A49: 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

Susan Richman1,Gemma Hemmings1,Phil Chambers1,Morag Taylor1,Henry Wood1,Emma Tinkler-Hundal1,Katie Southward1,Joseph Foster2,Assa Ouime2,Karen Spink2,Phil Quirke1

1Leeds Institute of Cancer and Pathology, Leeds, UK,2Affymetrix UK Ltd, High Wycombe, UK

Presenting date: Monday 2 November
Presenting time: 12.20-13.10

Background

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.

Method

Tissue microarrays were constructed from 2 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.

Results

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.

Conclusion

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.