B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary.
To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS.
Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p < 0.0001), and inferior OS (median 15.1 vs. 36.6 months; p < 0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively.
LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.
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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.
Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER cancer statistics review, 1975–2017, National Cancer Institute. Bethesda, MD. https://seer.cancer.gov/csr/1975_2017/ based on November 2019 SEER data submission, posted to the SEER web site, April 2020.
Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer. JAMA Oncol. 2017;3(2):194. https://doi.org/10.1001/jamaoncol.2016.3797.
Tie J, Gibbs P, Lipton L, Christie M, Jorissen R, Burgess A, et al. Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAFV600E mutation. Int J Cancer. 2011;128(9):2075–84.
Kalady M, DeJulius K, Sanchez J, Jarrar A, Liu X, Manilic E, et al. BRAF mutations in colorectal cancer are associated with distinct clinical characteristics and worse prognosis. Dis Colon Rectum. 2012;55(2):128–33. https://doi.org/10.1097/dcr.0b013e31823c08b3.
Scartozzi M, Giampieri R, Aprile G, Iacono D, Santini D, dell’Aquila E, et al. The distinctive molecular, pathological and clinical characteristics of BRAF-mutant colorectal tumors. Expert Rev Mol Diagn. 2015;15(8):979–87. https://doi.org/10.1586/14737159.2015.1047346.
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. 2012;48(10):1466–75.
Mendis S, Beck S, Lee B, Lee M, Wong R, Kosmider S, et al. Right versus left sided metastatic colorectal cancer: teasing out clinicopathologic drivers of disparity in survival. Asia Pac J Clin Oncol. 2019;15(3):136–43. https://doi.org/10.1111/ajco.13135.
Bylsma LC, Gillezeau C, Garawin TA, Kelsha MA, Fryzek JP, Sangare L, et al. Prevalence of RAS and BRAF mutations in metastatic colorectal cancer patients by tumor sidedness: a systematic review and meta-analysis. Cancer Med. 2020;9(3):1044–57. https://doi.org/10.1002/cam4.2747.
Suidan R, Leitao M, Zivanovic O, Gardner G, Long Roche K, Sonoda Y, et al. Predictive value of the Age-Adjusted Charlson Comorbidity Index on perioperative complications and survival in patients undergoing primary debulking surgery for advanced epithelial ovarian cancer. Gynecol Oncol. 2015;138(2):246–51. https://doi.org/10.1016/j.ygyno.2015.05.034.
Baran B, Mert Ozupek N, Yerli Tetik N, Acar E, Bekcioglu O, Baskin Y. Difference between left-sided and right-sided colorectal cancer: a focused review of literature. Gastroenterol Res. 2018;11(4):264–73. https://doi.org/10.14740/gr1062w.
Rowland A, Dias M, Wiese M, Kichenadasse G, McKinnon R, Karapetis C, Sorich M. 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. 2015;112(12):1888–94. https://doi.org/10.1038/bjc.2015.173.
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. 2015;51(5):587–94. https://doi.org/10.1016/j.ejca.2015.01.054.
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. 2008;26:5705–12.
Mao C, Liao R, Qiu L, Wang X, Ding H, Chen Q, et al. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. Mol Biol Rep. 2011;38:2219–23. https://doi.org/10.1007/s11033-010-0351-4.
Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25(13):1670–6.
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. 2014;371(17):1609–18.
Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (mCRC): Updated survival results of the phase III TRIBE trial by the GONO group. Lancet Oncol. 2015;16(13):1306–15. https://doi.org/10.1016/S1470-2045(15)00122-9.
Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632–43. https://doi.org/10.1056/NEJMoa1908075.
Kopetz S, Mcdonough SL, Lenz HJ, Magliocco AM, Atreya CE, Diaz LA, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). J Clin Oncol. 2017;35(15_Suppl):3505.
Grothey A, Tabernero J, Taieb J, Yaeger R, Yoshino T, Maiello E, et al. LBA-5 ANCHOR CRC: a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E-mutant metastatic colorectal cancer. Ann Oncol. 2020;31:S242–3.
Ducreux M, Chamseddine A, Laurent-Puig P, Smolenschi C, Hollebecque A, Dartigues P, et al. Molecular targeted therapy of BRAF-mutant colorectal cancer. Ther Adv Med Oncol. 2019;11:1758835919856494.
Andre T, Shiu K-K, Kim TW, Jensen BV, Jensen LH, Punt C, et al. (2020) Pembrolizumab vs. chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. J Clin Oncol 38(18_suppl):LBA4. https://doi.org/10.1200/JCO.2020.38.18_suppl.LBA4
Seppälä TT, Böhm JP, Friman M, Lahtinen L, Väyrynen VM, Liipo TK, et al. Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer. Br J Cancer. 2015;112(12):1966–75. https://doi.org/10.1038/bjc.2015.160.
Atreya CE, Greene C, McWhirter RM, Ikram NS, Allen IE, Van Loon K, et al. Differential radiographic appearance of BRAF V600E-mutant metastatic colorectal cancer in patients matched by primary tumor location. J Natl Compr Cancer Netw. 2016;14(12):1536–43. https://doi.org/10.6004/jnccn.2016.0165.
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Conflict of interest
Vanessa Wong’s research institution, Walter and Eliza Hall Institute of Medical Research, is the recipient of research grant funding from Pierre-Fabre, Amgen, Novartis, Roche, and Merck, for unrelated projects. Peter Gibbs has received research grants from Pierre-Fabre, honoraria from Roche, and consulting fees and lecture payments from MSD, Merck and Amgen. Jayesh Desai has received research grants from Roche/Genentech, Lilly, AstraZeneca, BeiGene, Novartis, Bristol Myers Squibb, and GlaxoSmithKline and consulting fees from Amgen, Pierre-Fabre, and BeiGene. Adnan Khattak, Brigette Ma, Jeanne Tie, Jeremy Shapiro, Louise Nott, Margaret Lee, Matthew Burge, Rachel Wong, Simone Steel, and Wei Hong have no conflicts of interest that might be relevant to the contents of this manuscript.
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Wong, V., Lee, M., Wong, R. et al. BRAFV600E Mutations Arising from a Left-Side Primary in Metastatic Colorectal Cancer: Are They a Distinct Subset?. Targ Oncol 16, 227–236 (2021). https://doi.org/10.1007/s11523-021-00793-7