Exploring the best treatment options for BRAF-mutant metastatic colon cancer

Article metrics



The BRAFV600E mutation is a well-accepted poor prognostic factor in patients with metastatic colorectal cancer (mCRC), as it confers Ras-independent stimulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway involved in proliferation, migration, angiogenesis and the suppression of apoptosis. Analysis of the potential predictive value of BRAF for treatment efficacy is inherently confounded by this known prognostic impact. Currently, approved therapeutic strategies for patients with BRAF-mutant (BRAF-mt) mCRC are suboptimal, and uncertainty exists regarding how to best treat these patients. Based on the available evidence, it is currently not possible to confirm the superiority of any available treatment options cited in European Society for Medical Oncology and National Comprehensive Cancer Network guidelines (that is, doublet or triplet chemotherapy regimens plus anti-vascular endothelial growth factor or anti-epidermal growth factor receptors), even if triplet chemotherapy plus bevacizumab is the most accepted standard regimen. In this review, we highlight still-emerging strategies that could be deployed to combat BRAF-mt mCRC, including triplet chemotherapy plus available biologic agents, rationally derived combinations of targeted agents and immunotherapy. While it is clear that the needs of patients with BRAF-mt mCRC are currently unmet, we are cautiously optimistic that the recently renewed research interest in these patients will yield clinically relevant insights and therapeutic strategies.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1


  1. 1.

    Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).

  2. 2.

    Van Cutsem, E., Cervantes, A., Adam, R., Sobrero, A., Van Krieken, J. H., Aderka, D. et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 27, 1386–1422 (2016).

  3. 3.

    Lièvre, A., Bachet, J.-B., Boige, V., Cayre, A., Le Corre, D., Buc, E. et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 26, 374–379 (2008).

  4. 4.

    Douillard, J.-Y., Oliner, K. S., Siena, S., Tabernero, J., Burkes, R., Barugel, M. et al. Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 369, 1023–1034 (2013).

  5. 5.

    Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

  6. 6.

    Andre, T., Lonardi, S., Wong, M., Lenz, H.-J., Gelsomino, F., Aglietta, M. et al. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): first report of the full cohort from CheckMate-142. J. Clin. Oncol. 36(4 Suppl), 553–553 (2018).

  7. 7.

    Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949 (2002).

  8. 8.

    Rad, R., Cadiñanos, J., Rad, L., Varela, I., Strong, A., Kriegl, L. et al. A genetic progression model of BrafV600E-induced intestinal tumorigenesis reveals targets for therapeutic intervention. Cancer Cell 24, 15–29 (2013).

  9. 9.

    De Roock, W., Claes, B., Bernasconi, D., De Schutter, J., Biesmans, B., Fountzilas, G. et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 11, 753–762 (2010).

  10. 10.

    Sorbye, H., Dragomir, A., Sundström, M., Pfeiffer, P., Thunberg, U., Bergfors, M. et al. High BRAF mutation frequency and marked survival differences in subgroups according to KRAS/BRAF mutation status and tumor tissue availability in a prospective population-based metastatic colorectal cancer cohort. PLoS ONE 10, e0131046 (2015).

  11. 11.

    Taieb, J., Zaanan, A., Le Malicot, K., Julié, C., Blons, H., Mineur, L. et al. Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab: a post hoc analysis of the PETACC-8 trial. JAMA Oncol. 2, 643 (2016).

  12. 12.

    Jones, J. C., Renfro, L. A., Al-Shamsi, H. O., Schrock, A. B., Rankin, A., Zhang, B. Y. et al. Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J. Clin. Oncol. 35, 2624–2630 (2017).

  13. 13.

    Johnson, B., Loree, J. M., Morris, V. K., Dasari, A., Pant, S., Raghav, K. P. S. et al. Activity of EGFR inhibition in atypical (non-V600E) BRAF-mutated metastatic colorectal cancer. J. Clin. Oncol. 37(4 Suppl), 596–596 (2019).

  14. 14.

    Guinney, J., Dienstmann, R., Wang, X., de Reyniès, A., Schlicker, A., Soneson, C. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3967.html (2015). Cited 18 July 2018.

  15. 15.

    Taieb, J., Le Malicot, K., Shi, Q., Penault Lorca, F., Bouché, O., Tabernero, J. et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. J. Natl Cancer Inst. 109, djw272 (2017).

  16. 16.

    Richman, S. D., Seymour, M. T., Chambers, P., Elliott, F., Daly, C. L., Meade, A. M. et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J. Clin. Oncol. 27, 5931–5937 (2009).

  17. 17.

    Van Cutsem, E., Köhne, C.-H., Láng, I., Folprecht, G., Nowacki, M. P., Cascinu, S. et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J. Clin. Oncol. 29, 2011–2019 (2011).

  18. 18.

    Di Nicolantonio, F., Martini, M., Molinari, F., Sartore-Bianchi, A., Arena, S., Saletti, P. et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J. Clin. Oncol. 26, 5705–5712 (2008).

  19. 19.

    Safaee Ardekani, G., Jafarnejad, S. M., Tan, L., Saeedi, A. & Li, G. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS ONE 7, e47054 (2012).

  20. 20.

    Heinemann, V., von Weikersthal, L. F., Decker, T., Kiani, A., Vehling-Kaiser, U., Al-Batran, S.-E. et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 15, 1065–1075 (2014).

  21. 21.

    Schwartzberg, L. S, Rivera, F, Karthaus, M, Fasola, G, Canon, J.-L. & Hecht, J. R. et al. PEAK: a randomized, multicenter phase ii study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J. Clin. Oncol. 32, 2240–2247 (2014).

  22. 22.

    Loupakis, F., Cremolini, C., Masi, G., Lonardi, S., Zagonel, V., Salvatore, L. et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N. Engl. J. Med. 371, 1609–1618 (2014).

  23. 23.

    Seligmann, J. F., Fisher, D., Elliott, F., Richman, S., Butler, R., Cheadle, J. et al. Exploring the poor outcomes of BRAF mutant (BRAF mut) advanced colorectal cancer (aCRC): analysis from 2,530 patients (pts) in randomized clinical trials (RCTs). J. Clin. Oncol. 33(15 Suppl), 3509–3509 (2015).

  24. 24.

    Wan, P. T., Garnett, M. J., Roe, S. M., Lee, S., Niculescu-Duvaz, D., Good, V. M. et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855–867 (2004).

  25. 25.

    Barras, D., Missiaglia, E., Wirapati, P., Sieber, O. M., Jorissen, R. N., Love, C. et al. BRAF V600E mutant colorectal cancer subtypes based on gene expression. Clin. Cancer Res. 23, 104–115 (2017).

  26. 26.

    Corcoran, R. B., Ebi, H., Turke, A. B., Coffee, E. M., Nishino, M., Cogdill, A. P. et al. EGFR-mediated reactivation of MAPK signaling contributes to insensitivity of BRAF-mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2, 227–235 (2012).

  27. 27.

    Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).

  28. 28.

    Morris, V., Overman, M. J., Jiang, Z.-Q., Garrett, C., Agarwal, S., Eng, C. et al. Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin. Colorectal Cancer 13, 164–171 (2014).

  29. 29.

    Masi, G., Loupakis, F., Salvatore, L., Fornaro, L., Cremolini, C., Cupini, S. et al. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol. 11, 845–852 (2010).

  30. 30.

    Loupakis, F., Cremolini, C., Salvatore, L., Masi, G., Sensi, E., Schirripa, M. et al. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur. J. Cancer 50, 57–63 (2014).

  31. 31.

    Cremolini, C., Loupakis, F., Antoniotti, C., Lupi, C., Sensi, E., Lonardi, S. et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 16, 1306–1315 (2015).

  32. 32.

    Bokemeyer, C., Van Cutsem, E., Rougier, P., Ciardiello, F., Heeger, S., Schlichting, M. et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur. J. Cancer 48, 1466–1475 (2012).

  33. 33.

    Phelip, J., Benhaim, L., Bouché, O., Christou, N., Desolneux, G., Dupré, A., et al. “Cancer colorectal métastatique”. Thésaurus National de Cancérologie Digestive. Thésaurus Natl Cancérologie Dig.; www.tncd.org (2019).

  34. 34.

    Benson, A. B., Venook, A. P., Al-Hawary, M. M., Cederquist, L., Chen, Y.-J., Ciombor, K. K. et al. NCCN guidelines insights: colon cancer, version 2.2018. J. Natl Compr. Cancer Netw JNCCN. 16, 359–369 (2018).

  35. 35.

    Ince, W. L., Jubb, A. M., Holden, S. N., Holmgren, E. B., Tobin, P., Sridhar, M. et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. JNCI J. Natl Cancer Inst. 97, 981–989 (2005).

  36. 36.

    Price, T. J., Hardingham, J. E., Lee, C. K., Weickhardt, A., Townsend, A. R., Wrin, J. W. et al. Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J. Clin. Oncol. 29, 2675–2682 (2011).

  37. 37.

    Wirapati, P., Pomella, V., Vandenbosch, B., Kerr, P., Maiello, E., Jeffery, G. M. et al. Velour trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity. J. Clin. Oncol. 35(15 Suppl), 3538–3538 (2017).

  38. 38.

    Yoshino, T., Obermannova, R., Bodoky, G., Prausová, J., Garcia-Carbonero, R., Ciuleanu, T.-E. et al. Are BRAF mutated metastatic colorectal cancer (mCRC) tumors more responsive to VEGFR-2 blockage? Analysis of patient outcomes by RAS/RAF mutation status in the RAISE study—a global, randomized, double-blind, phase III study. J. Clin. Oncol. 36(4 Suppl), 622–622 (2018).

  39. 39.

    Karapetis, C. S., Jonker, D., Daneshmand, M., Hanson, J. E., O’Callaghan, C. J., Marginean, C. et al. PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer—results from NCIC CTG/AGITG CO.17. Clin. Cancer Res. 20, 744–753 (2014).

  40. 40.

    Peeters, M., Oliner, K. S., Price, T. J., Cervantes, A., Sobrero, A. F., Ducreux, M. et al. Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin. Cancer Res. 21, 5469–5479 (2015).

  41. 41.

    Seymour, M. T., Brown, S. R., Middleton, G., Maughan, T., Richman, S., Gwyther, S. et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 14, 749–759 (2013).

  42. 42.

    Pietrantonio, F., Petrelli, F., Coinu, A., Di Bartolomeo, M., Borgonovo, K., Maggi, C. et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur. J. Cancer 51, 587–594 (2015).

  43. 43.

    Rowland, A., Dias, M. M., Wiese, M. D., Kichenadasse, G., McKinnon, R. A., Karapetis, C. S. et al. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br. J. Cancer 112, 1888–1894 (2015).

  44. 44.

    Geissler, M., Martens, U., Knorrenschield, R., Greeve, J., Florschuetz, A., Tannapfel, A. et al. 475O-mFOLFOXIRI + Panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer m(CRC): a randomized. Ann. Oncol. 28(Suppl 5), v158–v208 (2017).

  45. 45.

    Stintzing, S., Miller-Phillips, L., Modest, D. P., Fischer von Weikersthal, L., Decker, T., Kiani, A. et al. Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study. Eur. J. Cancer 79, 50–60 (2017).

  46. 46.

    Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

  47. 47.

    Gomez-Roca, C. A., Delord, J., Robert, C., Hidalgo, M., von Moos, R., Arance, A. et al. 535P Encorafenib (LGX818), an oral BRAF inhibitor, in patients with BRAF V600E metastatic colorectal cancer: results of dose expansion in an open-label, phase I study. Ann. Oncol. 25(Suppl 4), iv182–iv183 (2014).

  48. 48.

    Kopetz, S., Desai, J., Chan, E., Hecht, J. R., O’Dwyer, P. J., Lee, R. J. et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J. Clin. Oncol. 28(15 Suppl), 3534–3534 (2010).

  49. 49.

    Kopetz, S., Desai, J., Chan, E., Hecht, J. R., O’Dwyer, P. J., Maru, D. et al. Phase II Pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J. Clin. Oncol. 33, 4032–4038 (2015).

  50. 50.

    Hyman, D. M., Puzanov, I., Subbiah, V., Faris, J. E., Chau, I., Blay, J.-Y. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).

  51. 51.

    Corcoran, R. B., André, T., Atreya, C. E., Schellens, J. H. M., Yoshino, T., Bendell, J. C. et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAF V600E-mutant colorectal cancer. Cancer Discov. 8, 428–443 (2018).

  52. 52.

    Yaeger, R., Cercek, A., O’Reilly, E. M., Reidy, D. L., Kemeny, N., Wolinsky, T. et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin. Cancer Res. 21, 1313–1320 (2015).

  53. 53.

    Hong, D. S., Morris, V. K., El Osta, B., Sorokin, A. V., Janku, F., Fu, S. et al. Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAFV600E mutation. Cancer Discov. 6, 1352–1365 (2016).

  54. 54.

    Kopetz, S., McDonough, S. L., Morris, V. K., Lenz, H.-J., Magliocco, A. M., Atreya, C. E. et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J. Clin. Oncol. 35(4 Suppl), 520–520 (2017).

  55. 55.

    Mao, M., Tian, F., Mariadason, J. M., Tsao, C. C., Lemos, R., Dayyani, F. et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin. Cancer Res. 19, 657–667 (2013).

  56. 56.

    Elez, E., Schellens, J., Van Geel, R., Bendell, J., Spreafico, A., Schuler, M. et al. LBA-08 Results of a phase 1b study of the selective BRAF V600 inhibitor encorafenib in combination with cetuximab alone or cetuximab + alpelisib for treatment of patients with advanced BRAF-mutant metastatic colorectal cancer. Ann. Oncol. 26(Suppl 4), iv120 (2015).

  57. 57.

    Long, G. V., Stroyakovskiy, D., Gogas, H., Levchenko, E., de Braud, F., Larkin, J. et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 371, 1877–1888 (2014).

  58. 58.

    Van Cutsem, E., Atreya, C., André, T., Bendell, J., Schellens, J., Gordon, M. et al. LBA-07 updated results of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC). Ann. Oncol. 26(Suppl 4), iv119 (2015).

  59. 59.

    Rawson, J. B., Mrkonjic, M., Daftary, D., Dicks, E., Buchanan, D. D., Younghusband, H. B. et al. Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients. Br. J. Cancer 104, 1906–1912 (2011).

  60. 60.

    Schadendorf, D., Hodi, F. S., Robert, C., Weber, J. S., Margolin, K., Hamid, O. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).

  61. 61.

    Reck, M., Rodríguez-Abreu, D., Robinson, A. G., Hui, R., Csőszi, T., Fülöp, A. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).

  62. 62.

    Lapeyre-Prost, A., Terme, M., Pernot, S., Marcheteau, E., Pointet, A.-L., Voron, T. et al. Immune therapy in colorectal cancer. Colorec. Cancer 6, 1–10 (2017).

  63. 63.

    Weisenberger, D. J., Siegmund, K. D., Campan, M., Young, J., Long, T. I., Faasse, M. A. et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat. Genet. 38, 787–793 (2006).

  64. 64.

    English, D. R., Young, J. P., Simpson, J. A., Jenkins, M. A., Southey, M. C., Walsh, M. D. et al. Ethnicity and risk for colorectal cancers showing somatic BRAF V600E mutation or CpG island methylator phenotype. Cancer Epidemiol Biomarkers Prev. 17, 1774–1780 (2008).

  65. 65.

    Venderbosch, S., Nagtegaal, I. D., Maughan, T. S., Smith, C. G., Cheadle, J. P., Fisher, D. et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin. Cancer Res. 20, 5322–5330 (2014).

  66. 66.

    Lochhead, P., Kuchiba, A., Imamura, Y., Liao, X., Yamauchi, M., Nishihara, R. et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. JNCI J. Natl Cancer Inst. 105, 1151–1156 (2013).

  67. 67.

    Rosenbaum, M. W., Bledsoe, J. R., Morales-Oyarvide, V., Huynh, T. G. & Mino-Kenudson, M. PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes. Mod. Pathol. 29, 1104–1112 (2016).

  68. 68.

    Overman, M. J., McDermott, R., Leach, J. L., Lonardi, S., Lenz, H.-J., Morse, M. A. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 18, 1182–1191 (2017).

  69. 69.

    Overman, M. J., Lonardi, S., Wong, K. Y. M., Lenz, H.-J., Gelsomino, F., Aglietta, M. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability–high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018).

  70. 70.

    Frederick, D. T., Piris, A., Cogdill, A. P., Cooper, Z. A., Lezcano, C., Ferrone, C. R. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).

  71. 71.

    Van Cutsem, E., Cuyle, P.-J., Huijberts, S., Yaeger, R., Schellens, J. H. M., Elez, E. et al. BEACON CRC study safety lead-in (SLI) in patients with BRAFV600E metastatic colorectal cancer (mCRC): efficacy and tumor markers. J. Clin. Oncol. 36(4 Suppl), 627–627 (2018).

  72. 72.

    Samowitz, W. S., Sweeney, C., Herrick, J., Albertsen, H., Levin, T. R., Murtaugh, M. A. et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 65, 6063–6069 (2005).

  73. 73.

    Roth, A. D., Tejpar, S., Delorenzi, M., Yan, P., Fiocca, R., Klingbiel, D. et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J. Clin. Oncol. 28, 466–474 (2010).

  74. 74.

    Gavin, P. G., Colangelo, L. H., Fumagalli, D., Tanaka, N., Remillard, M. Y., Yothers, G. et al. Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value. Clin. Cancer Res. 18, 6531–6541 (2012).

  75. 75.

    André, T., de Gramont, A., Vernerey, D., Chibaudel, B., Bonnetain, F., Tijeras-Raballand, A. et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J. Clin. Oncol. 33, 4176–4187 (2015).

  76. 76.

    Sinicrope, F. A., Mahoney, M. R., Smyrk, T. C., Thibodeau, S. N., Warren, R. S., Bertagnolli, M. M. et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J. Clin. Oncol. 31, 3664–3672 (2013).

  77. 77.

    Modest, D. P., Ricard, I., Heinemann, V., Hegewisch-Becker, S., Schmiegel, W., Porschen, R. et al. Outcome according to KRAS-, NRAS-and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann. Oncol. 27, 1746–1753 (2016).

  78. 78.

    Innocenti, F., Ou, F.-S., Qu, X., Zemla, T. J., Niedzwiecki, D., Tam, R. et al. Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J. Clin. Oncol. 37, 1217–1227 (2019).

  79. 79.

    Falchook, G. S., Long, G. V., Kurzrock, R., Kim, K. B., Arkenau, T. H., Brown, M. P. et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379, 1893–1901 (2012).

  80. 80.

    van Geel, R. M. J. M., Tabernero, J., Elez, E., Bendell, J. C., Spreafico, A., Schuler, M. et al. A Phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF -mutant colorectal cancer. Cancer Discov. 7, 610–619 (2017).

  81. 81.

    Tabernero, J., Geel, R. V., Guren, T. K., Yaeger, R. D., Spreafico, A., Faris, J. E. et al. Phase 2 results: encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC). J. Clin. Oncol. 34(15 Suppl), 3544–3544 (2016).

Download references

Author information

J.T. and A.L.P. have designed the review, performed the bibliographical research and wrote the paper, they have contributed equally to this work. A.Z. and P.L.P. have participated in paper writing, critical corrections and improvement and to figures design.

Correspondence to Julien Taieb.

Ethics declarations

Competing interests

J.T. declared providing an advisory role for Roche, Merck, KGaA, Amgen Lilly, Baxalta, Servier and Sirtex Medical. A.L.P. declared a consultancy role for MERCK, MERCK SERONO and AMGEN/COHESIA. A.Z. had a consultancy role for Amgen, Baxter, Lilly, Merck Serono, MSD, Roche, Sanofi and Servier. P.L.P. declared a consultancy role for Amgen, Astrazeneca, Biocartis, Boehringer-Ingelheim, Merck, MSD, BMS, Roche and Sanofi.

Ethics approval and consent to participate

Not applicable


No sources of funding are to be reported for this study.

Consent to publish

Not applicable

Data availability

Not applicable


This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark