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Clinical Trial
. 2015 Mar 17;112(6):963-70.
doi: 10.1038/bjc.2015.37.

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

T J Price  1 , M A Bruhn  2 , C K Lee  3 , J E Hardingham  4 , A R Townsend  1 , K P Mann  3 , J Simes  3 , A Weickhardt  5 , J W Wrin  6 , K Wilson  3 , V Gebski  3 , G Van Hazel  7 , B Robinson  8 , D Cunningham  9 , N C Tebbutt  5
Affiliations
Clinical Trial

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

T J Price et al. Br J Cancer. .

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.

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Figures

Figure 1
Figure 1
CONSORT diagram MAX AGITG TRIAL: RAS analysis.
Figure 2
Figure 2
Hazard ratios for progression-free survival according to RAS and PIK3CA. Forest plot to demonstrate hazard ratios for progression-free survival in subgroup analyses by RAS and PIK3CA status.
Figure 3
Figure 3
Kaplan–Meier curves for overall survival according to RAS and PIK3CA status. A comparison of the overall survival of all patients according to their (A) RAS and (B) PIK3A status
See this image and copyright information in PMC

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