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Clinical Trial
. 2015 Jul 29;10(7):e0131091.
doi: 10.1371/journal.pone.0131091. eCollection 2015.

Genome Wide Association Study for Predictors of Progression Free Survival in Patients on Capecitabine, Oxaliplatin, Bevacizumab and Cetuximab in First-Line Therapy of Metastatic Colorectal Cancer

Jan Pander  1 , Lieke van Huis-Tanja  2 , Stefan Böhringer  3 , Tahar van der Straaten  1 , Hans Gelderblom  2 , Cornelis Punt  4 , Henk-Jan Guchelaar  1
Affiliations
Clinical Trial

Genome Wide Association Study for Predictors of Progression Free Survival in Patients on Capecitabine, Oxaliplatin, Bevacizumab and Cetuximab in First-Line Therapy of Metastatic Colorectal Cancer

Jan Pander et al. PLoS One. .

Abstract

Purpose: Despite expanding options for systemic treatment, survival for metastatic colorectal cancer (mCRC) remains limited and individual response is difficult to predict. In search of pre-treatment predictors, pharmacogenetic research has mainly used a candidate gene approach. Genome wide association (GWA) studies offer the benefit of simultaneously analyzing a large number of SNPs, in both known and still unidentified functional regions. Using a GWA approach, we searched for genetic markers affecting progression free survival (PFS) in mCRC patients treated with first-line capecitabine, oxaliplatin and bevacizumab (CAPOX-B), with or without cetuximab.

Patients and methods: 755 patients were included in the CAIRO2-trial, a multicenter phase III trial, randomizing between first-line treatment with CAPOX-B versus CAPOX-B plus cetuximab. Germline DNA and complete clinical information was available from 553 patients and genome wide genotyping was performed, using Illumina's OmniExpress beadchip arrays, with 647,550 markers passing all quality checks. Another 2,202,473 markers were imputated by using HapMap2. Association with PFS was analysed using a Cox proportional hazards model.

Results: One marker, rs885036, associated significantly with PFS (P = 2.17x10(-8)) showing opposite effects on PFS depending on treatment arm. The minor allele was associated with increased PFS in patients receiving cetuximab. A cluster of markers located on chromosome 8 associated with PFS, irrespective of treatment arm (P-values of 2.30x10(-7) to 1.04x10(-6)).

Conclusion: This is the first GWA study to find SNPs affecting PFS in mCRC patients treated with CAPOX-B, either with or without cetuximab. Rs885036 is a potential predictive marker for cetuximab efficacy. These markers need to be validated in independent treatment cohorts.

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Conflict of interest statement

Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: this study received funding in the form of unrestricted scientific grants from Roche, Merck-Serono, Sanofi-Aventis and DxS. This does not alter the authors' adherence to PLOS policies on sharing data and materials.

Figures

Fig 1
Fig 1. Cairo2 study flow-chart.
Fig 2
Fig 2. Manhattan plot of–log10 (P-value) of the Cox-proportional hazards model.
Adjusted for age, gender and treatment arm and the interaction of marker with treatment arm. The horizontal line represents the formal genome-wide significance level of 5x10-8.
Fig 3
Fig 3. Kaplan-Meyer survival curves according to rs885036 genotype.
A. Survival curves for patients in arm A, treated with CAPOX-B in first-line chemotherapy. B. Survival curves for patients in arm B, treated with CAPOX-B plus cetuximab in first-line chemotherapy.
Fig 4
Fig 4. Manhattan plot of–log10 (P-value) of the Cox-proprotional hazards model.
Adjusted for age, gender and treatment arm. The horizontal line represents the formal genome-wide significance level of 5x10-8. The topmost significant markers are circled, i.e. rs2936519, rs2928608, rs2928609, rs2912024, rs2978926, rs2928607.
See this image and copyright information in PMC

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