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Type: Journal article
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
Author: Price, T.
Bruhn, M.
Lee, C.
Hardingham, J.
Townsend, A.
Mann, K.
Simes, J.
Weickhardt, A.
Wrin, J.
Wilson, K.
Gebski, V.
Van Hazel, G.
Robinson, B.
Cunningham, D.
Tebbutt, N.
Citation: British Journal of Cancer, 2015; 112(6):963-970
Publisher: Nature Publishing Group
Issue Date: 2015
ISSN: 0007-0920
Statement of
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
RMID: 0030024352
DOI: 10.1038/bjc.2015.37
Appears in Collections:Medicine publications

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