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Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer
Open accessAbstract
Purpose: Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. Patients and Methods: We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results: KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. Conclusion: BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.
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“preclinical studies have provided a proof of principle that the combined inhibition of EGFR and BRAF can be synergistic in BRAF-mutant CRCs”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [52]
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“Although therapies targeting EGFR have some efficacy in CRCs without KRAS mutations (1, 5–8)”
From mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1 (2014) · cites this paper as [8]
In the citing paper
“However, the predictive impact of BRAF mutations is tempered by their low prevalence and is further biased by the prominent role of mutant BRAF as a negative prognostic biomarker [54]. Overall, the predictive power of this alteration remains immature and requires further prospective endorsement before clinical applicability [20, 33, 52, 55].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [52]
In the citing paper
“Mutations of BRAF, which encodes the cytoplasmic serine/threonine kinase immediately downstream of RAS, are found in 4–13 % of advanced CRCs and are usually mutually exclusive with KRAS mutations [20, 52].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [52]
In the citing paper
“The BRAF V600E mutation has been described as a predictor of tumor aggressiveness in metastatic disease [33, 52, 53]”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [52]
In the citing paper
“the best responses of CRC cell xenografts to such combinations were only disease stabilizations or mild tumor regressions [52, 58-60].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [52]
In the citing paper
“and also of low RRs to cetuximab and panitumumab [18, 20, 52, 53].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [52]
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InfluentialDistribution of KRAS and BRAF Mutations in Metastatic Colorectal Cancers in Turkish Patients
Görükmez, O., Yakut, T., Görükmez, Ö., Sağ, Ş. Ö., Karkucak, M., & Kanat, Ö. (2016) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2016.17.3.1175 · Cited by 13
“Approximately 35% of CRC tissues have a mutation in KRAS codon 12 or 13, which leads to activation in downstream pathways of EGFR (Di Nicolantonio et al., 2008; Marchoudi et al., 2013).”
BackgroundBRAF mutations in sporadic colorectal carcinoma from polish patients.
Wójcik, P., Okoń, K., Osuch, C., Klimkowska, A., & Tomaszewska, R. (2010) · PubMed · Cited by 13
Shi, S., Wang, K., Ugai, T., Giannakis, M., Cazaubiel, J., Chan, A. T., Giovannucci, E. L., Nowak, J. A., Meyerhardt, J. A., Ogino, S., et al. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02452-2 · Cited by 12
“Existing evidence indicates that CRC patients with activating KRAS or BRAF mutation do not bene fi t from epidermal growth factor receptor (EGFR)-targeting treatment [2, 3].”
BackgroundLentz, R. W., Friedrich, T. J., Blatchford, P. J., Jordan, K. R., Pitts, T. M., Robinson, H. R., Davis, S. L., Kim, S. S., Leal, A. D., Lee, M. R., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-24-0090 · Cited by 14
Tumor biology and cancer therapy – an evolving relationship
Seufferlein, T. T. W., Ahn, J., Krndija, D., Lother, U., Adler, G., & von Wichert, G. (2009) · Cell Communication and Signaling · doi:10.1186/1478-811x-7-19 · Cited by 12
“None of the patients with tumors exhibiting BRAF mutations responded to an EGFR antibody treatment, wheras none of the responders to the treatment had BRAF mutations [38].”
Aprile, G. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i46.8474 · Cited by 11
Chat-uthai, N., Vejvisithsakul, P. P., Udommethaporn, S., Meesiri, P., Danthanawanit, C., Wongchai, Y., Teerapakpinyo, C., Shuangshoti, S., & Poungvarin, N. (2018) · PLoS ONE · doi:10.1371/journal.pone.0198795 · Cited by 14
Ashktorab, H., Azimi, H., Varma, S. R., Lee, E. L., Laiyemo, A. O., Nickerson, M. L., & Brim, H. (2019) · Oncotarget · doi:10.18632/oncotarget.26721 · Cited by 12
“It is unclear to what extent the lack of response in KRAS wild-type CRCs is due to BRAF variants, but data suggest that mutated BRAF confers resistance to anti-EGFR therapy [45, 46].”
BackgroundEncorafenib plus cetuximab for the treatment of BRAF-V600E-mutated metastatic colorectal cancer
Ros, J., Gonzalez, N. S., Baraibar, I., Salvà, F., Tabernero, J. M., & Élez, E. (2022) · Therapeutic Advances in Gastroenterology · doi:10.1177/17562848221110644 · Cited by 12
NAKAMOTO, K., Nagahara, H., Maeda, K., Noda, E., Inoue, T., Yashiro, M., Nishiguchi, Y., Ohira, M., & Hirakawa, K. (2013) · Oncology Letters · doi:10.3892/ol.2013.1187 · Cited by 12
“EGFR copy number (16-18), the levels of expression of amphiregulin and epiregulin (19), FCGR2A and FCGR3A polymorphisms (20), BRAF mutation, PIK3CA mutation and PTEN inactivation (18,21-26) have been reported to be associated with response to Cmab, but at present, these markers cannot be used to select patients who ar…”
BackgroundFunctional TP53 mutations have no impact on response to cytotoxic agents in metastatic colon cancer
Netter, J., Lehmann‐Che, J., Lambert, J., Tallet, A., Lourenço, N., Soliman, H. R., Bertheau, P., Pariente, B., Chirica, M., Pocard, M. D., et al. (2015) · Bulletin du Cancer · doi:10.1016/j.bulcan.2014.12.010 · Cited by 12
Mao, C., Liao, R.-Y., & Chen, Q. (2010) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-010-0922-8 · Cited by 13
Effect of cetuximab treatment in squamous cell carcinomas
Nestor, M. (2010) · Tumor Biology · doi:10.1007/s13277-010-0018-8 · Cited by 13
“Since K-ras or BRAF mutations have been shown to occur in cetuximabresistant patients in metastatic colorectal cancer [7, 19], this cell line was an especially interesting subject for K-ras and BRAF mutation analyses.”
BackgroundEGFR(S) Inhibitors in the Treatment of Gastro-Intestinal Cancers: Whats New?
Kanwar, S. S., Nautiyal, J., & Majumdar, A. P. N. (2010) · Current Drug Targets · doi:10.2174/138945010791170851 · Cited by 12
Passot, G., Chun, Y. S., Kopetz, S., Overman, M. J., Conrad, C. H., Aloia, T. A., & Vauthey, J. (2016) · European Journal of Surgical Oncology · doi:10.1016/j.ejso.2016.02.249 · Cited by 12
Karadima, M. L., Saetta, A. A., Chatziandreou, I., Lazaris, A. C., Patsouris, E., & Tsavaris, N. (2016) · Pathology & Oncology Research · doi:10.1007/s12253-016-0056-7 · Cited by 12
Nanotherapeutics promises for colorectal cancer and pancreatic ductal adenocarcinoma
Bhaw‐Luximon, A., Goonoo, N., & Jhurry, D. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-42863-7.00006-2 · Cited by 12
Eruptive Squamous Cell Carcinomas after Vemurafenib Therapy
Mays, R. M., Curry, J. L., Kim, K., Tsai, K. Y., Arora, A., Khan, F. A., Ramirez‐Fort, M. K., & Ciurea, A. M. (2013) · Journal of Cutaneous Medicine and Surgery · doi:10.2310/7750.2013.12092 · Cited by 12
Targeting the serrated pathway of colorectal cancer with mutation in BRAF
Matos, P., Gonçalves, V., & Jordan, P. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.06.003 · Cited by 13
Advances in Biomarkers: Going Beyond the Carcinoembryonic Antigen
Lopez, N., & Peterson, C. Y. (2016) · Clinics in Colon and Rectal Surgery · doi:10.1055/s-0036-1584289 · Cited by 12
How the Lab is Changing Our View of Colorectal Cancer
Cremolini, C., & Pietrantonio, F. (2016) · Tumori Journal · doi:10.5301/tj.5000551 · Cited by 12
“The biological rationale underlying the potential role of BRAF V600E mutation in driving the resistance to EGFR inhibitors is supported by strong preclinical evidence (5) and was first confirmed in an extensive body of data from a number of large series reporting no response to anti-EGFRs alone in the chemorefractory…”
BackgroundMultidisciplinary management in rectal cancer
Hervas, A., de Paredes, M. G., & Martínez, E. L. (2010) · Clinical & Translational Oncology · doi:10.1007/s12094-010-0602-9 · Cited by 12
“This is the case of BRAF, PTEN and PI3K1 [138].”
BackgroundA Model of Primary Culture of Colorectal Cancer and Liver Metastasis to Predict Chemosensitivity
Brouquet, A., Taleb, P., Lot, A.-S., Beauchet, A., Julié, C., Prevost, G. P., Nordlinger, B., & Penna, C. (2009) · Journal of Surgical Research · doi:10.1016/j.jss.2009.04.039 · Cited by 12
“The identification of candidate genes or molecular signatures that are associated with either chemoresponsiveness or resistance [11, 22–24] has recently been developed and is currently extensively studied.”
BackgroundModjtahedi, H., Khelwatty, S. A., Kirk, R. S., Seddon, A. M., Essapen, S., Fitz, C. D. V., Wong, A. J., & Eccles, S. A. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.27 · Cited by 12
“…of EGFR ligands such as amphiregulin and epiregulin, and sensitivity to therapy with anti-EGFR mAbs (Amado et al, 2008; Cappuzzo et al, 2008; Di Nicolantonio et al, 2008; Jacobs et al, 2009; Modjtahedi and Essapen, 2009; Bardelli and Siena, 2010; De Roock et al, 2010; Oliveras-Ferraros et al,…”
Silvestris, N., Tommasi, S., Santini, D., Russo, A. D., Simone, G., Petriella, D., Maiello, E., Tonini, G., & Colucci, G. (2009) · Expert Opinion on Biological Therapy · doi:10.1517/14712590902870394 · Cited by 12
“As a consequence, the investigation of other biomarkers such as EGFR copy number and expression levels of EGFR ligands, phosphatase and tensin homolog (PTEN) loss or BRAF mutation may be useful to further refine the responder population [17,19,46,47].”
BackgroundInfluentialCamp, E. R., & Ellis, L. M. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2900 · Cited by 12
“The first report to extend the molecular analysis beyond RAS in patients with mCRC investigated the role of mutated BRAF as amarker of cetuximab resistance inWTKRAS tumors (13).”
BackgroundWild-type KRAS and BRAF could predict response to Cetuximab in Chinese colorectal cancer patients
Gao, J., Wang, T., Yu, J., Li, Y., & Shen, L. (2011) · Chinese Journal of Cancer Research · doi:10.1007/s11670-011-0271-4 · Cited by 11
“Positive PTEN expression could predict the response to Cetuximab in western and Chinese CRC patients[11,12], and patients with BRAF mutation in western CRC patients could not respond to Cetuximab and the prognosis of them was poor[13-16].”
BackgroundAnimal Models and Their Role in Imaging-Assisted Co-Clinical Trials
Peehl, D. M., Badea, C. T., Chenevert, T. L., Daldrup-Link, H. E., Ding, L., Dobrolecki, L. E., Houghton, A. M., Kinahan, P. E., Kurhanewicz, J. V., Lewis, M. T., et al. (2023) · Tomography · doi:10.3390/tomography9020053 · Cited by 11
Monoclonal Antibodies for Cancer Immunotherapy
Zarnani, A., Bozorgmehr, M., Shabani, M., Leila, B. Y., Ghaemimanesh, F., & Jeddi‐Tehrani, M. (2014) · Springer eBooks · doi:10.1007/978-3-662-44946-2_16 · Cited by 11
Mitogen-activated Protein Kinase Signaling in Inflammation-related Carcinogenesis
Manzoor, Z., Koo, J. E., & Koh, Y. (2014) · Journal of Bacteriology and Virology · doi:10.4167/jbv.2014.44.4.297 · Cited by 11
Caiazza, F., Elliott, L., Fennelly, D. W., Sheahan, K. D., Doherty, G. A., & Ryan, E. J. (2015) · Biomarkers in Medicine · doi:10.2217/bmm.15.5 · Cited by 13
Spotlight on bevacizumab in metastatic colorectal cancer: patient selection and perspectives
Bekaii‐Saab, T., Bupathi, M., & Ahn, D. H. (2016) · Gastrointestinal Cancer Targets and Therapy · doi:10.2147/gictt.s97740 · Cited by 13
“21,22 Neither RAS nor BRAF mutations have any predictive role for bevacizumab or other VEGF inhibitors.”
Yildirim, H. C., Gunenc, D., Almuradova, E., Sutcuoglu, O., & Yalcin, S. (2025) · Medicina · doi:10.3390/medicina61030408 · Cited by 10
“KRAS activating mutations also, play an important role in the EGFR signaling pathway by activating the RAS/RAF/MAPK signaling pathways and causing loss of EGFR regulation (RAS signaling pathways are shown in Figure 2) [20].”
Metadata
- Authors
- Di Nicolantonio, F., Martini, M., Molinari, F., Sartore-Bianchi, A., Arena, S., Saletti, P., De Dosso, S., Mazzucchelli, L., Frattini, M., Siena, S., & Bardelli, A.
- Affiliations
- From the Laboratory of Molecular Genetics, The Oncogenomics Center, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo; The Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda; Italian Foundation for Cancer Research–Institute of Molecular Oncology, Milan, Italy; Laboratory of Molecular Diagnostic, Istituto Cantonale di Patologia, Locarno; and Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- Venue
- Journal of Clinical Oncology
- Published
- 2008-12-10
- Volume
- 26
- Issue
- 35
- Pages
- 5705-5712
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2131413118
- Cited by
- 1,591
- References
- 38
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 25 · 2023: 32 · 2022: 35 · 2021: 48 · 2020: 71 · 2019: 54 · 2018: 57 · 2017: 67 · 2016: 126 · 2015: 108 · 2014: 147 · 2013: 146 · 2012: 148
- FWCI
- 87.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Oncosuisse
- Regione Piemonte
- 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
- BRAF wild-type, BRAF V600E mutation, KRAS mutation, cetuximab, panitumumab, metastatic colorectal cancer, EGFR inhibitors, treatment resistance, sorafenib, predictive biomarkers, progression-free survival, overall survival
- MeSH terms
- Cetuximab, Sorafenib, Panitumumab, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Agents, Benzenesulfonates, Cell Survival, Dose-Response Relationship, Drug, Female, Humans, Italy, Male, Middle Aged, Mutation, Neoplasm Metastasis, Niacinamide, Phenylurea Compounds, Proto-Oncogene Proteins, Pyridines, Retrospective Studies, Switzerland, Time Factors, Biomarkers, Tumor, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Disease-Free Survival, Patient Selection, ras Proteins, Drug Resistance, Neoplasm, HT29 Cells, Gene Expression Profiling, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Antibodies, Monoclonal, Humanized, ErbB Receptors
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