Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset
Open accessAbstract
Background The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial.Patients and methods We analyzed the prognostic impact of KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model.Results KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35-2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85-1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51-2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00-2.56; P = 0.051).Conclusion KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors.Clinical trial number This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.
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Mutations in exons 2-4 of KRAS and NRAS can lead to mCRC resistance to cetuximab and panitumumab.
“Mutations in exons 2–4 of KRAS and NRAS can lead to mCRC resistance to cetuximab and panitumumab [153,154].”
From Drug Resistance in Colorectal Cancer: From Mechanism to Clinic (2022) · cites this paper as [154]
Codon 13 mutations (G13D) in KRAS do not predict nonresponse with complete accuracy.
“However, codon 13 mutations (G13D) in KRAS do not predict nonresponse with complete accuracy [82].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [82]
Mutations in exons 2, 3 and 4 of KRAS and exons 2, 3 and 4 of NRAS are powerful predictors for cetuximab and panitumumab response in metastatic colorectal cancer.
“Mutations in exons 2, 3 and 4 of KRAS and exons 2, 3, and 4 of NRAS are powerful predictors for cetuximab and panitumumab response in mCRC [81, 82].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [82]
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Cites
Jemal, A., Siegel, R. L., Ward, E., Hao, Y., Xu, J., Murray, T., & Thun, M. J. (2008) · CA A Cancer Journal for Clinicians · doi:10.3322/ca.2007.0010 · Cited by 10,184 · see citing works
Genetic Alterations during Colorectal-Tumor Development
Vogelstein, B., Fearon, E. R., Hamilton, S. R., Kern, S. E., Preisinger, A. C., Leppert, M., de Vries-Smits, A. M. M., & Bos, J. L. (1988) · New England Journal of Medicine · doi:10.1056/nejm198809013190901 · Cited by 6,704 · see citing works
Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer
Van Cutsem, E., Köhne, C.-H., Hitre, E., Zaluski, J., Chang Chien, C.-R., Makhson, A., D'Haens, G., Pintér, T., Lim, R., Bodoky, G., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0805019 · Cited by 3,877 · see citing works
Self-citation<i>K-ras</i> Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer
Karapetis, C. S., Khambata-Ford, S., Jonker, D. J., O'Callaghan, C. J., Tu, D., Tebbutt, N. C., Simes, R. J., Chalchal, H., Shapiro, J. D., Robitaille, S., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0804385 · Cited by 3,622 · see citing works
COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer
Forbes, S. A., Bindal, N., Bamford, S., Cole, C., Kok, C. Y., Beare, D., Jia, M., Shepherd, R., Leung, K., Menzies, A., et al. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkq929 · Cited by 2,278 · see citing works
André, T., Boni, C., Navarro, M., Tabernero, J. M., Hickish, T., Topham, C., Bonetti, A. V., Clingan, P. R., Bridgewater, J. A., Rivera, F., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.20.6771 · Cited by 2,276 · see citing works
Self-citationLièvre, A., Bachet, J., Boige, V., Cayre, A., Corre, D. L., Buc, E., Ychou, M., Bouché, O., Landi, B., Louvet, C., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.12.5906 · Cited by 1,456 · see citing works
Self-citationRoth, A. D., Tejpar, S., Delorenzi, M., Yan, P., Fiocca, R., Klingbiel, D., Dietrich, D., Biesmans, B., Bodoky, G., Barone, C., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.23.3452 · Cited by 1,178 · see citing works
Bokemeyer, C., Bondarenko, I., Hartmann, J. T., de Braud, F., Schuch, G., Zubel, A., Celik, I., Schlichting, M., & Koralewski, P. (2011) · Annals of Oncology · doi:10.1093/annonc/mdq632 · Cited by 775 · see citing works
Kirsten ras mutations in patients with colorectal cancer: The multicenter “RASCAL” study
Andreyev, H. J. N., Norman, A. R., Clarke, P. A., Cunningham, D., & Oates, J. R. (1998) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/90.9.675 · Cited by 748 · see citing works
Hutchins, G. G. A., Southward, K., Handley, K., Magill, L., Beaumont, C., Stahlschmidt, J., Richman, S. D., Chambers, P. A., Seymour, M., Kerr, D. J., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.30.1366 · Cited by 681 · see citing works
ABC of colorectal cancer: Epidemiology
Boyle, P. (2000) · BMJ · doi:10.1136/bmj.321.7264.805 · Cited by 494 · see citing works
Weiss, J. M., Pfau, P. R., O’Connor, E. S., King, J., LoConte, N. K., Kennedy, G. D., & Smith, M. A. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.36.4414 · Cited by 411 · see citing works
Gavin, P. G., Colangelo, L. H., Fumagalli, D., Tanaka, N., Remillard, M. Y., Yothers, G., Kim, C., Taniyama, Y., Kim, S. I., Choi, H. J., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0605 · Cited by 320 · see citing works
Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer
Janakiraman, M., Vakiani, E., Zeng, Z., Pratilas, C. A., Taylor, B. S., Chitale, D., Halilovic, E., Wilson, M., Huberman, K., Ricarte Filho, J. C., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0192 · Cited by 290 · see citing works
Taı̈eb, J., Tabernero, J. M., Mini, E., Subtil, F., Folprecht, G., Laethem, J. V., Thaler, J., Bridgewater, J. A., Pétersen, L. N., Blons, H., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70227-x · Cited by 290 · see citing works
Self-citationSarasqueta, A. F., van Lijnschoten, G., Moerland, E., Creemers, G. J., Lemmens, V. E. P. P., Rutten, H. J. T., & van den Brule, A. J. C. (2010) · Annals of Oncology · doi:10.1093/annonc/mdq258 · Cited by 266 · see citing works
Imamura, Y., Morikawa, T., Liao, X., Lochhead, P. J., Kuchiba, A., Yamauchi, M., Qian, Z. R., Nishihara, R., Meyerhardt, J. A., Haigis, K. M., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-3210 · Cited by 249 · see citing works
Phipps, A. I., Buchanan, D. D., Makar, K. W., Win, A. K., Baron, J. A., Lindor, N. M., Potter, J. D., & Newcomb, P. A. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.118 · Cited by 238 · see citing works
Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study
Andreyev, J. N., Norman, A. R., Cunningham, D., Oates, J. R., Dix, B. R., Iacopetta, B. J., Young, J. P., Walsh, T. P., Ward, R. L., Hawkins, N., et al. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2001.1964 · Cited by 204 · see citing works
Self-citationPossible better long-term survival in left versus right-sided colon cancer - a systematic review.
Hansen, I. O., & Jess, P. (2012) · PubMed · Cited by 174 · see citing works
Yoon, H. H., Tougeron, D., Shi, Q., Alberts, S. R., Mahoney, M. R., Nelson, G. D., Nair, S., Thibodeau, S. N., Goldberg, R. M., Sargent, D. J., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-3140 · Cited by 155 · see citing works
Oliveíra, C. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh238 · Cited by 145 · see citing works
Phipps, A. I., Buchanan, D. D., Makar, K. W., Burnett‐Hartman, A. N., Coghill, A. E., Passarelli, M. N., Baron, J. A., Ahnen, D. J., Win, A. K., Potter, J. D., et al. (2012) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-12-0674 · Cited by 131 · see citing works
Are KRAS/BRAF Mutations Potent Prognostic and/or Predictive Biomarkers in Colorectal Cancers?
Yokota, T. (2012) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/187152012799014968 · Cited by 127 · see citing works
Prognostic Significance and Molecular Associations of Tumor Growth Pattern in Colorectal Cancer
Morikawa, T., Kuchiba, A., Qian, Z. R., Mino-Kenudson, M. A., Hornick, J. L., Yamauchi, M., Imamura, Y., Liao, X., Nishihara, R., Meyerhardt, J. A., et al. (2011) · Annals of Surgical Oncology · doi:10.1245/s10434-011-2174-5 · Cited by 97 · see citing works
Zhou, Q. H., Cheng, Y., Yang, J., Zhao, M., Zhang, L., Zhang, X.-C., Chen, Z., Yan, H., Song, Y., Chen, J., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu463 · Cited by 65 · see citing works
Benedix, F., Meyer, F. P., Kube, R., Kropf, S., Kuester, D., Lippert, H., Roessner, A., & Krüger, S. (2012) · Pathology - Research and Practice · doi:10.1016/j.prp.2012.07.003 · Cited by 44 · see citing works
Blons, H., Rouleau, É., Charrier, N., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068945 · Cited by 25 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- [5]5. Vogelstein B, Fearon ER, Hamilton SR et al. Genetic alterations during colorectaltumor development. N Engl J Med 1988; 319(9): 525 -532.
- [21]21. Yoon H, Tougeron D, Mahoney M et al. Prognostic impact of speci fi c KRAS mutations in codon 12 and 13 in 2,165 BRAF-wildtype colon cancers: results from NCCTG N0147 (Alliance). Eur J Cancer 2013; 49: S484.
Cited by
Sorted by citations
The Frequency of Ras Mutations in Cancer
Prior, I. A., Hood, F. E., & Hartley, J. L. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3682 · Cited by 1,130 · see citing works
From tumour heterogeneity to advances in precision treatment of colorectal cancer
Punt, C. J. A., Koopman, M., & Vermeulen, L. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.171 · Cited by 654 · see citing works
KRAS Alleles: The Devil Is in the Detail
Haigis, K. M. (2017) · Trends in Cancer · doi:10.1016/j.trecan.2017.08.006 · Cited by 373 · see citing works
Biomarker-guided therapy for colorectal cancer: strength in complexity
Sveen, A., Kopetz, S., & Lothe, R. A. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0241-1 · Cited by 320 · see citing works
Zhou, J., Ji, Q., & Li, Q. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02130-2 · Cited by 246 · see citing works
Jones, R. P., Sutton, P. A., Evans, J. P., Clifford, R., McAvoy, A., Lewis, J., Rousseau, A., Mountford, R., McWhirter, D., & Malik, H. Z. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.37 · Cited by 166 · see citing works
Drug Resistance in Colorectal Cancer: From Mechanism to Clinic
Wang, Q., Shen, X., Chen, G., & Du, J. (2022) · Cancers · doi:10.3390/cancers14122928 · Cited by 160 · see citing works
RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas
Serrano, C., Romagosa, C., Hernández‐Losa, J., Simonetti, S., Valverde, C., Moliné, T., Somoza, R., Pérez, M., Vélez, R., Vergés, R., et al. (2016) · Cancer · doi:10.1002/cncr.29733 · Cited by 59 · see citing works
Khawaja, H., Briggs, R., Latimer, C. H., Rassel, M., Griffin, D., Hanson, L., Bardelli, A., Di Nicolantonio, F., McDade, S. S., Scott, C. J., et al. (2023) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-22-0301 · Cited by 12 · see citing works
Yildirim, H. C., Gunenc, D., Almuradova, E., Sutcuoglu, O., & Yalcin, S. (2025) · Medicina · doi:10.3390/medicina61030408 · Cited by 10 · see citing works
- Authors
- Blons, H., Emile, J. F., Le Malicot, K., Julié, C., Zaanan, A., Tabernero, J., Mini, E., Folprecht, G., Van Laethem, J. L., Thaler, J., Bridgewater, J., Nørgård-Petersen, L., Van Cutsem, E., Lepage, C., Zawadi, M. A., Salazar, R., Laurent-Puig, P., & Taieb, J.
- Affiliations
- Inserm (FR)
- Université de Versailles Saint-Quentin-en-Yvelines (FR)
- Hôpital Ambroise-Paré (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Vall d'Hebron Hospital Universitari (ES)
- University of Florence (IT)
- University Hospital Carl Gustav Carus (DE)
- Klinikum Wels-Grieskirchen (AT)
- University College London (GB)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- ORCID
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 25
- Issue
- 12
- Pages
- 2378-2385
- ISSN
- 0923-7534 (ISSN-L)
- OpenAlex
- W2158910681
- Cited by
- 108
- References
- 29
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 7 · 2021: 13 · 2020: 12 · 2019: 9 · 2018: 9 · 2017: 11 · 2016: 15 · 2015: 13 · 2014: 1
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion, cc-by-nc-nd)
- HighWire Press Open Archive (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- Fédération Francophone de Cancérologie Digestive
- Merck KGaA and Sanofi-Aventis
- 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
- stage III colon cancer, colon adenocarcinoma, prognostic factors, time to recurrence, disease-free survival, adjuvant chemotherapy, FOLFOX, cetuximab, K-ras codon 12 mutation, tumor location, left-sided colon cancer
- MeSH terms
- Cetuximab, Aged, Antineoplastic Combined Chemotherapy Protocols, Leucovorin, Colonic Neoplasms, Exons, Female, Fluorouracil, Humans, Male, Middle Aged, Mutation, Organoplatinum Compounds, Prognosis, Genes, ras, Proto-Oncogene Proteins B-raf, Antibodies, Monoclonal, Humanized
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