Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab
BACKGROUND:Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesised that common germline variants within these pathways may also play similar roles. METH...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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BMJ
2017
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| _version_ | 1797104149733572608 |
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| author | Madi, A Fisher, D Maughan, TS Colley, JP Meade, AM Tejpar, S Van Den Bosch, B Maynard, J Humphreys, V Wasan, H Adams, RA Idziaszczyk, S Harris, R Kaplan, RS Cheadle, JP |
| author_facet | Madi, A Fisher, D Maughan, TS Colley, JP Meade, AM Tejpar, S Van Den Bosch, B Maynard, J Humphreys, V Wasan, H Adams, RA Idziaszczyk, S Harris, R Kaplan, RS Cheadle, JP |
| author_sort | Madi, A |
| collection | OXFORD |
| description | BACKGROUND:Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesised that common germline variants within these pathways may also play similar roles. METHODS:We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 patients with aCRC treated with oxaliplatin-fluoropyrimidine chemotherapy plus cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%. RESULTS:We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab-in patients with KRAS wild-type CRCs, 36.4% with one allele encoding proline responded, as compared with 71.2% homozygous for allele encoding serine (OR 0.23, 95% CI 0.09 to 0.56, p=0.0014), and this association was predictive for cetuximab (pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated. CONCLUSIONS:Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity. |
| first_indexed | 2024-03-07T06:29:46Z |
| format | Journal article |
| id | oxford-uuid:f598da79-b6b0-4aaf-8492-600a5541ad0b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:29:46Z |
| publishDate | 2017 |
| publisher | BMJ |
| record_format | dspace |
| spelling | oxford-uuid:f598da79-b6b0-4aaf-8492-600a5541ad0b2022-03-27T12:28:26ZComprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximabJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f598da79-b6b0-4aaf-8492-600a5541ad0bEnglishSymplectic Elements at OxfordBMJ2017Madi, AFisher, DMaughan, TSColley, JPMeade, AMTejpar, SVan Den Bosch, BMaynard, JHumphreys, VWasan, HAdams, RAIdziaszczyk, SHarris, RKaplan, RSCheadle, JPBACKGROUND:Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesised that common germline variants within these pathways may also play similar roles. METHODS:We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 patients with aCRC treated with oxaliplatin-fluoropyrimidine chemotherapy plus cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%. RESULTS:We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab-in patients with KRAS wild-type CRCs, 36.4% with one allele encoding proline responded, as compared with 71.2% homozygous for allele encoding serine (OR 0.23, 95% CI 0.09 to 0.56, p=0.0014), and this association was predictive for cetuximab (pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated. CONCLUSIONS:Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity. |
| spellingShingle | Madi, A Fisher, D Maughan, TS Colley, JP Meade, AM Tejpar, S Van Den Bosch, B Maynard, J Humphreys, V Wasan, H Adams, RA Idziaszczyk, S Harris, R Kaplan, RS Cheadle, JP Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab |
| title | Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab |
| title_full | Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab |
| title_fullStr | Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab |
| title_full_unstemmed | Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab |
| title_short | Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab |
| title_sort | comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to and toxicity from cetuximab |
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