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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]
In the citing paper
“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]
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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“BRAF mutation analysis BRAF V600E mutations are observed in approximately two-thirds of MSI-high CRCs caused by MLH1 promoter hypermethylation, however, it never occurs in Lynch syndrome100.”
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BackgroundInfluentialManagement of resectable colorectal lung metastases
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“From clinical studies, it has become clear that wild-type BRAF is required for response to EGFR therapy in metastatic colorectal cancer [25].”
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“More recently, it has been suggested that BRAF mutation could also be responsible of resistance to anti-EGFR monoclonal antibodies.(10,17)”
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“The poor outcome associated with BRAF mutations has been reported by several authors.(11,17) In the present investigation, we evaluate the patients with mCRC who received cetuximab in combination with capecitabine plus oxaliplatin (CAPOX) or capecitabine plus Key words: mCRC, anti-EGFR, KRAS, BRAF, codon 13, codon 12…”
BackgroundHER2 as a Predictive Biomarker and Treatment Target in Colorectal Cancer
Cuyper, A. D., den Eynde, M. V., & Machiels, J. (2020) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2020.02.007 · Cited by 51
Comparison of HER 2 expression between primary colorectal cancer and their corresponding metastases
Lee, W., Park, Y. H., Lee, J. N., Baek, J., Lee, T., & Ha, S. Y. (2014) · Cancer Medicine · doi:10.1002/cam4.228 · Cited by 49
“KRAS mutations have emerged as a key negative predictive factor for treatment response in patients receiving cetuximab [16, 17].”
BackgroundPredictive and prognostic biomarkers with therapeutic targets in advanced colorectal cancer
Luo, H. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i14.3858 · Cited by 51
Novel targeted agents for gastric cancer
Liu, L., Wu, N., & Li, J. (2012) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-5-31 · Cited by 48
“Based on data from metastatic colorectal cancer [52–54], panitumumab was investigated in a dose-finding trial in”
MethodBanck, M. S., & Grothey, A. F. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-0188 · Cited by 47
“Another member of the RAS-RAF-MAPK pathway that might be a candidate for predicting response to therapy with EGFR-targeting mAbs is the serine/threonine protein kinase BRAF (19).”
BackgroundChen, K., Shao, Y., Chen, H., Lin, Y., Lin, Z., Lai, M., Cheng, A., & Yeh, K. (2016) · BMC Cancer · doi:10.1186/s12885-016-2358-2 · Cited by 48
“BRAF has been shown to have a strong causal relationship with resistance to anti-EGFR antibodies in preclinical models, but the correlation in clinical settings is not statistically significant [9, 12, 13, 17].”
BackgroundWnt/β Catenin-Mediated Signaling Commonly Altered in Colorectal Cancer
Deitrick, J., & Pruitt, W. M. (2016) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2016.09.010 · Cited by 48
Methylation levels of LINE-1 in primary lesion and matched metastatic lesions of colorectal cancer
Murata, A., Baba, Y., Watanabe, M., Shigaki, H., Miyake, K., Ishimoto, T., Iwatsuki, M., Iwagami, S., Sakamoto, Y., Miyamoto, Y., et al. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.289 · Cited by 47
“In addition, there is emerging evidence that mutations in BRAF and PIK3CA are associated with resistance to EGFR-targeted agents (Di Nicolantonio et al, 2008; Sartore-Bianchi et al, 2009; De Roock et al, 2010; Maughan et al, 2011).”
BackgroundAshraf, S. Q., Nicholls, A. M., Wilding, J. L., Ntouroupi, T. G., Mortensen, N., & Bodmer, W. F. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218750110 · Cited by 49
“Previous in vitro studies have shown that BRAF V600E mutant cell lines (HT29 and COLO205) are resistant to cetuximab treatment (23, 24).”
BackgroundMethodGuedes, J. G., Veiga, I., Rocha, P., Pinto, P., Pinto, C., Pinheiro, M., Peixoto, A., Fragoso, M., Raimundo, A. C., Ferreira, P., et al. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-169 · Cited by 48
“0%) but comparable to the reported frequency range of 4-18% in mCRC without KRAS codon 2 mutations [25,27-30].”
Therapeutic modulation of k-ras signaling in colorectal cancer
Krens, L. L., Baas, J. M., Gelderblom, H. A. J., & Guchelaar, H. (2010) · Drug Discovery Today · doi:10.1016/j.drudis.2010.05.012 · Cited by 46
Bobkova, E. V., Weber, M. J., Xu, Z., Zhang, Y., Jung, J. O., Blume‐Jensen, P., Northrup, A. B., Kunapuli, P., Andersen, J. N., & Kariv, I. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.089946 · Cited by 47
Chua, W. M., Kho, P. S., Moore, M. M., Charles, K. A., & Clarke, S. J. (2010) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2010.07.012 · Cited by 45
“[200] 30–113 patients in single arm”
ResultInfluentialMorelli, M. P., Tentler, J. J., Kulikowski, G. N., Tan, A. C., Bradshaw‐Pierce, E. L., Pitts, T. M., Brown, A. M., Nallapareddy, S., Arcaroli, J. J., Serkova, N. J., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1507 · Cited by 46
“Although BRAF mutations are more common in melanoma (63%), papillary thyroid cancer (45%), and low grade ovarian cancers (50%), the BRAF V600E mutation has also been found in colorectal cancers that also exhibit defective DNA mismatch repair (5, 6).”
Scartozzi, M., Giampieri, R., Maccaroni, E., Mandolesi, A., Giustini, L., Silva, R., Zaniboni, A., Biscotti, T., Biagetti, S., Galizia, E., et al. (2012) · Annals of Oncology · doi:10.1093/annonc/mdr558 · Cited by 43
“For example, preliminary data about the role of b-RAF mutational status seemed initially promising for a straightforward application in the clinical practice, but a large subsequent analysis from the CRYSTAL trial demonstrated that b-RAF although possessing a possible prognostic role had no predictive value [4–9].”
ResultWinder, T., Zhang, W., Yang, D., Ning, Y., Bohanes, P., Gerger, A., Wilson, P. M., Pohl, A., Mauro, D. J., Langer, C., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2092 · Cited by 46
Bando, H., Yoshino, T., Shinozaki, E., Nishina, T., Yamazaki, K., Yamaguchi, K., Yuki, S., Kajiura, S., Fujii, S., Yamanaka, T., et al. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-405 · Cited by 46
“Recent retrospective studies have revealed that mutations in KRAS codons 61 and 146, BRAF, NRAS, and PIK3CA are also related to resistance to antiEGFR antibodies [8-13].”
BackgroundHuang, J., Nair, S., Mahoney, M. R., Nelson, G. D., Shields, A. F., Chan, E. W., Goldberg, R. M., Gill, S., Kahlenberg, M. S., Quesenberry, J. T., et al. (2014) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2013.12.002 · Cited by 46
Bledsoe, J. R., Kamionek, M., & Mino-Kenudson, M. A. (2014) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000000263 · Cited by 46
KRAS mutation testing in clinical practice
Perincheri, S., & Hui, P. (2014) · Expert Review of Molecular Diagnostics · doi:10.1586/14737159.2015.986102 · Cited by 46
Santini, D., Spoto, C., Loupakis, F., Vincenzi, B., Silvestris, N., Cremolini, C., Canestrari, E., Graziano, F., Galluccio, N., Salvatore, L., et al. (2010) · Annals of Oncology · doi:10.1093/annonc/mdq318 · Cited by 46
“A mutation in B-type Raf kinase (BRAF), located downstream of KRAS, has been implicated in the response to anti-EGFR treatment [2].”
BackgroundSomatic mutations of signaling genes in non-small-cell lung cancer
Sanders, H. R., & Albitar, M. X. (2010) · Cancer Genetics and Cytogenetics · doi:10.1016/j.cancergencyto.2010.07.134 · Cited by 50
Bond, C., & Whitehall, V. (2018) · Gastroenterology Research and Practice · doi:10.1155/2018/9250757 · Cited by 48
A Genomic Analysis Workflow for Colorectal Cancer Precision Oncology
Corti, G., Bartolini, A., Crisafulli, G., Novara, L., Rospo, G., Montone, M., Negrino, C., Mussolin, B., Buscarino, M., Isella, C., et al. (2019) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2019.02.008 · Cited by 45
Self-citationControversies and challenges regarding the impact of radiation therapy on survival
Chargari, C., Soria, J., & Deutsch, É. (2012) · Annals of Oncology · doi:10.1093/annonc/mds217 · Cited by 51
Xu, Q., Xu, A. T., Zhu, M., Tong, J. L., Xi Tao, X. U., & Ran, Z. H. (2013) · Journal of Digestive Diseases · doi:10.1111/1751-2980.12063 · Cited by 49
Eng, C. (2010) · The Oncologist · doi:10.1634/theoncologist.2009-0167 · Cited by 45
Estrella, J. S., Tetzlaff, M. T., Bassett, R. L., Patel, K. P., Williams, M. D., Curry, J. L., Rashid, A., Hamilton, S. R., & Broaddus, R. R. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0615 · Cited by 45
Biomarker in Colorectal Cancer
Schirripa, M., & Lenz, H. (2016) · The Cancer Journal · doi:10.1097/ppo.0000000000000190 · Cited by 47
“%) was reported in a cohort of prospectively collected unselected mCRC patients with a high rate of poor performance status (39% with performance status 2–4) and advanced age (37%with age >75 years), thus underlining that incidence of BRAF-mutant patients might be underestimated in clinical trials.64 The story of BRAF…”
BackgroundInoue, A., Deem, A. K., Kopetz, S., Heffernan, T. P., Draetta, G. F., & Carugo, A. (2019) · Cancers · doi:10.3390/cancers11091321 · Cited by 46
“7% frequency reported in metastatic CRC [47,48].”
Genetic and Epigenetic Biomarkers of Colorectal Cancer
Choong, M. K., & Tsafnat, G. (2011) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2011.04.020 · Cited by 45
Larki, P., Gharib, E., Taleghani, M. Y., Khorshidi, F., Mojarad, E. N., & Asadzadeh Aghdaei, H. (2017) · Europe PMC (PubMed Central) · doi:10.22074/cellj.2017.5123 · Cited by 44
“KRAS mutations as one of the most and bestdescribed prognostic factors in the prediction of the resistance to EGFR-targeting therapeutic agents, have been reported in nearby 40% of the patients affected with the CRC (16-20).”
BackgroundEpigenetic Regulation and Colorectal Cancer
Matsubara, N. (2011) · Diseases of the Colon & Rectum · doi:10.1097/dcr.0b013e318233a1ef · Cited by 46
Schlaeth, M., Berger, S., Derer, S., Klausz, K., Lohse, S., Dechant, M., Lazar, G. A., Schneider‐Merck, T., Peipp, M., & Valerius, T. (2010) · Cancer Science · doi:10.1111/j.1349-7006.2010.01505.x · Cited by 44
Pharmacogenetic tests in cancer chemotherapy: what physicians should know for clinical application
Lee, S., & McLeod, H. L. (2010) · The Journal of Pathology · doi:10.1002/path.2766 · Cited by 44
KRAS,NRASandBRAFmutations in Greek and Romanian patients with colorectal cancer: a cohort study
Negru, S. M., Papadopoulou, E., Apessos, A., Stănculeanu, D. L., Ciuleanu, E., Volovat, C. D., Croitoru, A. E., Kakolyris, S., Aravantinos, G., Ziras, N., et al. (2014) · BMJ Open · doi:10.1136/bmjopen-2013-004652 · Cited by 43
Clinical Biomarkers in Oncology
Roock, W. D., Biesmans, B., Schutter, J. D., & Tejpar, S. (2009) · Molecular Diagnosis & Therapy · doi:10.1007/bf03256319 · Cited by 44
Ulivi, P., Capelli, L., Valgiusti, M., Zoli, W., Scarpi, E., Chiadini, E., Rosetti, P., Bravaccini, S., Calistri, D., Saragoni, L., et al. (2012) · Journal of Translational Medicine · doi:10.1186/1479-5876-10-87 · Cited by 45
“Abbreviations CRC: Colorectal cancer; mCRC: Metastatic colorectal cancer; CTX: Cetuximab; ORR: Overall response rate.”
BackgroundInfluentialTherapeutic Antibodies in Cancer Therapy
Gasser, M., & Waaga-Gasser, A. M. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-32805-8_6 · Cited by 44
Yao, Y.-M., Donoho, G. P., Iversen, P. W., Zhang, Y., Horn, R. D. V., Forest, A., Novosiadly, R. D., Webster, Y., Ebert, P. J., Bray, S. M., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3250 · Cited by 45
“These include KRAS mutations in other codons (26–28), KRAS amplification (29), and NRAS and BRAF mutations (19, 27, 30, 31).”
BackgroundMultiplex detection of ctDNA mutations in plasma of colorectal cancer patients by PCR/SERS assay
Lyu, N., Rajendran, V. K., Diefenbach, R. J., Charles, K. A., Clarke, S. J., Engel, A. F., Sydney 1000 Colorectal Cancer Study Investigators*, Rizos, H., Molloy, M. P., & Wang, Y. (2020) · Nanotheranostics · doi:10.7150/ntno.48905 · Cited by 44
“In addition to their critical role in driving tumorigenesis, these mutations have been demonstrated to be strong negative predictors for response of CRC to anti-EGFR therapy [3, 7, 33, 34].”
BackgroundXu, J., He, J., Yang, H., Luo, X., Liang, Z., Chen, J., Cai, Z., Xu, J., & Ren‐Heidenreich, L. (2012) · Cancer Biomarkers · doi:10.3233/cbm-2012-0233 · Cited by 42
“apies [11–15].”
Ney, J. T., Froehner, S., Roesler, A., Buettner, R., & Merkelbach‐Bruse, S. (2012) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2011-0176-oa · Cited by 43
“Patients with wild-type KRAS and mutations in BRAF do not respond to anti-EGFR therapy, whereas wildtype BRAF status seems to increase the therapy efficiency.(7) Recently it was shown that BRAF mutations in colorectal cancer are of prognostic rather than predictive value.”
Background
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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