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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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ResultSelf-citationYang, Z., Wu, X., Huang, Y., Di, M., Zheng, D., Chen, J., Ding, H., Mao, C., & Tang, J.-L. (2013) · International Journal of Cancer · doi:10.1002/ijc.28153 · Cited by 79
“In studies with relevant information, patients were generally selected on the basis of the availability of tumor tissue samples and/or measurable lesions,27–31,35–39,41,42 while two studies recruited ‘consecutive patients’,19,34 and another two studies included patients whose treatment outcome ‘could be attributable o…”
ResultInfluentialBiomarker-Based Prediction of Response to Therapy for Colorectal Cancer
Ross, J. S., Torres‐Mora, J., Wagle, N., Jennings, T. A., & Jones, D. (2010) · American Journal of Clinical Pathology · doi:10.1309/ajcp2y8ktdpoaorh · Cited by 74
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PET imaging of HER1-expressing xenografts in mice with 86Y-CHX-A″-DTPA-cetuximab
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Targeting EGFR in non-small-cell lung cancer: Lessons, experiences, strategies
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“The EGFR activation triggers two main signaling pathways: KRAS-BRAF-MEK pathway, which sustains cell proliferation and in PIK3CA-AKT-mTOR axis, which is mainly involved in cell survival and motility.(90,91) Other critical activated pathways include the STAT signal cascade and ERBB mediated angiogenesis.”
BackgroundNew Strategies for Treatment of KRAS Mutant Metastatic Colorectal Cancer
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“Clin Cancer Res; 16(11) June 1, 2010 tations of BRAF, which encode for a protein acting downstream of KRAS, were also shown to be responsible for resistance to EGFR inhibitors in chemorefractory CRC (24, 35, 36).”
BackgroundSchrock, A. B., Pavlick, D. C., Klempner, S. J., Chung, J., Forcier, B., Welsh, A. W., Young, L., Leyland-Jones, B., Bordoni, R. E., Carvajal, R. D., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3103 · Cited by 71
“Extended RAS and BRAF testing is widely performed in colorectal carcinoma to guide the use of anti-EGFR antibody therapies, which have shown particular efficacy in patients with tumors wild type for KRAS, NRAS, and BRAF mutations (1, 2).”
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Molecular Testing for Gastrointestinal Cancer
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“inhibitors, and several studies have shown that BRAF V600E mutations were significantly predictable for resistance to singleagent EGFR inhibitor.(54,55) The predictive role of the BRAF V600E mutation remains inconclusive owing to its rare prevalence,(6,47) but the level of evidence for the BRAF V600E mutation in CRC i…”
MethodToward a Molecular Classification of Colorectal Cancer: The Role of BRAF
Thiel, A., & Ristimaki, A. P. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00281 · Cited by 78
“PREDICTIVE ROLE It has been suggested that in order for metastatic colorectal cancer patients to receive a response for treatment with monoclonal antibodies targeting EGFR (panitumumab and cetuximab, Figure 1C), the BRAF gene needs to be present as wild-type (37, 38).”
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“Nowadays, the percentage of patients with CRC metastasis may reach up to 30%, with a 5-year survival rate lower than 10% [17, 18].”
BackgroundThe Evolving Treatment Landscape in BRAF-V600E –Mutated Metastatic Colorectal Cancer
Tabernero, J. M., Ros, J., & Élez, E. (2022) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_349561 · Cited by 71
Methods of overcoming treatment resistance in colorectal cancer
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“Braf mutations [92,93], PIK3Ca 94,95] mutations and PTEN inactivation [96] have shown possible role in resistance to cetuximab although results re still unclear in this area.”
BackgroundResultThe Tumor Border Configuration of Colorectal Cancer as a Histomorphological Prognostic Indicator
Koelzer, V. H., & Lugli, A. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00029 · Cited by 71
Pitts, T. M., Tan, A. C., Kulikowski, G. N., Tentler, J. J., Brown, A. M., Flanigan, S. A., Leong, S., Coldren, C. D., Hirsch, F. R., Varella‐Garcia, M., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3191 · Cited by 73
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“A large body of prior work has shown that mutations in EGFR downstream effectors, such as KRAS (3), NRAS (4), BRAF (5), and PI3K (6), lead to a constitutive activation of the signaling pathway, thus bypassing a therapeutic block of the receptor.”
BackgroundMolecular Analysis of Colorectal Tumors within a Diverse Patient Cohort at a Single Institution
Sylvester, B. E., Huo, D., Khramtsov, A., Zhang, J., Smalling, R. V., Olugbile, S. O., Polite, B. N., & Olopade, O. I. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1397 · Cited by 68
“We assessed MSI status and KRAS and BRAF mutations, as they are involved in disease initiation, progression, and treatment response.[11-22] Although previously studied, these molecular pathways have not been characterized in African Americans, and their potential role in the aggressive tumor phenotypes and poor surviv…”
BackgroundGiovanella, L., Campennì, A., Treglia, G., Verburg, F. A., Trimboli, P., Ceriani, L., & Bongiovanni, M. (2015) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-015-3285-1 · Cited by 68
“Mutations for KRAS, HRAS and NRAS (exons 2 and 3, containing hotspot codons 12, 13 and 61) and for BRAF (exon 15, containing the region surrounding the hotspot codon 600) were investigated by direct sequencing of genomic DNA and analysed with Sequence Navigator software (Thermo Fisher Applied Biosystems, Foster City,…”
MethodKhan, K. H., Valeri, N., Dearman, C., Rao, S., Watkins, D. J., Starling, N., Chau, I., & Cunningham, D. (2019) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2019.09.001 · Cited by 70
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“The lack of response to targeted therapy, such as anti-EGFR antibodies, has 5 been correlated with mutations in the KRAS and BRAF oncogenes (3-6).”
BackgroundCorreale, P., Marra, M., Remondo, C., Migali, C., Misso, G., Arcuri, F., Vecchio, M. T. D., Carducci, A., Loiacono, L., Tassone, P., et al. (2010) · European Journal of Cancer · doi:10.1016/j.ejca.2010.03.005 · Cited by 67
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“[133].”
KRAS Mutation Testing in the Treatment of Metastatic Colorectal Cancer with Anti-EGFR Therapies
Soulières, D., Greer, W. L., Magliocco, A. M., Huntsman, D. D., Young, S. S., Tsao, M., & Kamel‐Reid, S. (2010) · Current Oncology · doi:10.3747/co.v17is1.614 · Cited by 66
Support vector machine classifier for prediction of the metastasis of colorectal cancer
Zhi, J., Sun, J., Wang, Z., & Ding, W. (2018) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2018.3359 · Cited by 67
“Patients with metastatic CRC have a poor 5-year survival rate of <10% (7).”
Luber, B., Deplazes, J., Keller, G., Walch, A. K., Rauser, S., Eichmann, M., Langer, R., Höfler, H., Hegewisch‐Becker, S., Folprecht, G., et al. (2011) · BMC Cancer · doi:10.1186/1471-2407-11-509 · Cited by 66
“Colorectal cancers lacking oncogenic alterations in genes encoding EGFR downstream effectors such as KRAS, BRAF, PIK3CA, and PTEN have the highest probability of response to anti-EGFR therapies [27,29].”
BackgroundMolecular Pathways and Cellular Metabolism in Colorectal Cancer
Hagland, H. R., Berg, M., Jolma, I. W., Carlsen, A., & Søreide, K. (2013) · Digestive Surgery · doi:10.1159/000347166 · Cited by 67
Mekenkamp, L. J., Tol, J., Dijkstra, J. R., de Krijger, I., Vink-Börger, M. E., van Vliet, S., Teerenstra, S., Kamping, E. J., Verwiel, E. T. P., Koopman, M., et al. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-292 · Cited by 69
“A mutation in the BRAF oncogene occurs in approximately 10% of mCRC patients and is restricted to KRAS wild-type tumours, and was first shown to have a negative predictive value for anti-EGFR therapy [10].”
BackgroundBlank, P. R., Moch, H., Szucs, T. D., & Schwenkglenks, M. M. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2267 · Cited by 67
“It was assumed that 70% of patients were wild-type KRAS and that 8% of this group (6% of the total) had a BRAF mutation status (8, 16, 31, 32).”
Roukos, D. H. (2009) · Expert Review of Molecular Diagnostics · doi:10.1586/erm.09.7 · Cited by 66
Mutation‐specific antibody detects mutant BRAFV600E protein expression in human colon carcinomas
Sinicrope, F. A., Smyrk, T. C., Tougeron, D., Thibodeau, S. N., Singh, S., Murányi, A., Shanmugam, K., Grogan, T. M., Alberts, S. R., & Shi, Q. (2013) · Cancer · doi:10.1002/cncr.28133 · Cited by 65
“(EGFR).(2,15) Given the prognostic and potential predictive utility of BRAF status, in addition to its role in distinguishing sporadic from germline causes of MSI in CRCs, BRAF has emerged as an important biomarker in clinical practice.”
BackgroundDNA methylation biomarkers in colorectal cancer: Clinical applications for precision medicine
Fatemi, N., Tierling, S., Es, H. A., Varkiani, M., Mojarad, E. N., Aghdaei, H. A., Walter, J., & Totonchi, M. (2022) · International Journal of Cancer · doi:10.1002/ijc.34186 · Cited by 66
Predictive and Prognostic Markers in Colorectal Cancer
George, B., & Kopetz, S. (2011) · Current Oncology Reports · doi:10.1007/s11912-011-0162-3 · Cited by 66
“Di Nicolantonio et al. [ 77 ] added a translational correlate to their study by adding a BRAF inhibitor (sorafenib) in combination with cetuximab to two BRAF-mutated colorectal cancer cell lines (HT-29 and COLO-205); in their in vitro assay, the combination inhibited cell proliferation very modestly but elicited a str…”
BackgroundInfluentialNovel Points of Attack for Targeted Cancer Therapy
Røsland, G. V., & Engelsen, A. S. T. (2014) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12313 · Cited by 66
Aberrant signaling pathways in pancreatic cancer: A two compartment view
McCleary‐Wheeler, A. L., McWilliams, R. R., & Fernández-Zapico, M. E. (2011) · Molecular Carcinogenesis · doi:10.1002/mc.20827 · Cited by 69
“alignment with the now well-established absence of benefit with EGFR inhibition in KRAS mutated colorectal cancer [120,121].”
BackgroundMehner, C., Oberg, A. L., Goergen, K. M., Kalli, K. R., Maurer, M. J., Nassar, A., Goode, E. L., Keeney, G. L., Jatoi, A., Radisky, D. C., et al. (2017) · Genes & Cancer · doi:10.18632/genesandcancer.142 · Cited by 65
“Mutational screening is also a useful approach to patient stratification in metastatic colorectal carcinoma, where mutations in EGFR pathway mediators KRAS, NRAS, BRAF, and PIK3CA are negative predictors of efficacy for anti-EGFR therapeutics [56-58].”
BackgroundFeller, J. K., Yang, S., & Mahalingam, M. (2012) · Modern Pathology · doi:10.1038/modpathol.2012.168 · Cited by 64
Spreafico, A., Tentler, J. J., Pitts, T. M., Tan, A. C., Gregory, M. A., Arcaroli, J. J., Klauck, P. J., McManus, M. C., Hansen, R. J., Kim, J., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3140 · Cited by 64
“The multiple gene abnormalities and molecular alterations that are a hallmark of cancer affect proliferation and survival may be specifically targeted by novel anticancer agents (44-46).”
The Therapeutic Potential of MAPK/ERK Inhibitors in the Treatment of Colorectal Cancer
Pashirzad, M., Khorasanian, R., Fard, M. M., Arjmand, M., Langari, H., Khazaei, M., Soleimanpour, S., Rezayi, M., Ferns, G. A., Hassanian, S. M., et al. (2021) · Current Cancer Drug Targets · doi:10.2174/1568009621666211103113339 · Cited by 68
Chen, J., Guo, F., Shi, X., Zhang, L., Zhang, A., Jin, H., & He, Y. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-802 · Cited by 66
“The BRAF mutation frequency in CRC patients from Western countries is 1015% [37-39].”
Kwon, M. J., Lee, S. E., Kang, S. Y., & Choi, Y. (2011) · Pathology - Research and Practice · doi:10.1016/j.prp.2011.10.002 · Cited by 64
Igarashi, H., Kurihara, H., Mitsuhashi, K., Ito, M., Okuda, H., Kanno, S., Naito, T., Yoshii, S., Takahashi, H., Kusumi, T., et al. (2014) · Annals of Surgical Oncology · doi:10.1245/s10434-014-4264-7 · Cited by 63
“BRAF also has been reported to demonstrate a correlation between mutation and resistance to treatment with anti-EGFR therapeutics.(7,11,13,14,16,50) In the current study, mutations in KRAS (codon 61 and 146), NRAS (codon 12, 13, and 61), and BRAF (V600E) were detected in 7, 7, and 6 patients, respectively, among 102 p…”
BackgroundAnalysis of the BRAFV600E Mutation in Central Nervous System Tumors
Myung, J. K., Cho, H., Park, C., Kim, S., Lee, S., & Park, S. (2012) · Translational Oncology · doi:10.1593/tlo.12328 · Cited by 65
“Additionally, it seems to be a strong negative prognostic factor for colorectal carcinoma, and increasing evidence suggests that this mutation corresponds with resistance to anti–epidermal growth factor receptor (EGFR) therapy [22–24].”
BackgroundMolecular predictive and prognostic markers in colon cancer
Winder, T., & Lenz, H. (2010) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2010.03.005 · Cited by 64
“001, respectively).(42) However, the latest data from the CRYSTAL trial, presented on ASCO 2009, did not confirm B-Raf as a predictor for resistance to anti-EGFR monoclonal antibody treatment.”
ResultScartozzi, M., Mandolesi, A., Giampieri, R., Bittoni, A., Pierantoni, C., Zaniboni, A., Galizia, G., Giustini, L., Silva, R. R., Bisonni, R., et al. (2011) · The Oncologist · doi:10.1634/theoncologist.2010-0119 · Cited by 63
18F-FDG PET/CT imaging in rectal cancer: relationship with theRASmutational status
Lovinfosse, P., Koopmansch, B., Lambert, F., Jodogne, S., Kustermans, G., Hatt, M., Visvikis, D., Seidel, L., Polus, M., Albert, A., et al. (2016) · British Journal of Radiology · doi:10.1259/bjr.20160212 · Cited by 63
Che, M., Huang, J. C., Hung, J., Lin, Y.-C., Huang, M.-J., Lai, H., Hsu, W., Liang, J., & Huang, M. (2014) · Oncotarget · doi:10.18632/oncotarget.1981 · Cited by 62
“However, anti-EGFR therapy resistance is associated with KRAS or BRAF mutation [38, 39].”
BackgroundMizukami, T., Izawa, N., Nakajima, T. E., & Sunakawa, Y. (2019) · Drugs · doi:10.1007/s40265-019-01113-0 · Cited by 62
Kuan, S., Navina, S., Cressman, K. L., & Pai, R. K. (2013) · Human Pathology · doi:10.1016/j.humpath.2013.10.026 · Cited by 61
Cetuximab in the treatment of patients with colorectal cancer
Garrett, C. R., & Eng, C. (2011) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2011.582464 · Cited by 60
Development and progression of colorectal neoplasia
Manne, U., Shanmugam, C., Katkoori, V. R., Bumpers, H. L., & Grizzle, W. E. (2011) · Cancer Biomarkers · doi:10.3233/cbm-2011-0160 · Cited by 68
“Mutations in the BRAF gene may be useful for predicting the ef fi cacy/response to EGFR inhibitors, such as cetuximab and panitumumab, as is expression of KRAS gene mutations [329].”
Molecular markers for colon diagnosis, prognosis and targeted therapy
Herzig, D. O., & Tsikitis, V. L. (2014) · Journal of Surgical Oncology · doi:10.1002/jso.23806 · Cited by 63
Franchi, A., Degl’Innocenti, D. R., Palomba, A., Miligi, L., Paiar, F., Franzese, C., & Santucci, M. (2013) · Pathology & Oncology Research · doi:10.1007/s12253-013-9730-1 · Cited by 61
“The presence of BRAF activating mutations affects the response to therapies based on EGFR-targeting, but sensitivity may be restored by the multikinase inhibitor sorafenib [18].”
BackgroundPrognostic and predictive biomarkers in metastatic colorectal cancer anti-EGFR therapy
Nigro, C. L., Ricci, V., Vivenza, D., Granetto, C., Fabozzi, T., Miraglio, E., & Merlano, M. C. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i30.6944 · Cited by 61
The therapeutic potential of targeting the BRAF mutation in patients with colorectal cancer
Bahrami, A., Hesari, A., Khazaei, M., Hassanian, S. M., Ferns, G. A., & Avan, A. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25952 · Cited by 60
“Similarly, no responses were seen in the 11 BRAF mutations patients who were treated with panitumumab or cetuximab (Di Nicolantonio et al., 2008).”
BackgroundPersonalized Medicine—Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer
Koulis, C., Yap, R. J., Engel, R. M., Jardé, T., Wilkins, S., Solon, J. G., Shapiro, J. D., Abud, H. E., & McMurrick, P. J. (2020) · Cancers · doi:10.3390/cancers12040812 · Cited by 60
“An example of this is observed in CIMP-H tumors found to be MSI-positive, harboring the BRAF mutation results in a good prognosis [41].”
BackgroundHecht, J. R., Douillard, J., Schwartzberg, L. S., Grothey, A., Kopetz, S., Rong, A., Oliner, K. S., & Sidhu, R. (2015) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2015.05.008 · Cited by 63
“While some studies have suggested that patients with BRAF mutations may be less likely to respond to anti-EGFR therapy [41,58] others have not.”
BackgroundPredictive and Prognostic Biomarkers for Targeted Therapy in Metastatic Colorectal Cancer
Asghar, U. S., Hawkes, E. A., & Cunningham, D. (2010) · Clinical Colorectal Cancer · doi:10.3816/ccc.2010.n.040 · Cited by 61
Esophagogastric cancer: Targeted agents
Ku, G. Y., & Ilson, D. H. (2010) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2009.12.009 · Cited by 59
Krebs, M., Renehan, A. G., Backen, A. C., Gollins, S., Chau, I., Hasan, J., Valle, J. W., Morris, K. L., Beech, J., Ashcroft, L., et al. (2014) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2014.12.006 · Cited by 61
Saridaki, Z., Weidhaas, J. B., Lenz, H., Laurent‐Puig, P., Jacobs, B., Schutter, J. D., Roock, W. D., Salzman, D. W., Zhang, W., Yang, D., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0348 · Cited by 61
“Mounting evidence from retrospective studies suggest that the BRAF V600E mutation also confers resistant to antiEGFR MoAbs (14, 17-20), and, although not entirely clear yet, it also appears that PIK3CAmutant tumors derive no or little benefit from anti-EGFR moAbs treatment (14, 21-23).”
BackgroundClinico-pathological nomogram for predicting BRAF mutational status of metastatic colorectal cancer
Loupakis, F., Moretto, R., Aprile, G., Muntoni, M., Cremolini, C., Iacono, D., Casagrande, M., Ferrari, L., Salvatore, L., Schirripa, M., et al. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.399 · Cited by 60
“…Guidelines in Oncology (NCCN Guidelines), 2015), the predictive role towards anti-EGFRs of V600E activating mutation of BRAF is still debated (Di Nicolantonio et al, 2008; Laurent-Puig et al, 2009; Loupakis et al, 2009; Souglakos et al, 2009; De Roock et al, 2010) To this extent, studies have…”
BackgroundToon, C. W., Chou, A., DeSilva, K., Chan, J., Patterson, J., Clarkson, A., Sioson, L., Jankova, L., & Gill, A. J. (2014) · Modern Pathology · doi:10.1038/modpathol.2013.200 · Cited by 59
Nivolumab in the Treatment of Microsatellite Instability High Metastatic Colorectal Cancer
Sarshekeh, A. M., Overman, M. J., & Kopetz, S. (2018) · Future Oncology · doi:10.2217/fon-2017-0696 · Cited by 60
Morandi, L., de Biase, D., Visani, M., Cesari, V., Maglio, G. D., Pizzolitto, S., Pession, A., & Tallini, G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036084 · Cited by 59
“the impact of BRAF mutations on TKI treatment response is currently being investigated [14].”
BackgroundNayak, T. K., Garmestani, K., Baidoo, K. E., Milenic, D. E., & Brechbiel, M. W. (2010) · Journal of Nuclear Medicine · doi:10.2967/jnumed.109.071290 · Cited by 59
Evolving Therapies and FAK Inhibitors for the Treatment of Cancer
Dunn, K. B., Heffler, M., & Golubovskaya, V. (2010) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/187152010794728657 · Cited by 59
Rosa, M. D., Rega, D., Costabile, V., Duraturo, F., Niglio, A., Izzo, P., Pace, U., & Delrio, P. (2016) · Therapeutic Advances in Gastroenterology · doi:10.1177/1756283x16659790 · Cited by 61
Gong, J., Cho, M. T., Sy, M., Salgia, R., & Fakih, M. (2017) · Oncotarget · doi:10.18632/oncotarget.15030 · Cited by 117
McDaid, W. J., Greene, M. K., Johnston, M. C., Pollheimer, E., Smyth, P., McLaughlin, K., Van Schaeybroeck, S., Straubinger, R. M., Longley, D. B., & Scott, C. J. (2019) · Nanoscale · doi:10.1039/c9nr07257h · Cited by 58
Molecular Diagnostics of Colorectal Cancer
Bedeir, A., & Krasinskas, A. M. (2011) · Archives of Pathology & Laboratory Medicine · doi:10.5858/2010-0613-rair.1 · Cited by 59
Mutations in the RAS and PI3K pathways are associated with metastatic location in colorectal cancers
Lan, Y., Lin, J., Lin, C., Yang, S., Lin, C., Wang, H., Chen, W., Lin, T., Jiang, J., & Chang, S. (2015) · Journal of Surgical Oncology · doi:10.1002/jso.23895 · Cited by 58
“The KRAS mutation status is a negative predictor of metastatic colorectal cancers in patients receiving cetuximab treatment [4], but KRAS mutations are only found in approximately 30–40% of nonresponsive patients [5].”
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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