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Novel Approach for Clinical Validation of the cobas KRAS Mutation Test in Advanced Colorectal Cancer.

ABSTRACT: Our objective was to assess the performance of the cobas test versus comparators for KRAS mutation status and predicting clinical response to anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC).mCRC samples from 398 patients from Roche study NO16968 (XELOXA) and 82 supplemental samples were tested with the cobas(®) KRAS mutation test (cobas test), the therascreen(®) KRAS RGQ PCR kit test (therascreen test), and Sanger sequencing as the reference method for detecting mutations in codons 12/13.For 461 eligible samples, the cobas test, therascreen test, and sequencing had invalid results for 5.2, 10.8, and 2.6 % of specimens, respectively. Valid cobas and therascreen test results had similar KRAS mutation-positive rates (37.3 vs. 36.3 %, respectively); sequencing was 28.5 %. Positive and negative percent agreement (PPA/NPA) between the cobas test and sequencing was 96.9 % (95 % confidence interval [CI] 92.2-98.8), and 88.7 % (95 % CI 84.7-91.8), respectively. PPA/NPA between the cobas and therascreen tests was 93.3 % (95 % CI 88.1-96.3) and 96.5 % (95 % CI 93.5-98.1), respectively. Bridging analysis from NCIC-CO.17 and NCT00113763 using the cobas test yielded modeled hazard ratios for overall survival and progression-free survival (PFS) of 0.558 (95 % CI 0.422-0.752) and 0.413 (95 % CI 0.304-0.550), respectively, for cetuximab and 0.989 (95 % CI 0.778-1.299) and 0.471 (95 % CI 0.360-0.626), respectively, for panitumumab, demonstrating significant efficacy in the KRAS-negative population for PFS.The cobas test showed similar accuracy to the therascreen test for detecting KRAS mutations and could appropriately identify mCRC patients ineligible for anti-EGFR therapy as demonstrated by bridging analysis results.

SUBMITTER: Sharma A

PROVIDER: S-EPMC4879158 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Novel Approach for Clinical Validation of the cobas KRAS Mutation Test in Advanced Colorectal Cancer.

Sharma Abha A Zhang Guili G Aslam Shagufta S Yu Karen K Chee Melody M Palma John F JF

Molecular diagnosis & therapy 20160601 3

<h4>Aim</h4>Our objective was to assess the performance of the cobas test versus comparators for KRAS mutation status and predicting clinical response to anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC).<h4>Methods</h4>mCRC samples from 398 patients from Roche study NO16968 (XELOXA) and 82 supplemental samples were tested with the cobas(®) KRAS mutation test (cobas test), the therascreen(®) KRAS RGQ PCR kit test (therascreen test), and San ...[more]

PMID: 26984642

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Project description:ObjectiveTo present the technical verification and clinical validation of the companion diagnostic assay, cobas® EZH2 Mutation Test (cobas EZH2 Test), targeting gain-of-function EZH2 mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). The focus is on patient clinical samples proving that the test met the performance criteria required for FDA approval of a companion diagnostic test.DesignEpizyme, Inc., Eisai Co., Ltd., and Roche Molecular Systems, Inc., collaborated to develop the cobas EZH2 Test on an RT-PCR platform. The assay design needed to detect the gain-of-function EZH2 mutations found in FL and DLBCL indications. Thus, the test was optimized for investigational purposes in a clinical trial setting. Part of its technical verification included testing of patient tumor samples with a documented diagnosis of FL and DLBCL procured from commercial vendors, and the clinical validation used patient samples from the Epizyme clinical study. Both the technical performance verification method correlation study (104 clinical commercially acquired samples) and the clinical validation accuracy study (341 patient samples from the therapeutic study) used next-generation sequencing as a reference method to establish true vs. false results by cobas EZH2 Test. The reproducibility study used a 15-member panel of DNA samples with varying EZH2 mutation status from procured clinical FL and DLBCL patient samples under multiple variables.ResultsSingle and rare, infrequent double EZH2 mutations were detected in FL and DLBCL samples. Agreements between results from cobas EZH2 and sequencing were >98% from commercial clinical samples and from the therapeutic study clinical samples. The reproducibility study obtained 178 to 180 valid results for each panel member, with an overall invalid rate of 0.37%. The agreement for each per panel member was 100%.Conclusioncobas EZH2 Test data demonstrated that the test is reliable and will perform well in a commercial customer environment.

Project description:BackgroundAnti-EGFR antibody-based treatment is an important therapeutic strategy for advanced colorectal cancer (CRC); despite this, several mutations--including KRAS, BRAF, and PIK3CA mutations, and HER2 amplification--are associated with the mechanisms underlying the development of resistance to anti-EGFR therapy. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC.MethodsKRAS, BRAF, and PIK3CA mutations were determined by Cobas real-time polymerase chain reaction (PCR) in 191 advanced CRC patients with distant metastasis. Microsatellite instability (MSI) status was determined by a fragmentation assay and HER2 amplification was assessed by silver in situ hybridization. In addition, KRAS mutations were investigated by the Sanger sequencing method in 97 of 191 CRC cases.ResultsMutations in KRAS, BRAF, and PIK3CA were found in 104 (54.5%), 6 (3.1%), and 25 (13.1%) cases of advanced CRC, respectively. MSI-high status and HER2 amplification were observed in 3 (1.6%) and 16 (8.4%) cases, respectively. PIK3CA mutations were more frequently found in KRAS mutant type (18.3%) than KRAS wild type (6.9%) (P = 0.020). In contrast, HER2 amplifications and BRAF mutations were associated with KRAS wild type with borderline significance (P = 0.052 and 0.094, respectively). In combined analyses with KRAS, BRAF and HER2 status, BRAF mutations or HER2 amplifications were associated with the worst prognosis in the wild type KRAS group (P = 0.004). When comparing the efficacy of detection methods, the results of real time PCR analysis revealed 56 of 97 (57.7%) CRC cases with KRAS mutations, whereas Sanger sequencing revealed 49 cases (50.5%).ConclusionsKRAS mutations were found in 54.5% of advanced CRC patients. Our results support that subgrouping using PIK3CA and BRAF mutation or HER2 amplification status, in addition to KRAS mutation status, is helpful for managing advanced CRC patients.

Dataset Information

Novel Approach for Clinical Validation of the cobas KRAS Mutation Test in Advanced Colorectal Cancer.

Publications

Novel Approach for Clinical Validation of the cobas KRAS Mutation Test in Advanced Colorectal Cancer.

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