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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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“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]
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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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“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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“…but additional testing for tumor genes such as serine/threonine-protein kinase B-Raf (BRAF) or neuroblastoma N-Rras (NRAS) could be useful to identify patients who might benefit the most from anti-EGF agents [Di Nicolantonio et al. 2008; Laurent-Puig et al. 2009; Khambata-Ford et al. 2007].”
BackgroundAndré, T., Blons, H., Mabro, M., Chibaudel, B., Bachet, J., Tournigand, C., Bennamoun, M., Artru, P., Nguyen, S., Ebenezer, C., et al. (2012) · Annals of Oncology · doi:10.1093/annonc/mds465 · Cited by 95
Metastatic colorectal cancer KRAS genotyping in routine practice: results and pitfalls
Lamy, A., Blanchard, F., Pessot, F. L., Sesboüé, R., Fiore, F. D., Bossut, J., Fiant, E., Frébourg, T., & Sabourin, J. (2011) · Modern Pathology · doi:10.1038/modpathol.2011.60 · Cited by 93
“V600E mutation in anti-EGFR monoclonal antibodies therapy, but there is a consensus concerning the value of this mutation as a very strong negative prognostic factor in colorectal cancer”
BackgroundHER2: An emerging target in colorectal cancer
Greally, M., Kelly, C. M., & Cercek, A. (2018) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2018.07.001 · Cited by 94
Exploring and modelling colon cancer inter-tumour heterogeneity: opportunities and challenges
Buikhuisen, J. Y., Torang, A., & Medema, J. P. (2020) · Oncogenesis · doi:10.1038/s41389-020-00250-6 · Cited by 96
“The EGFR-targeting antibody cetuximab is also used under the pre-requisite of wildtype KRAS or BRAF status, as mutations in these oncogenes render tumours insensitive to EGFR-targeted therapy 9,11,12 .”
BackgroundFrequent mutations of KRAS in addition to BRAF in colorectal serrated adenocarcinoma
Stefanius, K., Ylitalo, L., Tuomisto, A., Kuivila, R., Kantola, T., Sirniö, P., Karttunen, T. J., & Mäkinen, M. J. (2011) · Histopathology · doi:10.1111/j.1365-2559.2011.03821.x · Cited by 92
“The high frequency of KRAS mutations in serrated adenocarcinomas also indicates that most serrated adenocarcinomas are natively insensitive to epidermal growth factor receptor-blocking therapies, which are increasingly being used to treat metastatic colorectal cancer.(33,34)”
BackgroundTherapeutic Antibodies Against Cancer
Adler, M. J., & Dimitrov, D. S. (2012) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2012.02.013 · Cited by 94
“There is more recent evidence that mutations in B-raf may also predict no response to either cetuximab or panitumumab [154].”
BackgroundBaas, J. M., Krens, L. L., Guchelaar, H.-J., Morreau, H., & Gelderblom, H. (2011) · The Oncologist · doi:10.1634/theoncologist.2011-0024 · Cited by 89
Oberst, M. D., Fuhrmann, S. R., Mulgrew, K. A., Amann, M., Cheng, L., Lutterbuese, P., Richman, L. K., Coats, S., Baeuerle, P. A., & Hammond, S. A. (2014) · mAbs · doi:10.4161/19420862.2014.975660 · Cited by 92
Borràs, E., Jurado, I., Hernán, I., Gamundi, M. J., Dias, M. M. D. S., Martí, I., Mañé, B., Arcusa, À., Agúndez, J. A. G., Blanca, M., et al. (2011) · BMC Cancer · doi:10.1186/1471-2407-11-406 · Cited by 88
“Data from retrospective studies suggest that mutated BRAF, which is present in 5-10% of colorectal tumours, can affect the response to anti-EGFR monoclonal antibodies in patients with wild type KRAS [14-16], 40-60% of whom do not respond to such therapy [17].”
BackgroundXie, T., Huang, M., Wang, Y., Wang, L., Chen, C., & Chu, X. (2016) · Cellular Physiology and Biochemistry · doi:10.1159/000452525 · Cited by 90
Mauri, G., Pizzutilo, E. G., Amatu, A., Bencardino, K. B., Palmeri, L., Bonazzina, E. F., Tosi, F., Stella, G. C., Burrafato, G., Scaglione, F., et al. (2018) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2018.12.006 · Cited by 90
Self-citationPopulation Pharmacokinetic Analysis of Panitumumab in Patients With Advanced Solid Tumors
Ma, P., Yang, B., Wang, Y., Peterson, M. C., Narayanan, A., Sutjandra, L., Rodriguez, R. D., & Chow, A. T. (2009) · The Journal of Clinical Pharmacology · doi:10.1177/0091270009344989 · Cited by 91
Leto, S. M., & Trusolino, L. (2014) · Journal of Molecular Medicine · doi:10.1007/s00109-014-1161-2 · Cited by 87
“…studies have provided a proof of principle that the combined inhibition of EGFR and BRAF can be synergistic in BRAF-mutant CRCs; however, it is worth noting that the best responses of CRC cell xenografts to such combinations were only disease stabilizations or mild tumor regressions [52, 58-60].”
InfluentialEpidermal Growth Factor Receptor: Pathway, Therapies, and Pipeline
Goffin, J. R., & Zbuk, K. M. (2013) · Clinical Therapeutics · doi:10.1016/j.clinthera.2013.08.007 · Cited by 88
“Several studies have suggested that BRAF 1290 mutations are associated with either a lack of response or a dramatically inferior response to EGFR mAbs compared with wild-type BRAF.121,135,136 However, a retrospective analysis of data from 2 large-scale randomized trials of cetuximab with or without FOLFIRI or FOLFOX s…”
BackgroundKRAS Mutation Testing in Human Cancers: The Pathologist's Role in the Era of Personalized Medicine
Wang, H. L., Lopategui, J. R., Amin, M. B., & Patterson, S. D. (2010) · Advances in Anatomic Pathology · doi:10.1097/pap.0b013e3181c6962f · Cited by 90
“Therefore, should routine pretreatment practice also include testing for mutations in other genes downstream of the EGFR, such as BRAF? In a retrospective analysis of patients with mCRC treated with panitumumab or cetuximab, BRAF V600E mutations resulted in a lack of response to treatment and significantly shorter pro…”
BackgroundKelley, R. K., & Venook, A. P. (2011) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2011.03.001 · Cited by 87
Mao, C., Liao, R.-Y., Qiu, L., Wang, X.-W., Ding, H., & Chen, Q. (2010) · Molecular Biology Reports · doi:10.1007/s11033-010-0351-4 · Cited by 91
Keating, G. M. (2010) · Drugs · doi:10.2165/11205090-000000000-00000 · Cited by 94
A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy
Zhang, L., Yang, J., Cai, J., Song, X., Deng, J., Huang, X., Chen, D., Yang, M., Wery, J., Li, S., et al. (2013) · Scientific Reports · doi:10.1038/srep02992 · Cited by 86
Pietrantonio, F., Cremolini, C., Petrelli, F., Bartolomeo, M. D., Loupakis, F., Maggi, C., Antoniotti, C., de Braud, F., Falcone, A., & Iacovelli, R. (2015) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2015.05.016 · Cited by 86
Mattia, E. D., Cecchin, E., & Toffoli, G. (2015) · Drug Resistance Updates · doi:10.1016/j.drup.2015.05.003 · Cited by 89
Precision medicine in colorectal cancer: the molecular profile alters treatment strategies
Tran, N. H., Cavalcante, L. L., Lubner, S. J., Mulkerin, D. L., LoConte, N. K., Clipson, L. J., Matkowskyj, K. A., & Deming, D. A. (2015) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834015591952 · Cited by 85
Helbling, D., Bodoky, G., Gautschi, O. P., Sun, H., Bosman, F. T., Gloor, B., Burkhard, R., Winterhalder, R., Madlung, A., Rauch, D., et al. (2012) · Annals of Oncology · doi:10.1093/annonc/mds519 · Cited by 86
“Gaedcke J, Grade M, Jung K et al.. KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy.”
InfluentialSelf-citationInno, A., Di Salvatore, M., Cenci, T., Martini, M., Orlandi, A., Strippoli, A., Ferrara, A. M., Bagalà, C., Cassano, A., Larocca, L. M., et al. (2011) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2011.03.028 · Cited by 83
Self-citationBronte, G., Silvestris, N., Castiglia, M., Galvano, A., Passiglia, F., Sortino, G., Cicero, G., Rolfo, C. D., Peeters, M., Bazan, V., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4959 · Cited by 85
IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
Colomer, C., Margalef, P., Villanueva, A., Vert, A., Pecharromán, I., Solé, L., Gonzàlez‐Farré, M., Alonso‐Marañón, J., Montagut, C. O., Martínez‐Iniesta, M., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.05.036 · Cited by 84
oden-Gangloff, A., Fiore, F. D., Bibeau, F., Lamy, A., Bougeard, G., Charbonnier, F., Blanchard, F., Tougeron, D., Ychou, M., Boissière‐Michot, F., et al. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6605008 · Cited by 90
Treatment of Metastatic Colorectal Cancer
Davies, J. M., & Goldberg, R. M. (2011) · Seminars in Oncology · doi:10.1053/j.seminoncol.2011.05.009 · Cited by 86
Sensitive detection of BRAF V600E mutation by Amplification Refractory Mutation System (ARMS)-PCR
Huang, T., Zhuge, J., & Zhang, W. W. (2013) · Biomarker Research · doi:10.1186/2050-7771-1-3 · Cited by 83
Wong, R., & Cunningham, D. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.19.5024 · Cited by 84
Antibodies to TWEAK Receptor Inhibit Human Tumor Growth through Dual Mechanisms
Culp, P., Choi, D., Zhang, Y., Yin, J., Seto, P., Ybarra, S. E., Su, M., Sho, M., Steinle, R., Wong, M. H. L., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1929 · Cited by 82
“In patients, the anti-EGFR antibodies have been shown not to be effective in patients with activating Kras and Braf mutations, suggesting that blocking EGFR signaling is critical for their activity (44, 45).”
BackgroundPander, J., Gelderblom, H. A. J., Antonini, N. F., Tol, J., van Krieken, J. H., van der Straaten, T., Punt, C. J. A., & Guchelaar, H. (2010) · European Journal of Cancer · doi:10.1016/j.ejca.2010.03.017 · Cited by 83
“However, the KRAS mutation status does not completely predict the response to cetuximab and other tumour characteristics such as BRAF mutation status have been investigated.(9,10) The severity of acneiform skin rash is also associated with the efficacy of cetuximab(2,3), but as this adverse event occurs after therapy…”
BackgroundLøes, I. M., Immervoll, H., Angelsen, J., Horn, A., Geisler, J., Busch, C., Lønning, P. E., & Knappskog, S. (2014) · Tumor Biology · doi:10.1007/s13277-014-2711-5 · Cited by 81
“In malignant melanoma (MM), this mutation (and to a smaller extent the less frequent V600K mutation) indicates utility of BRAF inhibitors (such as vemurafenib and dabrafenib) [1, 2], whereas in colorectal cancer (CRC), V600E is suspected to account for resistance to EGFR antibodies in patients harbouring KRAS wild-typ…”
BackgroundAdackapara, C., Sholl, L. M., Barletta, J. A., & Hornick, J. L. (2013) · Histopathology · doi:10.1111/his.12154 · Cited by 81
“Expression or up-regulation of EGFR may be detected in CRC by immunohistochemistry (IHC), fluorescence in-situ hybridization, or chromogenic in-situ hybridization, although these findings do not predict treatment efficacy.(4) One populationbased study examining the clinicopathological characteristics associated with a…”
BackgroundTargeted KRAS Mutation Assessment on Patient Tumor Histologic Material in Real Time Diagnostics
Kotoula, V., Charalambous, E., Biesmans, B., Malousi, A., Vrettou, E., Fountzilas, G., & Karkavelas, G. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007746 · Cited by 80
“Because these methods are easily applicable (the IVD DxS-KRAS, in particular) and highly efficient, it is expected that their use will spread dramatically, especially if more hot-spot point mutations enter diagnostics [55,56,57].”
MethodPaz-Ares, L. G., Gomez‐Roca, C., Delord, J., Cervantes, A. M. R., Markman, B., Corral, J., Soria, J., Bergé, Y., Roda, D., Russell-Yarde, F., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.34.8888 · Cited by 80
Chibaudel, B., Bonnetain, F., Tournigand, C., Bengrine-Lefèvre, L., Teixeira, L., Artru, P., Desrame, J., Larsen, A. K., André, T., Louvet, C., et al. (2011) · The Oncologist · doi:10.1634/theoncologist.2011-0039 · Cited by 80
Cutsem, E. V., Dicato, M. A., Arber, N., Berlin, J. D., Cervantes, A. M. R., Ciardiello, F., de Gramont, A., Díaz‐Rubio, E., Ducreux, M. P., Geva, R., et al. (2010) · Annals of Oncology · doi:10.1093/annonc/mdq273 · Cited by 80
Targeted therapies in colorectal cancer—an integrative view by PPPM
Hagan, S., Orr, M. C. M., & Doyle, B. J. (2013) · The EPMA Journal · doi:10.1186/1878-5085-4-3 · Cited by 88
“This was compared to a 30% disease progression rate in patients whose tumour retained PTEN expression [124].”
Tol, J., Dijkstra, J. R., Vink-Börger, M. E., Nagtegaal, I. D., Punt, C. J. A., van Krieken, J. H., & Ligtenberg, M. J. L. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00788.x · Cited by 81
“Other molecular determinants that are involved in the response to anti-EGFR antibodies, such as BRAF mutations [26], PIK3CA mutations [27] and EGFR gene copy number changes [28], may become relevant selection parameters for this type of treatment.”
BackgroundPanitumumab in Patients with KRAS Wild-Type Colorectal Cancer after Progression on Cetuximab
Wadlow, R. C., Hezel, A. F., Abrams, T. A., Blaszkowsky, L. S., Fuchs, C. S., Kulke, M. H., Kwak, E. L., Meyerhardt, J. A., Ryan, D. P., Szymonifka, J. D., et al. (2011) · The Oncologist · doi:10.1634/theoncologist.2011-0452 · Cited by 81
Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521 Polymorphism
Braig, F., Kriegs, M., Voigtlaender, M., Habel, B., Grob, T. J., Biskup, K., Blanchard, V., Sack, M., Thalhammer, A., Batalla, I. B., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0754 · Cited by 81
RAS and BRAF in metastatic colorectal cancer management
Gong, J., Cho, M. T., & Fakih, M. (2016) · Journal of Gastrointestinal Oncology · doi:10.21037/jgo.2016.06.12 · Cited by 84
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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