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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.

Pander J, van Huis-Tanja L, Böhringer S, van der Straaten T, Gelderblom H, Punt C, Guchelaar HJ - PLoS ONE (2015)

Bottom Line: 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)).

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, The Netherlands; PO box 9600, 2300 RC Leiden, The Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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pone.0131091.g003: 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.

Mentions: Initially, analyses were performed including the interaction term of genetic markers with treatment arm as a covariate. The Manhattan plot for these analyses is shown in Fig 2 and details for the ten most significant markers are provided in Table 2. Markers with a differential effect according to treatment arm may actually reflect predictive markers for cetuximab efficacy. One marker (rs885036, position 98671226) on chromosome 2q12 showed a highly significant interaction with treatment arm (P = 2.17x10-8). In a stratified analysis, this SNP proved to have a contrasting effect in both treatment arms. Kaplan-Meyer survival curves for PFS according to genotype are shown in Fig 3. For patients treated with CAPOX-B, the G allele associated with shorter PFS (AA 13.47 months [95%CI 12.16–16.43]; AG 12.22 months [95%CI 9.17–14.32]; GG 9.00 months [95%CI 7.56–10.68]). For patients treated with CAPOX-B plus cetuximab, the G allele associated with increased PFS (AA 7.31 months [95%CI 6.53–10.05]; AG 10.05 months [95%CI 8.83–12.16]; GG 12.35 months [95%CI 10.35–15.44]).


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.

Pander J, van Huis-Tanja L, Böhringer S, van der Straaten T, Gelderblom H, Punt C, Guchelaar HJ - PLoS ONE (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4519298&req=5

pone.0131091.g003: 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.
Mentions: Initially, analyses were performed including the interaction term of genetic markers with treatment arm as a covariate. The Manhattan plot for these analyses is shown in Fig 2 and details for the ten most significant markers are provided in Table 2. Markers with a differential effect according to treatment arm may actually reflect predictive markers for cetuximab efficacy. One marker (rs885036, position 98671226) on chromosome 2q12 showed a highly significant interaction with treatment arm (P = 2.17x10-8). In a stratified analysis, this SNP proved to have a contrasting effect in both treatment arms. Kaplan-Meyer survival curves for PFS according to genotype are shown in Fig 3. For patients treated with CAPOX-B, the G allele associated with shorter PFS (AA 13.47 months [95%CI 12.16–16.43]; AG 12.22 months [95%CI 9.17–14.32]; GG 9.00 months [95%CI 7.56–10.68]). For patients treated with CAPOX-B plus cetuximab, the G allele associated with increased PFS (AA 7.31 months [95%CI 6.53–10.05]; AG 10.05 months [95%CI 8.83–12.16]; GG 12.35 months [95%CI 10.35–15.44]).

Bottom Line: 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)).

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, The Netherlands; PO box 9600, 2300 RC Leiden, The Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus