Gene Expression Profile of BRCAness That Correlates With Responsiveness to Chemotherapy and With Outcome in Patients With Epithelial Ovarian Cancer

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 08/2010; 28(22):3555-61. DOI: 10.1200/JCO.2009.27.5719
Source: PubMed


To define a gene expression profile of BRCAness that correlates with chemotherapy response and outcome in epithelial ovarian cancer (EOC).
A publicly available microarray data set including 61 patients with EOC with either sporadic disease or BRCA(1/2) germline mutations was used for development of the BRCAness profile. Correlation with platinum responsiveness was assessed in platinum-sensitive and platinum-resistant tumor biopsy specimens from six patients with BRCA germline mutations. Association with poly-ADP ribose polymerase (PARP) inhibitor responsiveness and with radiation-induced RAD51 foci formation (a surrogate of homologous recombination) was assessed in Capan-1 cell line clones. The BRCAness profile was validated in 70 patients enriched for sporadic disease to assess its association with outcome.
The BRCAness profile accurately predicted platinum responsiveness in eight out of 10 patient-derived tumor specimens, and between PARP-inhibitor sensitivity and resistance in four out of four Capan-1 clones. [corrected] When applied to the 70 patients with sporadic disease, patients with the BRCA-like (BL) profile had improved disease-free survival (34 months v 15 months; log-rank P = .013) and overall survival (72 months v 41 months; log-rank P = .006) compared with patients with a non-BRCA-like (NBL) profile, respectively. The BRCAness profile maintained independent prognostic value in multivariate analysis, which controlled for other known clinical prognostic factors.
The BRCAness profile correlates with responsiveness to platinum and PARP inhibitors and identifies a subset of sporadic patients with improved outcome. Additional evaluation of this profile as a predictive tool in patients with sporadic EOC is warranted.

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Available from: Toshiyasu Taniguchi, Jul 18, 2014
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    • "Moreover, targeted therapies are underdevelopment that exploit the defect in HR, inhibiting poly(ADP-ribose)polymerase (PARP), and creating a lethal submission of DNA repair by interrupting base excision repair. BRCA mutations confer sensitivity to PARP inhibitors and it has been suggested that this sensitivity may extend to other FA-BRCA (HR) genes as well [37] [38] [39] [40]. This population of probands was referred nationwide for testing, making our data set large and generalizable to patient cohorts with a history of breast or ovarian cancer. "
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    ABSTRACT: Objective: Genetic predisposition to ovarian cancer is well documented. With the advent of next generation sequencing, hereditary panel testing provides an efficient method for evaluating multiple genes simultaneously. Therefore, we sought to investigate the contribution of 19 genes identified in the literature as increasing the risk of hereditary breast and ovarian cancer (HBOC) in a BRCA1 and BRCA2 negative population of patients with a personal history of breast and/or ovarian cancer by means of a hereditary cancer panel. Methods: Subjects were referred for multi-gene panel testing between February 2012 and March 2014. Clinical data was ascertained from requisition forms. The incidence of pathogenic mutations (including likely pathogenic), and variant of unknown significance were then calculated for each gene and/or patient cohort. Results: In this cohort of 911 subjects, panel testing identified 67 mutations. With 7.4% of subjects harboring a mutation on this multi-gene panel, the diagnostic yield was increased, compared to testing for BRCA1 and BRCA2 mutations alone. In the ovarian cancer probands, the most frequently mutated genes were BRIP1 (n=8; 1.72%) and MSH6 (n=6; 1.29%). In the breast cancer probands, mutations were most commonly observed in CHEK2 (n=9; 2.54%), ATM (n=3; 0.85%), and TP53 (n=3; 0.85%). Conclusions: Although further studies are needed to clarify the exact management of patients with a mutation in each gene, this study highlights information that can be captured with panel testing and provides support for incorporation of panel testing into clinical practice.
    Gynecologic Oncology 01/2015; 137(1). DOI:10.1016/j.ygyno.2015.01.537 · 3.77 Impact Factor
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    • "The BRCA-likeCGH status is probably not the only way to identify tumors that are sensitive to DNA DSB-inducing agents. Several potential predictive markers have been described in nonrandomized studies, such as RAD51 staining [45], gene expression profiling [46], telomere aberrations [47], BRCA1-promoter methylation, and BRCA1 gene expression measurements [10]. "
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    ABSTRACT: Introduction BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2-mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy. Methods Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-likeCGH status, others as non-BCRA-likeCGH. Stage-III patients (n = 249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy. Results Among patients with BRCA-likeCGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-likeCGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P = 0.004). Half of all BRCA-likeCGH tumors were ER-positive. Conclusions Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-likeCGH patients) and those without benefit (non-BRCA-likeCGH patients).
    Breast cancer research: BCR 05/2014; 16(3):R47. DOI:10.1186/bcr3655 · 5.49 Impact Factor
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    • "Meta-analysis signature TCGA signature Verhaak et al. signature G) Bentink et al. 2012 Crijns et al. 2009 Yoshihara et al. 2010 Mok et al. 2009 Bonome et al. 2008 Tothill et al. 2008 Dressman et al. 2007 Konstantinopoulos et al. 2010 Gillet et al. 2012 Yoshihara et al. 2012 Overall 0.5 1.0 2.0 4.0 8.0 Hazard ratio 0 20 40 60 80 100 A Meta-analysis signature Survival (%) HR = 2.19; 95% CI = 1.84 to 2.61 0 300 900 1500 Time (days) No. at risk High risk 521 453 323 221 144 100 60 Low risk 510 476 409 331 247 174 129 0 20 40 60 80 100 B Signature + stage + debulking Survival (%) HR = 2.17; 95% CI = 1.78 to 2.65 0 300 900 1500 Time (days) No. at risk High risk 403 359 267 180 114 79 50 Low risk 403 378 330 263 199 139 102 0 20 40 60 80 100 C Stage and debulking only Survival (%) HR = 1.45; 95% CI = 1.2 to 1.77 0 300 900 1500 Time (days) No. at risk High risk 383 340 273 193 144 96 65 Low risk 423 397 324 250 169 122 87 0 20 40 60 80 100 D TCGA signature Survival (%) HR = 1.83; 95% CI = 1.54 to 2.17 0 300 900 1500 Time (days) No. at risk High risk 516 446 326 230 156 103 71 Low risk 515 483 406 322 235 171 118 0 20 40 60 80 100 E Verhaak et al. signature Survival (%) HR = 1.83; 95% CI = 1.54 to 2.17 0 300 900 1500 Time (days) No. at risk High risk 526 453 329 232 156 103 67 Low risk 505 476 403 320 235 171 122 0 20 40 60 80 100 F Verhaak et al. multivariable Survival (%) HR = 1.97; 95% CI = 1.61 to 2.4 0 300 900 1500 Time (days) No. at risk High risk 403 354 266 180 122 87 51 Low risk 403 383 331 263 191 131 101 High risk Low risk "
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    ABSTRACT: Ovarian cancer causes more than 15000 deaths per year in the United States. The survival of patients is quite heterogeneous, and accurate prognostic tools would help with the clinical management of these patients. We developed and validated two gene expression signatures, the first for predicting survival in advanced-stage, serous ovarian cancer and the second for predicting debulking status. We integrated 13 publicly available datasets totaling 1525 subjects. We trained prediction models using a meta-analysis variation on the compound covariable method, tested models by a "leave-one-dataset-out" procedure, and validated models in additional independent datasets. Selected genes from the debulking signature were validated by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in two further independent cohorts of 179 and 78 patients, respectively. All statistical tests were two-sided. The survival signature stratified patients into high- and low-risk groups (hazard ratio = 2.19; 95% confidence interval [CI] = 1.84 to 2.61) statistically significantly better than the TCGA signature (P = .04). POSTN, CXCL14, FAP, NUAK1, PTCH1, and TGFBR2 were validated by qRT-PCR (P < .05) and POSTN, CXCL14, and phosphorylated Smad2/3 were validated by immunohistochemistry (P < .001) as independent predictors of debulking status. The sum of immunohistochemistry intensities for these three proteins provided a tool that classified 92.8% of samples correctly in high- and low-risk groups for suboptimal debulking (area under the curve = 0.89; 95% CI = 0.84 to 0.93). Our survival signature provides the most accurate and validated prognostic model for early- and advanced-stage high-grade, serous ovarian cancer. The debulking signature accurately predicts the outcome of cytoreductive surgery, potentially allowing for stratification of patients for primary vs secondary cytoreduction.
    Journal of the National Cancer Institute 04/2014; 106(5). DOI:10.1093/jnci/dju048 · 12.58 Impact Factor
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