KRAS and BRAF mutational status in primary colorectal tumors and related metastatic sites: Biological and clinical implications
Abstract
Background KRAS and BRAF mutations in primary colorectal tumors (PT) are predictive of nonresponse to anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (mCRC). The question of primary resistance to anti-EGFR treatment as a result of the presence of KRAS or BRAF mutations only in metastases has been raised but not resolved.Methods We analyzed the mutational status of KRAS and BRAF in 64 new patients with mCRC and performed a systematic review of published data from 285 patients.Results A total of 285 and 95 matched PT/metastases were available for the analysis of the KRAS and the BRAF status, respectively. An identical mutational pattern of KRAS in PT and the matching metastases were reported in all the cases but 14 (5%). In six cases (2%), KRAS was mutated in the PT and wild type in the metastatic site, whereas in eight cases (3%), KRAS was wild type in the PT and mutated in the metastatic site. An identical mutational pattern of BRAF in PT and the matching metastases was reported in all but two cases (3%). In one case (1.5%), BRAF was mutated in the PT and wild type in the metastatic site, whereas in one case (1.5%), BRAF was wild type in the PT and mutated in the metastatic site.Conclusions The acquisition by metastases of a KRAS or a BRAF mutation that was not present in the PT is a rare event, occurring in 5% of cases of mCRC. This is not a frequent mechanism of primary resistance to anti-EGFR treatments in mCRC.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Pulmonary metastases have a markedly higher discordance rate (approximately 30%) compared to other sites.
“pulmonary metastases have shown a markedly higher discordance rate (approximately 30%) compared to other sites [54,55]”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [55]
Cites
Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., Bets, D., Mueser, M., Harstrick, A., Verslype, C., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa033025 · Cited by 5,035 · see citing works
Amado, R. G., Wolf, M., Peeters, M., Van Cutsem, E., Siena, S., Freeman, D. J., Juan, T., Sikorski, R., Suggs, S., Radinsky, R., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.7116 · Cited by 3,207 · see citing works
<i>KRAS</i> Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer
Lièvre, A., Bachet, J.-B., Le Corre, D., Boige, V., Landi, B., Emile, J.-F., Côté, J.-F., Tomasic, G., Penna, C., Ducreux, M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0191 · Cited by 2,229 · see citing works
EGFR Antagonists in Cancer Treatment
Ciardiello, F., & Tortora, G. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0707704 · Cited by 2,063 · see citing works
Van Cutsem, E., Peeters, M., Siena, S., Humblet, Y., Hendlisz, A., Neyns, B., Canon, J.-L., Van Laethem, J.-L., Maurel, J., Richardson, G., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.08.1620 · Cited by 1,979 · see citing works
Cetuximab for the Treatment of Colorectal Cancer
Jonker, D. J., O'Callaghan, C. J., Karapetis, C. S., Zalcberg, J. R., Tu, D., Au, H.-J., Berry, S. R., Krahn, M., Price, T., Simes, R. J., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa071834 · Cited by 1,904 · see citing works
Di Nicolantonio, F., Martini, M., Molinari, F., Sartore-Bianchi, A., Arena, S., Saletti, P., De Dosso, S., Mazzucchelli, L., Frattini, M., Siena, S., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.18.0786 · Cited by 1,591 · cited 6× · see citing works
“This is not a frequent mechanism of primary resistance to anti-EGFR treatments in mCRC.”
BackgroundInfluentialHyperactive Ras in developmental disorders and cancer
Schubbert, S., Shannon, K., & Bollag, G. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2109 · Cited by 1,583 · see citing works
Cetuximab in the treatment of colorectal cancer.
Goldberg, R. M., Venook, A. P., & Schilsky, R. L. (2004) · PubMed · Cited by 1,518 · see citing works
Lièvre, 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
Cohen, S., Carpenter, G., & King, L. E. (1980) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)85573-4 · Cited by 858 · see citing works
Benvenuti, S., Sartore-Bianchi, A., Di Nicolantonio, F., Zanon, C., Moroni, M., Veronese, S., Siena, S., & Bardelli, A. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4158 · Cited by 830 · see citing works
De Roock, W., Piessevaux, H., De Schutter, J., Janssens, M., De Hertogh, G., Personeni, N., Biesmans, B., Van Laethem, J.-L., Peeters, M., Humblet, Y., et al. (2008) · Annals of Oncology · doi:10.1093/annonc/mdm496 · Cited by 827 · see citing works
Metastasis genes: A progression puzzle
Bernards, R., & Weinberg, R. A. (2002) · Nature · doi:10.1038/418823a · Cited by 801 · 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
Di Fiore, F., Blanchard, F., Charbonnier, F., Le Pessot, F., Lamy, A., Galais, M. P., Bastit, L., Killian, A., Sesboüé, R., Tuech, J. J., et al. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6603685 · Cited by 734 · see citing works
Cappuzzo, F., Finocchiaro, G., Rossi, E., Jänne, P. A., Carnaghi, C., Calandri, C., Bencardino, K., Ligorio, C., Ciardiello, F., Pressiani, T., et al. (2008) · Annals of Oncology · doi:10.1093/annonc/mdm492 · Cited by 267 · see citing works
Guerrero, S., Casanova, I., Farré, L., Mazo, A., Capellá, G., & Mangues, R. (2000) · PubMed · Cited by 243 · see citing works
Santini, D., Loupakis, F., Vincenzi, B., Floriani, I., Stasi, I., Canestrari, E., Rulli, E., Maltese, P. E., Andreoni, F., Masi, G., et al. (2008) · The Oncologist · doi:10.1634/theoncologist.2008-0181 · Cited by 234 · see citing works
Mutations of KRAS and BRAF in Primary and Matched Metastatic Sites of Colorectal Cancer
Artale, S. A., Bianchi, A. S., Veronese, S. M., Gambi, V., Sarnataro, C., Gambacorta, M., Lauricella, C., & Siena, S. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.18.7286 · Cited by 216 · 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
Epidermal growth factor-receptor-protein kinase interactions.
Cohen-Schwartz, S., Carpenter, G., & King, L. J. (1981) · PubMed · Cited by 178 · see citing works
KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression
Oliveíra, C., Velho, S., Moutinho, C., Ferreira, A. M., Preto, A., Domingo, E., Capelinha, A. F., Duval, A., Hamelin, R., Machado, J. C., et al. (2006) · Oncogene · doi:10.1038/sj.onc.1209758 · Cited by 176 · see citing works
Étienne-Grimaldi, M.-C., Formento, J., Francoual, M., François, É., Formento, P., Renée, N., Laurent‐Puig, P., Chazal, M., Benchimol, D., Delpéro, J., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4906 · Cited by 151 · see citing works
Self-citationRs, K., Waghorne, C. G., Korczak, B. M., et al. (1988) · PubMed · Cited by 105 · see citing works
Oudejans, J. J., Slebos, R. J. C., Zoetmulder, F. A. N., Mooi, W. J., & Rodenhuis, S. (1991) · International Journal of Cancer · doi:10.1002/ijc.2910490613 · Cited by 100 · see citing works
Italiano, A., Saint‐Paul, M., Caroli‐Bosc, F., et al. (2005) · Annals of Oncology · doi:10.1093/annonc/mdi282 · Cited by 100 · see citing works
Self-citationMolecular abnormalities in liposarcoma: role of MDM2 and CDK4-containing amplicons at 12q13-22
Pilotti, S., Torre, G. D., Lavarino, C. E., Sozzi, G., Minoletti, F., Vergani, B., Azzarelli, A., Rilke, F. O., & Pierotti, M. A. (1998) · The Journal of Pathology · doi:10.1002/(sici)1096-9896(199806)185:2 · Cited by 98 · see citing works
K‐ras point mutations in human colorectal carcinomas: Relation to aneuploidy and metastasis
Suchy, B., Zietz, C., & Rabes, H. M. (1992) · International Journal of Cancer · doi:10.1002/ijc.2910520107 · Cited by 76 · see citing works
Tórtola, S., Steinert, R., Hantschick, M., et al. (2001) · Journal of Clinical Oncology · doi:10.1200/jco.2001.19.11.2837 · Cited by 63 · see citing works
Bibeau, F., Boissière‐Michot, F., Sabourin, J., et al. (2006) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-006-0247-9 · Cited by 49 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
ESMO consensus guidelines for the management of patients with metastatic colorectal cancer
Van Cutsem, E., Cervantes, A., Adam, R., Sobrero, A., Van Krieken, J. H., Aderka, D., Aranda Aguilar, E., Bardelli, A., Benson, A., Bodoky, G., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw235 · Cited by 3,421 · see citing works
Molecular epidemiology and diagnostics of KRAS mutations in human cancer
Timar, J., & Kashofer, K. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09915-5 · Cited by 334 · see citing works
Knijn, N., Mekenkamp, L. J. M., Klomp, M., Vink-Börger, M. E., Tol, J., Teerenstra, S., Meijer, J. W. R., Tebar, M., Riemersma, S., van Krieken, J. H. J. M., et al. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.26 · Cited by 291 · see citing works
Mao, C., Wu, X.-Y., Yang, Z.-Y., Threapleton, D. E., Yuan, J.-Q., Yu, Y.-Y., & Tang, J.-L. (2015) · Scientific Reports · doi:10.1038/srep08065 · Cited by 107 · see citing works
Baas, J. M., Krens, L. L., Guchelaar, H.-J., Morreau, H., & Gelderblom, H. (2011) · The Oncologist · doi:10.1634/theoncologist.2011-0024 · Cited by 89 · see citing works
Watanabe, T., Kobunai, T., Yamamoto, Y., Matsuda, K., Ishihara, S., Nozawa, K., Iinuma, H., Shibuya, H., & Eshima, K. (2011) · Diseases of the Colon & Rectum · doi:10.1097/dcr.0b013e31821d37a3 · Cited by 82 · see citing works
Takeda, M., Yoshida, S., Inoue, T., Sekido, Y., Hata, T., Hamabe, A., Ogino, T., Miyoshi, N., Uemura, M., Yamamoto, H., et al. (2025) · Cancers · doi:10.3390/cancers17030428 · Cited by 82 · see citing works
Oliveras‐Ferraros, C., Vazquez‐Martin, A., Cufí, S., Queralt, B., Báez, L., Guardeño, R., Hernández‐Yagüe, X., Martin‐Castillo, B., Brunet, J., & Menendez, J. A. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22952 · Cited by 47 · see citing works
- Authors
- Italiano, A., Hostein, I., Soubeyran, I., Fabas, T., Benchimol, D., Evrard, S., Gugenheim, J., Becouarn, Y., Brunet, R., Fonck, M., François, E., Saint-Paul, M.-C., & Pedeutour, F.
- Affiliations
- Institut Bergonié (FR)
- Centre National de la Recherche Scientifique (FR)
- Centre Hospitalier Universitaire de Nice (FR)
- Venue
- Annals of Surgical Oncology
- Published
- 2010-01-05
- Volume
- 17
- Issue
- 5
- Pages
- 1429-1434
- ISSN
- 1068-9265 (ISSN-L)
- 1534-4681
- OpenAlex
- W2006099824
- Cited by
- 114
- References
- 31
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 15 · 2015: 8 · 2014: 9 · 2013: 14 · 2012: 15
- FWCI
- 8.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Annals of Surgical Oncology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- KRAS mutation, BRAF mutation, metastatic colorectal cancer, anti-EGFR antibody resistance, anti-EGFR therapy
- MeSH terms
- Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, DNA, Neoplasm, Female, Humans, Male, Middle Aged, Mutation, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Proto-Oncogene Proteins, Biomarkers, Tumor, Colorectal Neoplasms, Polymerase Chain Reaction, Proto-Oncogene Proteins p21(ras), ras Proteins, Proto-Oncogene Proteins B-raf, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
