Richman, SD orcid.org/0000-0003-3993-5041, Hemmings, GJ, Chambers, P et al. (8 more authors) (2015) Loss of pTEN Expression is Strongly Associated with the Presence of the BRAF V600E Mutation, and Further Complicates Combination Treatment Strategies for Patients with Advanced Colorectal Cancer. In: Journal of Pathology. Dublin Pathology 2015. 8th Joint Meeting of the British Division of the International Academy of Pathology and the Pathological Society of Great Britain & Ireland, 23-25 Jun 2015, Dublin, Ireland. Wiley , S14-S14.
Abstract
Treatment for advanced colorectal cancer is moving to combination therapies, targeting multiple signalling pathways. Indeed, MRC FOCUS4 has been designed to assess this. We determined pTEN protein expression, and assessed this in relation to other biomarkers associated with signalling downstream of the epidermal growth factor receptor. Tissue microarrays were constructed from 2 advanced colorectal cancer (aCRC) clinical trials (FOCUS and PICCOLO) for immunohistochemistry (IHC). Mutation status of KRAS, NRAS, PIK3CA and BRAF was assessed by pyrosequencing. Copy number variation was assessed on Oncoscan® FFPE Assay Kit (Affymetrix Inc.). pTEN protein expression was correlated with mutation status, MMR status, primary tumour location and copy number. pTEN protein expression for 1288 patients showed complete loss of expression in 85/787 (10.8%) - FOCUS and 64/501 (12.8%) - PICCOLO. BRAF mutation status was significantly different between the pTEN negative and pTEN positive populations (p<0.0001), with significantly more pTEN negative tumours having the BRAF V600E mutation. Loss of pTEN expression correlated with genomic deletions involving the pTEN gene. 20/30 (66%) of pTEN negative tumours exhibited loss of the pTEN region (10q), half of which were focal deletions. Only 54/202 (26.7%) pTEN positive tumours showed deletions of this region, and none were focal events. There was no significant difference in either primary tumour site or MMR status (p=0.1765) between the pTEN negative and pTEN positive populations. Signalling pathways do not stand in isolation; they are interlinked in a complex signalling network. Current treatment interventions must target the correct pathway combinations if patients are to benefit from targeted therapy. Our data suggests a subset of patients may require dual AKT and MEK pathway inhibition, in addition to anti-EGFR monoclonal antibody therapy and inhibition of BRAF.
Metadata
Item Type: | Proceedings Paper |
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Authors/Creators: |
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Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Pathology & Tumour Biology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 20 Oct 2016 10:01 |
Last Modified: | 20 Oct 2016 10:01 |
Published Version: | https://doi.org/10.1002/path.4631 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/path.4631 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:97500 |