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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The predictive impact of BRAF mutations is tempered by their low prevalence and biased by the prognostic role of mutant BRAF, so its predictive power remains immature and requires further prospective endorsement.
“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]
BRAF mutations are found in 4-13% of advanced colorectal cancers and are usually mutually exclusive with KRAS mutations.
“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]
Combined inhibition of EGFR and BRAF can be synergistic in BRAF-mutant colorectal cancers.
“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]
The BRAF V600E mutation is a predictor of tumor aggressiveness in metastatic colorectal cancer.
“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]
Best responses of colorectal cancer cell xenografts to combined EGFR and BRAF inhibition were only disease stabilizations or mild tumor regressions.
“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]
The BRAF V600E mutation is a predictor of low response rates to cetuximab and panitumumab.
“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 mutations, which are mutually exclusive with KRAS, have also been associated to lack of response to cetuximab and panitumumab (9).”
Self-citationRoock, W. D., de Vriendt, V., Normanno, N., Ciardiello, F., & Tejpar, S. (2010) · The Lancet Oncology · doi:10.1016/s1470-2045(10)70209-6 · Cited by 605 · see citing works
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Genetic and biological hallmarks of colorectal cancerPreprint
Li, J., Ma, X., Chakravarti, D., Shalapour, S., & DePinho, R. A. (2021) · Genes & Development · doi:10.1101/gad.348226.120 · Cited by 588 · see citing works
“The clinical effectiveness of EGFR blockade is dictated by themutational status of its downstream signaling components (DiNicolantonio et al. 2008); specifically, gain-offunction mutations in RAS, RAF,MEK, or ERK can maintain cancer cell proliferation and survival upon EGFR inhibition.”
BackgroundRichman, S. D., Seymour, M. T., Chambers, P., Elliott, F., Daly, C. L., Meade, A. M., Taylor, G., Barrett, J. H., & Quirke, P. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.22.4295 · Cited by 560 · see citing works
Loupakis, F., Ruzzo, A., Cremolini, C., Vincenzi, B., Salvatore, L., Santini, D., Masi, G., Stasi, I., Canestrari, E., Rulli, E., et al. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6605177 · Cited by 562 · see citing works
“In particular, Di Nicolantonio et al (2008) recently found that none of 11 BRAF-mutated patients, among 79 KRAS codon 12 and 13 wild type, responded to anti-EGFR moAbs.”
BackgroundClassifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations
Dankner, M., Rose, A. A. N., Rajkumar, S., Siegel, P. M., & Watson, I. R. (2018) · Oncogene · doi:10.1038/s41388-018-0171-x · Cited by 553 · see citing works
Epidermal growth factor receptor targeting in cancer: a review of trends and strategies
Yewale, C., Baradia, D., Vhora, I., Patil, S., & Misra, A. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.07.100 · Cited by 533 · see citing works
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Resistance to anti-EGFR therapy in colorectal cancer: From heterogeneity to convergent evolution
Misale, S., Di Nicolantonio, F., Sartore-Bianchi, A., Siena, S., & Bardelli, A. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0462 · Cited by 513 · see citing works
“Several reports have shown a significant negative predictive value for BRAFV600E mutations in relation to response to single-agent cetuximab or panitumumab (20, 21, 23, 27, 30, 31).”
BackgroundSelf-citationSiena, S., Bianchi, A. S., Nicolantonio, F. D., Balfour, J., & Bardelli, A. (2009) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djp280 · Cited by 526 · see citing works
Self-citationMetastatic Colorectal Cancer: Current State and Future Directions
Fakih, M. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.7633 · Cited by 529 · see citing works
BRAFMutation in Metastatic Colorectal Cancer
Tol, J., Nagtegaal, I. D., & Punt, C. J. A. (2009) · New England Journal of Medicine · doi:10.1056/nejmc0904160 · Cited by 524 · see citing works
Pharmacologic resistance in colorectal cancer: a review
Hammond, W. A., Swaika, A., & Mody, K. (2015) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834015614530 · Cited by 520 · see citing works
Rational combinations of targeted cancer therapies: background, advances and challenges
Jin, H., Wang, L., & Bernards, R. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00615-z · Cited by 503 · see citing works
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“In addition to the prognostic impact of BRAF mutations in CRC, retrospective data suggested that these mutations may be predictive of primary resistance to the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) cetuximab (C) and panitumumab (P) [11–13].”
BackgroundCapper, D., Preusser, M., Habel, A., Sahm, F., Ackermann, U., Schindler, G., Pusch, S., Mechtersheimer, G., Zentgraf, H., & von Deimling, A. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0841-z · Cited by 470 · see citing works
“For colorectal carcinoma, BRAF mutation is a strong negative prognostic factor and there is increasing evidence that BRAF V600E mutation corresponds with resistance to antiepidermal growth factor receptor (EGFR) therapy [13, 15].”
BackgroundEGFR/Ras/MAPK Signaling Mediates Adult Midgut Epithelial Homeostasis and Regeneration in Drosophila
Jiang, H., Grenley, M. O., Bravo, M. J., Blumhagen, R. Z., & Edgar, B. A. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.11.026 · Cited by 455 · see citing works
“…antibodies against EGFR (panitumumab or cetuximab) are effective in treating CRC, provided that activating mutations in downstream KRAS or BRAF are not present, further emphasizing the critical role for EGFR signaling during CRC development (Amado et al., 2008; Di Nicolantonio et al., 2008).”
BackgroundEGFR Signaling and Drug Discovery
Lurje, G., & Lenz, H. (2009) · Oncology · doi:10.1159/000279388 · Cited by 439 · see citing works
“KRAS and PI3K mutations in turn dysregulate mechanisms modulating tumor angiogenesis and apoptosis that are normally controlled by multiple homeostatic mechanisms, including signals from the EGFR. Other promising markers of resistance to EGFR-targeted therapies include BRAF mutations and PTEN expression. In a recent s…”
BackgroundImplications for KRAS status and EGFR-targeted therapies in metastatic CRC
Normanno, N., Tejpar, S., Morgillo, F., De Luca, A., Van Cutsem, E., & Ciardiello, F. (2009) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2009.111 · Cited by 436 · see citing works
Baldus, S. E., Schaefer, K.-L., Engers, R., Hartleb, D., Stoecklein, N. H., & Gabbert, H. E. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-2446 · Cited by 432 · see citing works
“Thus, in a series of 113 patients receiving cetuximab or panitumumab, none of the 11 patients with tumors carrying BRAF mutations in a wild-type KRAS background responded to therapy (22).”
BackgroundColorectal cancer tumour markers and biomarkers: Recent therapeutic advances
Lech, G. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i5.1745 · Cited by 418 · see citing works
Labianca, R., Beretta, G. D., Kildani, B., Milesi, L., Merlin, F., Mosconi, S., Pessi, M. A., Prochilo, T., Quadri, A., Gatta, G., et al. (2010) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2010.01.010 · Cited by 409 · see citing works
“[217] Di NF, Martini M, Molinari F, et al.”
BackgroundLoupakis, F., Pollina, L., Stasi, I., Ruzzo, A., Scartozzi, M., Santini, D., Masi, G., Graziano, F., Cremolini, C., Rulli, E., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.20.2796 · Cited by 403 · see citing works
BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer
Yokota, T., Ura, T., Shibata, N., Takahari, D., Shitara, K., Nomura, M., Kondo, C., Mizota, A., Utsunomiya, S., Muro, K., et al. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.19 · Cited by 399 · see citing works
Dias-Santagata, D. C., Akhavanfard, S., David, S. S., Vernovsky, K., Kuhlmann, G., Boisvert, S. L., Stubbs, H., McDermott, U., Settleman, J. E., Kwak, E. L., et al. (2010) · EMBO Molecular Medicine · doi:10.1002/emmm.201000070 · Cited by 392 · see citing works
“While the clinical benefit observed with some targeted agents is encouraging, it has become clear that for such strategies to be successful, it will be necessary to identify the patient population carrying the genetic abnormalities targeted by each drug (McDermott et al, 2007; Sos et al, 2009).”
BackgroundYe, L., Liu, T., Ren, L., Wei, Y., Zhu, D., Zai, S.-Y., Ye, Q., Yu, Y., Xu, B., Qin, X.-Y., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.8308 · Cited by 392 · see citing works
Kopetz, S., Guthrie, K. A., Morris, V. K., Lenz, H., Magliocco, A. M., Maru, D. M., Yan, Y., Lanman, R. B., Manyam, G. C., Hong, D. S., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.20.01994 · Cited by 390 · see citing works
Seymour, M., Brown, S., Middleton, G., Maughan, T., Richman, S. D., Gwyther, S. J., Lowe, C., Seligmann, J., Wadsley, J., Maisey, N. R., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70163-3 · Cited by 387 · see citing works
Frequency of <i>KRAS</i>, <i>BRAF</i>, and <i>NRAS</i> mutations in colorectal cancer
Vaughn, C. P., ZoBell, S. D., Furtado, L. V., Baker, C. L., & Samowitz, W. S. (2011) · Genes, Chromosomes and Cancer · doi:10.1002/gcc.20854 · Cited by 377 · see citing works
“…data on the response of BRAF mutated tumors (Phillips et al., 2010; Tol et al., 2010), multiple studies have suggested that mutations in other KRAS codons and other genes downstream of EGFR may also confer drug resistance (Di Nicolantonio et al., 2008; Loupakis et al., 2009; De Roock et al., 2010).”
BackgroundLncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc
Tang, J., Yan, T., Bao, Y.-J., Shen, C., Yu, C., Zhu, X., Tian, X., Guo, F., Liang, Q., Liu, Q., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11447-8 · Cited by 374 · see citing works
Colorectal cancer molecular biology moves into clinical practice
Pritchard, C. C., & Grady, W. M. (2010) · Gut · doi:10.1136/gut.2009.206250 · Cited by 340 · see citing works
Luca, A. C., Mersch, S., Deenen, R., Schmidt, S., Messner, I., Schäfer, K.-L., Baldus, S. E., Huckenbeck, W., Piekorz, R. P., Knoefel, W. T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059689 · Cited by 341 · see citing works
“KRAS and BRAF mutational status of patients is usually assessed before EGFR treatment on the basis that only patients exhibiting BRAF and KRAS wild type profit from treatments with anti-EGFR therapies [29,30].”
BackgroundSchütte, M., Risch, T., Abdavi-Azar, N., Boehnke, K., Schumacher, D., Keil, M., Yildirimman, R., Jandrasits, C., Borodina, T. A., Amstislavskiy, V. S., et al. (2017) · Nature Communications · doi:10.1038/ncomms14262 · Cited by 333 · see citing works
Mechanisms of resistance to anti-EGFR therapy in colorectal cancer
Zhao, B., Wang, L., Qiu, H., Zhang, M., Sun, L., Peng, P., Yu, Q., & Yuan, X. (2017) · Oncotarget · doi:10.18632/oncotarget.14012 · Cited by 319 · see citing works
“Sorafenib, a potent inhibitor of the V600E B-RAF protein, which is also a well-known multi-targeted kinase inhibitor, has shown pronounced activity in combination with cetuximab in V600E BRAF-mutant CRC cells [118].”
BackgroundAnti-epidermal growth factor receptor monoclonal antibodies in cancer therapy
Martinelli, E., Palma, R. D., Orditura, M., Vita, F. D., & Ciardiello, F. (2009) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2009.03992.x · Cited by 334 · see citing works
Rectal and colon cancer: Not just a different anatomic site
Tamás, K., Walenkamp, A., de Vries, E. G. E., van Vugt, M. A. T. M., Beets‐Tan, R. G. H., van Etten, B., de Groot, D. J. A., & Hospers, G. A. P. (2015) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2015.06.007 · Cited by 335 · see citing works
“Activating mutations inv-raf murine sarcoma viral 14 oncogene homolog B (BRAF)mutation (V600E)are enriched in sporadic tumors with MLH1 15 hypermethylation [50-51], which can render them resistant to currently used EGFR-inhibitors 16 [52].”
BackgroundPortrait of the PI3K/AKT pathway in colorectal cancer
Danielsen, S. A., Eide, P. W., Nesbakken, A., Guren, T. K., Leithe, E., & Lothe, R. A. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.09.008 · Cited by 326 · see citing works
Rowland, A., Dias, M. M., Wiese, M. D., Kichenadasse, G., McKinnon, R. A., Karapetis, C. S., & Sorich, M. J. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.173 · Cited by 319 · see citing works
“…pathway, and is implicated as a source of impaired response to anti-EGFR mAbs in patients with mCRC (Benvenuti et al, 2007; Cappuzzo et al, 2008; Di Nicolantonio et al, 2008; Freeman et al, 2008; Laurent-Puig et al, 2009; Loupakis et al, 2009; Molinari et al, 2009; Perrone et al, 2009;…”
BackgroundHigh frequency of BRAF V600E mutations in ameloblastoma
Kurppa, K. J., Catón, J., Morgan, P. R., Ristimaki, A. P., Ruhin, B., Kellokoski, J. K., Elenius, K., & Heikinheimo, K. (2013) · The Journal of Pathology · doi:10.1002/path.4317 · Cited by 311 · see citing works
“Specific genetic markers predict the response to EGFRtargeted cancer drugs in the clinic and in vitro [12–20].”
BackgroundMajumder, B., Ulaganathan, B., Thiyagarajan, S., Radhakrishnan, P., Narasimhan, H., Dhandapani, M., Brijwani, N., Pinto, D. D., Prasath, A., Shanthappa, B., et al. (2015) · Nature Communications · doi:10.1038/ncomms7169 · Cited by 307 · see citing works
Isella, C., Brundu, F. G., Bellomo, S. E., Galimi, F., Zanella, E. R., Porporato, R., Petti, C., Fiori, A., Orzan, F., Senetta, R., et al. (2017) · Nature Communications · doi:10.1038/ncomms15107 · Cited by 298 · see citing works
“We and others have identified a number of genetic alterations that associate with resistance to cetuximab 12,36–39 .”
BRAF mutant colorectal cancer: prognosis, treatment, and new perspectives
Sanz‐García, E., Argilés, G., Élez, E., & Tabernero, J. M. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx401 · Cited by 302 · see citing works
“For instance, no responses were observed in BRAF-mt mCRC patients who were treated with cetuximab-irinotecan [37] or cetuximab or panitumumab [38].”
BackgroundOrigin and quantification of circulating DNA in mice with human colorectal cancer xenografts
Thierry, A. R., Mouliere, F. C., Gongora, C., Ollier, J., Robert, B., Ychou, M., Rio, M. D., & Molina, F. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq421 · Cited by 299 · see citing works
“Ultimately this animal model might be useful for developing accurate and sensitive diagnostic tests for SNPs detection which are required for predicting the response to new potent anti-cancer compounds (25,26) and to determine whether ctDNA has any function or pathological effects (37,54,55).”
BackgroundMethodThe EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death
Pozzi, C., Cuomo, A., Spadoni, I., Magni, E., Silvola, A., Conte, A., Sigismund, S., Ravenda, P. S., Bonaldi, T., Zampino, M. G., et al. (2016) · Nature Medicine · doi:10.1038/nm.4078 · Cited by 292 · see citing works
Prenen, H., De Schutter, J., Jacobs, B., De Roock, W., Biesmans, B., Claes, B., Lambrechts, D., Van Cutsem, E., & Tejpar, S. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2961 · Cited by 291 · see citing works
Knijn, N., Mekenkamp, L. J. M., Klomp, M., Vink-Börger, M. E., Tol, J., Teerenstra, S., Meijer, J. W. R., Tebar, M., Riemersma, S., van Krieken, J. H. J. M., et al. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.26 · Cited by 291 · see citing works
“Efficacy of anti-EGFR therapy was suggested to be further restricted to patients with BRAF wild-type tumours (Di Nicolantonio et al, 2008).”
Molecularly targeted cancer therapy: some lessons from the past decade
Huang, M., Shen, A., Ding, J., & Geng, M. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.11.004 · Cited by 289 · see citing works
Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer
Janakiraman, M., Vakiani, E., Zeng, Z., Pratilas, C. A., Taylor, B. S., Chitale, D., Halilovic, E., Wilson, M., Huberman, K., Ricarte Filho, J. C., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0192 · Cited by 290 · see citing works
“Our analysis suggests that a broader assessment of RAS mutations beyond the most common mutations in exon 2 is warranted and would lead to the identification of a mutation predicted to confer EGFR inhibitor resistance in close to 50% of patients with colorectal cancer (12, 19).”
BackgroundBiomarker-guided therapy for colorectal cancer: strength in complexity
Sveen, A., Kopetz, S., & Lothe, R. A. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0241-1 · Cited by 320 · see citing works
Comparative Genomic Analysis of Primary Versus Metastatic Colorectal Carcinomas
Vakiani, E., Janakiraman, M., Shen, R., Sinha, R., Zeng, Z., Shia, J., Cercek, A., Kemeny, N. E., D'Angelica, M. I., Viale, A. J., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.38.2994 · Cited by 282 · see citing works
Yaeger, R., Cercek, A., O'Reilly, E. M., Reidy, D. L., Kemeny, N., Wolinsky, T., Capanu, M., Gollub, M. J., Rosen, N., Berger, M. F., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2779 · Cited by 276 · see citing works
“Patients with metastatic BRAF-mutated CRC are less responsive to current chemotherapy(2-4) and do not benefit from anti-epidermal growth factor receptor (EGFR) antibodies in the chemotherapy-refractory setting(5-7).”
Sinicrope, F. A., Mahoney, M. R., Smyrk, T. C., Thibodeau, S. N., Warren, R. S., Bertagnolli, M. M., Nelson, G. D., Goldberg, R. M., Sargent, D. J., & Alberts, S. R. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.48.9591 · Cited by 279 · see citing works
Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab
Brand, T. M., Iida, M., & Wheeler, D. L. (2011) · Cancer Biology & Therapy · doi:10.4161/cbt.11.9.15050 · Cited by 275 · see citing works
Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future Directions
Zarour, L. R., Anand, S., Billingsley, K. G., Bisson, W. H., Cercek, A., Clarke, M. F., Coussens, L. M., Gast, C. E., Geltzeiler, C. B., Hansen, L., et al. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.01.006 · Cited by 273 · see citing works
Bianchi, A. S., Pietrantonio, F., Lonardi, S., Mussolin, B., Rua, F., Crisafulli, G., Bartolini, A., Fenocchio, E., Amatu, A., Manca, P., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01886-0 · Cited by 282 · see citing works
Self-citationDulak, A. M., Schumacher, S. E., van Lieshout, J., Imamura, Y., Fox, C., Shim, B., Ramos, A. H., Saksena, G., Baca, S. C., Baselga, J. M., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3893 · Cited by 270 · see citing works
“Colorectal cancer (CRC) genomes have been studied extensively (3, 4); the value of this information is realized by persuasive evidence that KRAS and BRAF mutations in CRC predict lack of response to cetuximab (5, 6).”
A Convergence-Based Framework for Cancer Drug Resistance
Konieczkowski, D. J., Johannessen, C. M., & Garraway, L. A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.025 · Cited by 258 · see citing works
“Likewise, EGFR (Katayama et al., 2012; Sasaki et al., 2011), ERBB3 (Wilson et al., 2015), and KIT (Katayama et al., 2012) can rescue inhibition of ALK in ALK-rearranged NSCLC (reviewed in Niederst and Engelman, 2013).”
The current state of molecular testing in the treatment of patients with solid tumors, 2019
El‐Deiry, W. S., Goldberg, R. M., Lenz, H., Shields, A. F., Gibney, G. T., Tan, A. R., Brown, J., Eisenberg, B., Heath, E. I., Phuphanich, S., et al. (2019) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21560 · Cited by 264 · see citing works
Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer
Coppedè, F. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i4.943 · Cited by 264 · see citing works
Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening
Verissimo, C. S., Overmeer, R. M., Ponsioen, B., Drost, J., Mertens, S., Verlaan-Klink, I., Gerwen, B. V., van der Ven, M., Wetering, M. V. D., Egan, D. A., et al. (2016) · eLife · doi:10.7554/elife.18489 · Cited by 263 · see citing works
Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges
Koncina, E., Haan, S., Rauh, S., & Letellier, E. (2020) · Cancers · doi:10.3390/cancers12020319 · Cited by 261 · see citing works
“Several studies have suggested that BRAF mutations (which are RAS wild-type and may therefore benefit from anti-EGFR therapy) predict the lack of response to anti-EGFR treatments in CRC [22,39,40,42].”
BackgroundSartore-Bianchi, A., Di Nicolantonio, F., Nichelatti, M., Molinari, F., De Dosso, S., Saletti, P., Martini, M., Cipani, T., Marrapese, G., Mazzucchelli, L., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007287 · Cited by 259 · see citing works
“We and others have recently demonstrated that the V600E mutation can also preclude responsiveness to panitumumab or cetuximab in mCRC patients and cellular models of CRC [20].”
BackgroundSelf-citationPrognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer
Arrington, A. K., Heinrich, E. L., Lee, W., Duldulao, M., Patel, S., Sanchez, J., Garcia-Aguilar, J., & Kim, J. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms131012153 · Cited by 244 · see citing works
“Interestingly, BRAF mutations, which are predominantly mutually exclusive of mutant KRAS, have also been associated with resistance to anti-EGFR treatment in colorectal cancer [53,55].”
BackgroundNCCN Task Force Report: Evaluating the Clinical Utility of Tumor Markers in Oncology
Febbo, P. G., Ladanyi, M., Aldape, K., Marzo, A. M. D., Hammond, M. E. H., Hayes, D. F., Iafrate, A. J., Kelley, R. K., Marcucci, G., Ogino, S., et al. (2011) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2011.0137 · Cited by 256 · see citing works
Parseghian, C. M., Loree, J. M., Morris, V. K., Liu, X., Clifton, K., Napolitano, S., Henry, J. T., Pereira, A. A. L., Vilar, E., Johnson, B., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy509 · Cited by 256 · see citing works
Molecular pathology of lung cancer: key to personalized medicine
Liang Cheng, C., Alexander, R. E., MacLennan, G. T., Cummings, O. W., Montironi, R., Antonio Lopez-beltran, B., Cramer, H. M., Davidson, D. D., & Zhang, S. (2012) · Modern Pathology · doi:10.1038/modpathol.2011.215 · Cited by 245 · see citing works
“214 Mutations in BRAF have been shown to impair responsiveness to panitumumab or cetuximab in patients with colorectal carcinomas”
BackgroundPrecision oncology in metastatic colorectal cancer — from biology to medicine
Nicolantonio, F. D., Vitiello, P. P., Marsoni, S., Siena, S., Tabernero, J. M., Trusolino, L., Bernards, R., & Bardelli, A. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00495-z · Cited by 238 · see citing works
Self-citationMasi, G., Loupakis, F., Salvatore, L., Fornaro, L., Cremolini, C., Cupini, S., Ciarlo, A., Monte, F. D., Cortesi, E., AMOROSO, D., et al. (2010) · The Lancet Oncology · doi:10.1016/s1470-2045(10)70175-3 · Cited by 239 · see citing works
Clinical development of targeted and immune based anti-cancer therapies
Seebacher, N. A., Stacy, A. E., Porter, G., & Merlot, A. M. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1094-2 · Cited by 235 · see citing works
- 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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