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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]
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“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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“clear that patients with loss-of-function mutations in PTEN or BRAF are also unresponsive to cetuximab (2; 3).”
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“Total, n (%) 98 (7) 183 (13) 93 (7) 1029 (73) Sex, n (%) Female 57 (58) 136 (74) 53 (57) 468 (46) Male 41 (42) 47 (26) 40 (43) 561 (55) Anatomic site, n (%) Cecum 20 (20) 50 (28) 33 (36) 182 (18) Ascending colon 31 (32) 64 (36) 25 (27) 110 (11) Transverse colon 16 (16) 40 (23) 21 (23) 71 (7) Descending colon 9 (9) 5 (…”
KRAS Mutation in Colon Cancer: A Marker of Resistance to EGFR-I Therapy
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Clinical relevance of colorectal cancer molecular subtypes
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Detection of KRAS and BRAF Mutations in Colorectal Carcinoma
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Stintzing, S., Miller‐Phillips, L., Modest, D. P., von Weikersthal, L. F., Decker, T. W., Kiani, A., Vehling‐Kaiser, U., Al-Batran, S.-E., Heintges, T., Kahl, C., et al. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.03.023 · Cited by 138
“Optimal treatment of BRAF-mutant mCRC still remains an open question [16,18].”
BackgroundResultLuo, X.-J., Zhao, Q., Liu, J. S., Zheng, J., Qiu, M., Ju, H., & Xu, R. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.12.017 · Cited by 140
“Mutations in KRAS and BRAF seem to be mutually exclusive.(60,61) BRAF mutation was considered a prognosticator for poor survival in stage II/III CRC patients receiving adjuvant chemotherapy.”
BackgroundMalapelle, U., de-las-Casas, C. M., Rocco, D., Garzón, M., Pisapia, P., Jordana‐Ariza, N., Russo, M., Sgariglia, R., Luca, C. D., Pepe, F., et al. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.8 · Cited by 136
“…genome to develop a customised panel targeting six genes (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRa) that are associated with treatment outcome in NSCLC, GIST, CRC and metastatic melanoma (Lynch et al, 2004; Antonescu, 2008; Di Nicolantonio et al, 2008; Lièvre et al, 2008; Chapman et al, 2011).”
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Towards novel paradigms for cancer therapy
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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
Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients
Hsu, H., Thiam, T. K., Lu, Y., Yeh, C. Y., Tsai, W., You, J. F., Hung, H., Tsai, C., Hsu, A., Chen, H., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.8076 · Cited by 134
“also found that BRAF mutations were associated with unfavorable clinical outcomes for cetuximab- or panitumumab-based therapies [28].”
BackgroundMostert, B., Jiang, Y., Sieuwerts, A. M., Wang, H., Vries, J. B., Biermann, K., Kraan, J., Lalmahomed, Z. S., van Galen, A., de Weerd, V., et al. (2012) · International Journal of Cancer · doi:10.1002/ijc.27987 · Cited by 133
“Although the testing of the BRAF oncogene is not yet obligatory before anti-EGFR therapy is started, accumulating data do show its predictive value.(12,13,16) Two patients with BRAFmt metastases would probably not benefit from anti-EGFR treatment, although their BRAFwt primary tumor suggests otherwise.”
BackgroundAnti-epidermal growth factor receptor monoclonal antibodies in cancer treatment
Capdevila, J., Élez, E., Macarulla, T. M., Ramos, F. J., Ruiz-Echarri, M., & Tabernero, J. M. (2009) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2009.02.001 · Cited by 131
“with resistance to cetuximab or panitumumab in mCRC patients.(72,73) In these retrospective studies BRAF mutations were detected in approximately 10–15% of KRAS wild-type patients.”
BackgroundLannagan, T. R. M., Lee, Y. K., Wang, T., Roper, J., Bettington, M. L., Fennell, L., Vrbanac, L., Jonavicius, L., Somashekar, R., Gieniec, K. A., et al. (2018) · Gut · doi:10.1136/gutjnl-2017-315920 · Cited by 134
Time Trend Analysis of Primary Tumor Resection for Stage IV Colorectal Cancer
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Review of Histopathological and Molecular Prognostic Features in Colorectal Cancer
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“found to be impeded by the presence of BRAF V600E mutation and restored (in a cellular model of CRC cells) by BRAF inhibitor sorafenib [214].”
BackgroundResultInfluentialImplementing prognostic and predictive biomarkers in CRC clinical trials
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“BRAF mutational status The BRAF V600E mutation is mutually exclusive with mutations in KRAS and occurs in approximately 8–15% of patients with wild-type KRAS”
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“The published study suggesting that BRAF mutant tumors were resistant to EGFR therapies was a small study [13].”
BackgroundAre 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
“Therefore, the oncogenic activation of the RAS signaling pathway impairs the response of colorectal cancer cells to cetuximab [6-10, 41].”
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Targeting MET as a strategy to overcome crosstalk-related resistance to EGFR inhibitors
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Cetuximab in metastatic or recurrent head and neck cancer: the EXTREME trial
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“The effect of mutations in PIK3CA and PTEN are debated with regard to anti-EGFR therapy [26,28,29].”
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EGFR and KRAS in Colorectal Cancer
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The Role of KRAS Mutation Testing in the Management of Patients With Metastatic Colorectal Cancer
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Complex roles of the old drug aspirin in cancer chemoprevention and therapy
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“Although the presence of KRAS or BRAF mutation in colorectal cancer is associated with resistance to cetuximab (20, 21), the EGFR”
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“Metastatic colorectal carcinomas with BRAF V600E mutations have demonstrated a worse prognosis and resistance to anti-epidermal growth factor receptor (EGFR) therapy [15].”
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Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer
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“This is not a frequent mechanism of primary resistance to anti-EGFR treatments in mCRC.”
BackgroundInfluentialOncogenic mutations as predictive factors in colorectal cancer
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Predictive role of UCA1-containing exosomes in cetuximab-resistant colorectal cancer
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“Four trials [29,34,36,37] provided survival curves available for separately calculating HRs and variances for PFS and OS, to compare BRAF WT to BRAF mutant patients.”
MethodResult
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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