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

Price, T J; Bruhn, M A; Lee, C K; Hardingham, J E; Townsend, A R; Mann, K P; Simes, J; Weickhardt, A; Wrin, J W; Wilson, K; Gebski, V; Van Hazel, G; Robinson, B; Cunningham, D; Tebbutt, N C

doi:10.1038/bjc.2015.37

Cited by 39Colorectal Cancer Treatments and StudiesColorectal Cancer Surgical TreatmentsGenetic factors in colorectal cancer

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

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Price, T J, Bruhn, M A, Lee, C K, Hardingham, J E, Townsend, A R, Mann, K P, Simes, J, Weickhardt, A +7 more·2015·British Journal of Cancer

DOI 10.1038/bjc.2015.37PMC PMC4366893

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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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Addition of bevacizumab to chemotherapy contributes to PFS regardless of KRAS mutation status.
“In studies evaluating the addition of bevacizumab to chemotherapy agents, the addition of bevacizumab contributes to PFS, regardless of KRAS mutation status [17,18].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [17]

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Correlation of PI3KCAand extended RAS gene mutation status with outcomes from the phase III AGITG MAX involving capecitabine (C) alone or in combination with bevacizumab (B) with or without mitomycin C (M) in advanced colorectal cancer (CRC).
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Authors: Price, T. J., Bruhn, M. A., Lee, C. K., Hardingham, J. E., Townsend, A. R., Mann, K. P., Simes, J., Weickhardt, A., Wrin, J. W., Wilson, K., Gebski, V, Van Hazel, G., Robinson, B., Cunningham, D., & Tebbutt, N. C.
Affiliations: Queen Elizabeth Hospital (AU)
The University of Adelaide (AU)
The University of Sydney (AU)
Ludwig Cancer Research (AU)
Christchurch Hospital (NZ)
Royal Marsden Hospital (GB)
Corresponding author: Price, T J
ORCID: Price, T J
Lee, C K
Hardingham, J E
Townsend, A R
Weickhardt, A
Wrin, J W
Wilson, K
Gebski, V
Robinson, B
Cunningham, D
Tebbutt, N C
Venue: British Journal of Cancer
Publisher: Springer Science and Business Media LLC
Published: 2015-03
Volume: 112
Issue: 6
Pages: 963-970
ISSN: 0007-0920 (ISSN-L)
1532-1827
DOI: 10.1038/bjc.2015.37
PMC: PMC4366893
OpenAlex: W2014590712
Cited by: 39
References: 32
Citations by year: 2025: 2 · 2024: 4 · 2021: 3 · 2020: 5 · 2019: 6 · 2018: 3 · 2017: 7 · 2016: 7 · 2015: 2
FWCI: 2.77
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0 (tdm)
Locations: British Journal of Cancer (publishedVersion, cc-by-nc-sa)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
UWA Profiles and Research Repository (University of Western Australia) (submittedVersion, other-oa)
Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-sa)
The Sydney eScholarship Repository (The University of Sydney) (submittedVersion, cc-by-nc-sa)
Funders: Cancer Australia
Cancer Institute NSW
National Health and Medical Research Council
Topics: Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords: RAS mutations, PIK3CA mutation, advanced colorectal cancer, capecitabine, bevacizumab, mitomycin C, predictive biomarkers, prognostic factors, KRAS exon 2, NRAS, progression-free survival, overall survival, anti-EGFR antibody resistance
MeSH terms: Bevacizumab, Capecitabine, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Deoxycytidine, DNA, Neoplasm, Female, Fluorouracil, Humans, Male, Mutation, Prognosis, Genes, ras, Colorectal Neoplasms, Mitomycin, Phosphatidylinositol 3-Kinases, Class I Phosphatidylinositol 3-Kinases, Antibodies, Monoclonal, Humanized

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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

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