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

摘要

Background: Mutations affecting RAS genes are now established predictive markers of nonresponse to anti-EGFR antibodies inudadvanced CRC. This analysis assessed the prognostic and predictive impact of extended RAS and PIK3CA gene mutation status inudpatients receiving capecitabine plus or minus bevacizumab (±mitomycin C) in the randomised phase III MAX study.udMethods: DNA was extracted from archival macrodissected formalin-fixed paraffin-embedded tumour tissue. Mutation status wasuddetermined using pyrosequencing, confirmed with Sanger sequencing (for equivocal RAS) and correlated with efficacy outcomes.udPredictive analyses were undertaken using a test for interaction involving both C vs CBþCBM.udResults: 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 asudfollows: 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.udExtended 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–ud1.25)). The RAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS (HR 0.56 (0.37–0.85) forudRAS MT and HR 0.69 (0.5–0.97) for RAS WT; P for interaction 0.50). The PIK3CA mutation was neither predictive forudbevacizumab effect nor prognostic.udConclusion: Of KRAS exon 2 WT patients, 10% had additional RAS mutations. Neither all RAS gene mutation status nor PIK3CAudmutation status was prognostic for PFS or OS, or predictive of bevacizumab outcome in patients with advanced CRC.