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|Title:||Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX STUDY involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer|
Van Hazel, G.
|Citation:||British Journal of Cancer, 2015; 112(6):963-970|
|Publisher:||Nature Publishing Group|
|T J Price, M A Bruhn, C K Lee, J E Hardingham, A R Townsend, K P Mann, J Simes, A Weickhardt, J W Wrin, K Wilson, V Gebski, G Van Hazel, B Robinson, D Cunningham and N C Tebbutt|
|Abstract:||BACKGROUND: Mutations affecting RAS genes are now established predictive markers of nonresponse to anti-EGFR antibodies in advanced CRC. This analysis assessed the prognostic and predictive impact of extended RAS and PIK3CA gene mutation status in patients receiving capecitabine plus or minus bevacizumab (±mitomycin C) in the randomised phase III MAX study. METHODS: DNA was extracted from archival macrodissected formalin-fixed paraffin-embedded tumour tissue. Mutation status was determined using pyrosequencing, confirmed with Sanger sequencing (for equivocal RAS) and correlated with efficacy outcomes. Predictive analyses were undertaken using a test for interaction involving both C vs CB+CBM. RESULTS: Of the available 280 of the 471 (59.4%) patients, mutations in KRAS exons 2, 3 and 4 and NRAS 2, 3 and 4 were as follows: 32%, 2.9%, 2.2%, 1.4%, 0.7% and 0% (total RAS MT 39%). The PIK3CA MT rate was 7.5% exon 9 and 3.6% exon 20. Extended RAS gene mutation status (WT vs MT) had no prognostic impact for PFS (HR 0.91 (0.71-1.17)) or OS (HR 0.95 (0.71-1.25)). The RAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS (HR 0.56 (0.37-0.85) for RAS MT and HR 0.69 (0.5-0.97) for RAS WT; P for interaction 0.50). The PIK3CA mutation was neither predictive for bevacizumab effect nor prognostic. CONCLUSION: Of KRAS exon 2 WT patients, 10% had additional RAS mutations. Neither all RAS gene mutation status nor PIK3CA mutation status was prognostic for PFS or OS, or predictive of bevacizumab outcome in patients with advanced CRC.|
|Keywords:||Humans; Colorectal Neoplasms; Mitomycin; Fluorouracil; DNA, Neoplasm; Deoxycytidine; Antineoplastic Combined Chemotherapy Protocols; Prognosis; Mutation; Genes, ras; Adult; Aged; Aged, 80 and over; Female; Male; Phosphatidylinositol 3-Kinases; Class I Phosphatidylinositol 3-Kinases; Antibodies, Monoclonal, Humanized; Bevacizumab; Capecitabine|
|Description:||Presented in part at the American Society of Clinical Oncology annual meeting, Chicago 31 May to 3 June 2014.|
|Rights:||© 2015 Cancer Research UK|
|Appears in Collections:||Medicine publications|
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