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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]
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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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“EGFR signaling can be targeted by either monoclonal antibodies, as cetuximab or panitumumab [9,10], which bind the extracellular domain of EGFR, or tyrosine kinase inhibitors, such as erlotinib or gefitinib [11,12], which interfere with the ATP-binding site of the EGFR catalytic domain.”
BackgroundMontagut, C. O., Iglesias, M., Arumí, M., Bellosillo, B., Gallén, M., Martinez-Fernandez, A., Martinez-Aviles, L. M., Cañadas, I., Dalmases, A., Moragón, E., et al. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605612 · Cited by 29
Pharmacogenetics and biomarkers in colorectal cancer
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Shimoyama, S. (2011) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-011-1583-2 · Cited by 30
“Third, especially in advanced CRC, the treatment outcomes of molecular targeting therapies depend on the mutation status of K-Ras (human homolog of the Kirsten rat sarcoma-2 virus oncogene) or B-Raf, a downstream protein of Ras/Raf/MAPK axis [ 34 ].”
BackgroundDerbel, O., Wang, Q., Desseigne, F., Rivoire, M. L., Méeus, P., Peyrat, P., Stella, M., Martel‐Lafay, I., Lemaistre, A., & de la Fouchardière, C. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-200 · Cited by 29
“[30] who found 1 V600E allele in 43 rectal samples and Fransen et al.”
BackgroundRetrospective clinical analysis for drug rescue: for new indications or stratified patient groups
Cavalla, D., & Singal, C. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.09.019 · Cited by 29
Amagai, Y., Fujiyuki, T., Yoneda, M., Shoji, K., Furukawa, Y., Sato, H., & Kai, C. (2016) · Scientific Reports · doi:10.1038/srep24572 · Cited by 29
ERCC1 and TS Expression as Prognostic and Predictive Biomarkers in Metastatic Colon Cancer
Choueiri, M., Shen, J. P., Gross, A. M., Huang, J. K.-L., Ideker, T., & Fanta, P. T. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126898 · Cited by 29
“These markers include the mutation status of KRAS[9, 10], BRAF [11, 12] and TP53[13–15].”
BackgroundDono, M., Massucco, C., Chiara, S., Sonaglio, C., Mora, M., Truini, A., Cerruti, G., Zoppoli, G. M., Ballestrero, A., Truini, M., et al. (2012) · Molecular Medicine · doi:10.2119/molmed.2012.00175 · Cited by 28
Tural, D. G., Batur, Ş., Erdamar, S., Akar, E., Kepil, N., Mandel, N. M., & Serdengeçti, S. (2013) · Tumor Biology · doi:10.1007/s13277-013-1138-8 · Cited by 28
“However, 4 1 % of patients had neither KRAS nor BRAF mutations and yet still did not respond to EGFR antibody containing therapy [10].”
BackgroundInfluentialPower, D. G., Shah, M. A., Asmis, T. R., García, J. J., & Kemeny, N. E. (2009) · Investigational New Drugs · doi:10.1007/s10637-009-9268-y · Cited by 28
“The predictive value of activating KRAS mutations and, more recently, BRAF mutations downstream of the EGFR has helped to define a subset of patients likely to respond to EGFR monoclonal antibodies [16–24].”
BackgroundKim, R. Y., Xu, H., Myllykangas, S., & Ji, H. P. (2011) · Personalized Medicine · doi:10.2217/pme.11.16 · Cited by 28
Somatic DNA mutation analysis in targeted therapy of solid tumours.
Yu, B., O'Toole, S. A., & Trent, R. J. (2015) · PubMed Central · doi:10.3978/j.issn.2224-4336.2015.04.04 · Cited by 29
Cidón, E. U., Alonso, P., & Masters, B. (2016) · Clinical Medicine Insights Oncology · doi:10.4137/cmo.s34542 · Cited by 28
Potential biomarkers for anti-EGFR therapy in metastatic colorectal cancer
Yang, J., Li, S., Wang, B., Wu, Y., Chen, Z., Lv, M., Lin, Y., & Yang, J. (2016) · Tumor Biology · doi:10.1007/s13277-016-5140-9 · Cited by 29
“None of the BRAF-mutated patients responded to anti-EGFR therapy, whereas none of the responders carried BRAF mutations [43].”
BackgroundAu, T. H., Wang, K., Stenehjem, D. D., & Garrido‐Laguna, I. (2017) · Journal of Gastrointestinal Oncology · doi:10.21037/jgo.2017.01.04 · Cited by 29
Anti-EGFR Therapy to Treat Metastatic Colorectal Cancer: Not for All
Martins, M., Mansinho, A., Cruz-Duarte, R., Lobo-Martins, S., & Costa, L. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-02771-1_8 · Cited by 26
Treatment of BRAF-V600E mutant metastatic colorectal cancer: new insights and biomarkers
Ros, J., Rodríguez-Castells, M., Gonzalez, N. S., Baraibar, I., Salvà, F., Tabernero, J. M., & Élez, E. (2023) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2023.2236794 · Cited by 29
Multi-modality treatment of colorectal liver metastases
Cai, G.-X. (2012) · World Journal of Gastroenterology · doi:10.3748/wjg.v18.i1.16 · Cited by 28
Pietrantonio, F., Perrone, F., Biondani, P., Maggi, C., Lampis, A., Bertan, C. M., Venturini, F., Tondulli, L., Ferrari, D., Ricci, V., et al. (2013) · Cancer Biology & Therapy · doi:10.4161/cbt.26343 · Cited by 28
Prognostic impact of hyponatraemia in patients with colorectal cancer
Choi, J. S., Bae, E. H., Ma, S. K., Kweon, S., & Kim, S. W. (2014) · Colorectal Disease · doi:10.1111/codi.12878 · Cited by 28
Biomarkers in colorectal cancer
Markman, B., Rodríguez-Freixinós, V., & Tabernero, J. M. (2010) · Clinical & Translational Oncology · doi:10.1007/s12094-010-0502-z · Cited by 32
“As a predictive biomarker, results from at least two studies in anti-EGFR mAb-treated mCRC patients reported that in the KRAS WT population, those patients also WT for BRAF have superior RR, PFS and OS compared with those harbouring BRAF mutations [ 53 , 54].”
Microsatellite Instability and Adjuvant Fluorouracil Chemotherapy: A Mismatch?
Ng, K., & Schrag, D. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.9314 · Cited by 29
How Many Diseases Are Colorectal Cancer?
Greystoke, A., & Mullamitha, S. (2012) · Gastroenterology Research and Practice · doi:10.1155/2012/564741 · Cited by 28
“Most series suggest no benefit from EGFR therapies [74–76].”
BackgroundKras in metastatic colorectal cancer
WICKI, A. N., Herrmann, R., & Christofori, G. (2010) · Swiss Medical Weekly · doi:10.4414/smw.2010.13112 · Cited by 28
Han, S., Oh, D., Im, S., Park, S. R., Lee, K., SONG, H. S., Lee, N., Lee, K. H., Choi, I. S., Lee, M. H., et al. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01447.x · Cited by 26
Weidlich, S., Walsh, K., Crowther, D., Burczynski, M. E., FEUERSTEIN, G. Z., CAREY, F. A., Steele, R. J., Wolf, C. R., Miele, G., & Smith, G. C. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.197 · Cited by 27
“A similar differential response to cetuximab has recently been associated with mutations in other EGFR-dependent signalling molecules including B-Raf and PIK3CA (Nicolantonio et al, 2008; Prenen et al, 2009; Sartore-Bianchi et al, 2009).”
BackgroundInfluentialKRAS Mutation Analysis by PCR: A Comparison of Two Methods
Bolton, L. M., Reiman, A., Lucas, K., Timms, J. M., & Cree, I. A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0115672 · Cited by 27
“V600E in BRAF, a downstream signalling molecule of KRAS, has been identified in around 5% of colorectal cancer tumors, though somewhat higher in this series at 10%, and results in activation of the MAPK signalling pathway [14].”
BackgroundTargeted Therapeutic Agents for Colorectal Cancer
Chee, C. E., & Sinicrope, F. A. (2010) · Gastroenterology Clinics of North America · doi:10.1016/j.gtc.2010.08.017 · Cited by 27
Weickhardt, A. J., Tebbutt, N. C., & Mariadason, J. M. (2010) · Current Cancer Drug Targets · doi:10.2174/156800910793357961 · Cited by 27
“Although the data are more limited, tumours with BRAF mutations also appear to have intrinsic resistance to EGFR inhibitors [24, 25].”
BackgroundAdvances in Circulating Tumor DNA Analysis
Perakis, S. O., Auer, M., Belic, J., & Heitzer, E. (2017) · Advances in clinical chemistry · doi:10.1016/bs.acc.2016.11.005 · Cited by 28
Pang, S.-W., Awi, N. J., Armon, S., Lim, W. W.-D., Low, J. S.-H., Peh, K.-B., Peh, S., & Teow, S. (2019) · Diagnostics · doi:10.3390/diagnostics10010009 · Cited by 28
“This is exemplified by the lower overall response rate (ORR) of anti-EGFR mAb in mutant BRAF compared with mutant Exon 2 KRAS [62].”
BackgroundBRAF-mutated colorectal adenocarcinomas: Pathological heterogeneity and clinical implications
Angerilli, V., Sabella, G., Centonze, G., Lonardi, S., Bergamo, F., Mangogna, A., Pietrantonio, F., Fassan, M., & Milione, M. (2022) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2022.103647 · Cited by 27
IκB kinase‐α coordinates BRD4 and JAK/STAT signaling to subvert DNA damage‐based anticancer therapy
Pecharromán, I., Solé, L., Villanueva, D. A., Lobo‐Jarne, T., Alonso‐Marañón, J., Bertran, J., Guillén, Y., Montoto, Á., Martínez‐Iniesta, M., García‐Hernández, V., et al. (2023) · The EMBO Journal · doi:10.15252/embj.2023114719 · Cited by 27
“However, these therapeutic strategies are primarily restricted to the subset of tumors not carrying KRAS or BRAF mutations (Amado et al , 2008; Di Nicolantonio et al , 2008).”
BackgroundSoda, H., Maeda, H., Hasegawa, J., Takahashi, T., Hazama, S., Fukunaga, M., Kono, E., Kotaka, M., Sakamoto, J., Nagata, N., et al. (2015) · BMC Cancer · doi:10.1186/s12885-015-1685-z · Cited by 26
“In addition, patients with BRAF (V600E) mutation metastatic colorectal cancer (mCRC) were excluded from the study because of the possible relationships between the BRAF (V600E) mutation of mCRC and a poor response to cetuximab treatment, and/or the mutation and a poor prognosis [12–14].”
BackgroundIn vitro combined treatment with cetuximab and trastuzumab inhibits growth of colon cancer cells
Luca, T., Barresi, V., Privitera, G., Musso, N., Caruso, M., Condorelli, D. F., & Castorina, S. (2014) · Cell Proliferation · doi:10.1111/cpr.12125 · Cited by 27
Pre-trial inter-laboratory analytical validation of the FOCUS4 personalised therapy trial
Richman, S. D., Adams, R., Quirke, P., Butler, R., Hemmings, G., Chambers, P. A., Roberts, H. C., James, M. D., Wozniak, S., Bathia, R., et al. (2015) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2015-203097 · Cited by 27
Scartozzi, M., Giampieri, R., Maccaroni, E., Mandolesi, A., Biagetti, S., Alfonsi, S., Giustini, L., Loretelli, C., Faloppi, L., Bittoni, A., et al. (2012) · Journal of Translational Medicine · doi:10.1186/1479-5876-10-71 · Cited by 29
“In fact preliminary data about the role of bRAF 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 [29,30].”
ResultMicroRNA-645 is an oncogenic regulator in colon cancer
Guo, S., Guo, X., Wang, J., Wang, C. Y., Yang, R. H., Wang, F. H., Li, X., Hondermarck, H., Thorne, R. F., Wang, Y., et al. (2017) · Oncogenesis · doi:10.1038/oncsis.2017.37 · Cited by 27
Yokota, T., Shibata, N., Ura, T., Takahari, D., Shitara, K., Muro, K., & Yatabe, Y. (2010) · Translational research · doi:10.1016/j.trsl.2010.05.007 · Cited by 27
Ye, H., Liu, Y., Wu, K., Luo, H., & Cui, L. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00584-z · Cited by 27
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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