JT Moysich Kirsten K Toland Amanda E AE Lambrechts Diether D Ellis Steve S Frost Debra D Brenton James D JD Tischkowitz Marc M Easton Douglas F DF Antoniou Antonis A Chenevix-Trench Georgia G Gayther Simon A SA Bowtell David D Pharoah Paul D P PD

Clinical cancer research : an official journal of the American Association for Cancer Research 20141114 3

<h4>Purpose</h4>To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis.<h4>Experimental design</h4>We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using ...[more]

PMID: 25398451

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Project description:BACKGROUND:BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients. The prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of these hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies. METHODS:Mining and statistical analyses of the original DNA and RNA sequencing data and The Cancer Genome Atlas data were performed. To interpret the data, we have used published literature and web available resources such as Gene Ontology, The Cancer immunome Atlas and the Cancer Research Institute iAtlas. RESULTS:We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but they express a range of phenotypes similar to sporadic cancers. All breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC) also express a high degree of HRD. CONCLUSIONS:TMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of "BRCAness" and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition. TRIAL REGISTRATION:Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent TNBC or HGSOC (NCT01623349), first posted on June 20, 2012. The design and the outcome of the clinical trial is not in the scope of this study.

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.

Project description:Background:This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients, who later participated in a clinical trial. BRCA1/2 germline mutation related hereditary cancers are candidates for new immune therapeutic interventions. However, contrary to what is expected of tumors with compromised DNA repair, a prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort, was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of BRCA1/2 related hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies. Methods:Mining and statistical analyses of the original DNA and RNA sequencing data and data available from The Cancer Genome Atlas (TCGA) were performed using the R computing environment. To interpret the data, we have used published literature and web available resources such as Gene Ontology Tools, The Cancer immunome Atlas (TCIA) and the Cancer Research Institute iAtlas. Results: We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but that they express a range of phenotypes similar to sporadic cancers. Importantly, BRCA2 germline mutation related breast tumors have a different profile of genomic instability compared to those related to BRCA1. However, all breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC), but not other types of breast cancer, also express a high degree of HRD. Conclusion: : Tumor mutation burdon (TMB) is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of “BRCAness” and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition.

Dataset Information

Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.

Publications

Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.

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