Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.

Article  PubMed  Google Scholar 

Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34. https://doi.org/10.1056/NEJMoa1305275.

Article  CAS  PubMed  Google Scholar 

Van Cutsem E, Lenz HJ, Kohne CH, Heinemann V, Tejpar S, Melezinek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33(7):692–700. https://doi.org/10.1200/JCO.2014.59.4812.

Article  CAS  PubMed  Google Scholar 

Stahler A, Heinemann V, Ricard I, von Einem JC, Giessen-Jung C, Westphalen CB, Michl M, Heinrich K, Miller-Phillips L, Jelas I, Stintzing S, Modest DP. Current treatment options in RAS mutant metastatic colorectal cancer patients: a meta-analysis of 14 randomized phase III trials. J Cancer Res Clin Oncol. 2020;146(8):2077–87. https://doi.org/10.1007/s00432-020-03290-y.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gimple RC, Wang X. RAS: striking at the core of the oncogenic circuitry. Front Oncol. 2019;9:965. https://doi.org/10.3389/fonc.2019.00965.

Article  PubMed  PubMed Central  Google Scholar 

Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72(10):2457–67. https://doi.org/10.1158/0008-5472.CAN-11-2612.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7. https://doi.org/10.1038/nature11252.

Article  CAS  Google Scholar 

Rimbert J, Tachon G, Junca A, Villalva C, Karayan-Tapon L, Tougeron D. Association between clinicopathological characteristics and RAS mutation in colorectal cancer. Mod Pathol. 2018;31(3):517–26. https://doi.org/10.1038/modpathol.2017.119.

Article  CAS  PubMed  Google Scholar 

Domingo E, Ramamoorthy R, Oukrif D, Rosmarin D, Presz M, Wang H, Pulker H, Lockstone H, Hveem T, Cranston T, Danielsen H, Novelli M, Davidson B, Xu ZZ, Molloy P, Johnstone E, Holmes C, Midgley R, Kerr D, Sieber O, Tomlinson I. Use of multivariate analysis to suggest a new molecular classification of colorectal cancer. J Pathol. 2013;229(3):441–8. https://doi.org/10.1002/path.4139.

Article  CAS  PubMed  PubMed Central  Google Scholar 

•• Cervantes A, Adam R, Rosello S, Arnold D, Normanno N, Taieb J, Seligmann J, De Baere T, Osterlund P, Yoshino T, Martinelli E, Committee EG. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022. https://doi.org/10.1016/j.annonc.2022.10.003. This is the latest ESMO guideline about the treatment of metastatic colorectal cancer and represents the current standard of care.

Kazazi-Hyseni F, Beijnen JH, Schellens JH. Bevacizumab. Oncologist 2010;15(8):819-825. https://doi.org/10.1634/theoncologist.2009-0317.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42. https://doi.org/10.1056/NEJMoa032691.

Article  CAS  PubMed  Google Scholar 

Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7(9):987–9. https://doi.org/10.1038/nm0901-987.

Article  CAS  PubMed  Google Scholar 

Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10(2):145–7. https://doi.org/10.1038/nm988.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jang HJ, Kim BJ, Kim JH, Kim HS. The addition of bevacizumab in the first-line treatment for metastatic colorectal cancer: an updated meta-analysis of randomized trials. Oncotarget. 2017;8(42):73009–16. https://doi.org/10.18632/oncotarget.20314.

Article  PubMed  PubMed Central  Google Scholar 

Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9. https://doi.org/10.1200/jco.2007.14.9930.

Article  CAS  PubMed  Google Scholar 

Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D’Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. 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. 2015;16(13):1306–15. https://doi.org/10.1016/S1470-2045(15)00122-9.

Article  CAS  PubMed  Google Scholar 

Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371(17):1609–18. https://doi.org/10.1056/NEJMoa1403108.

Article  CAS  PubMed  Google Scholar 

Punt CJA, Bond MJG, Bolhuis K, Loosveld O, Helgason HH, Groot JWd, Hendriks MP, Kerver ED, Liem MSL, Rijken AM, Verhoef C, Wilt JHWd, Jong KPD, Kazemier G, Amerongen MJv, Engelbrecht MRW, Klaase JM, Komurcu A, Lopez-Yurda MI, Swijnenburg R-J. FOLFOXIRI + bevacizumab versus FOLFOX/FOLFIRI + bevacizumab in patients with initially unresectable colorectal liver metastases (CRLM) and right-sided and/or RAS/BRAFV600E-mutated primary tumor: phase III CAIRO5 study of the Dutch Colorectal Cancer Group. J Clin Oncol. 2022;40(17_suppl):LBA3506-LBA3506. https://doi.org/10.1200/JCO.2022.40.17_suppl.LBA3506.

Cremolini C, Antoniotti C, Stein A, Bendell J, Gruenberger T, Rossini D, Masi G, Ongaro E, Hurwitz H, Falcone A, Schmoll HJ, Di Maio M. Individual patient data meta-analysis of FOLFOXIRI plus bevacizumab versus doublets plus bevacizumab as initial therapy of unresectable metastatic colorectal cancer. J Clin Oncol. 2020;Jco2001225. https://doi.org/10.1200/jco.20.01225.

Lenz H-J, Cutsem EV, Limon ML, Wong KYM, Hendlisz A, Aglietta M, García-Alfonso P, Neyns B, Luppi G, Cardin DB, Dragovich T, Shah U, Abdullaev S, Gricar J, Ledeine J-M, Overman MJ, Lonardi S. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol. 2022;40(2):161–70. https://doi.org/10.1200/jco.21.01015.

Article  CAS  PubMed  Google Scholar 

Le DT, Kim TW, Van Cutsem E, Geva R, Jäger D, Hara H, Burge M, O’Neil B, Kavan P, Yoshino T, Guimbaud R, Taniguchi H, Elez E, Al-Batran SE, Boland PM, Crocenzi T, Atreya CE, Cui Y, Dai T, Marinello P, Diaz LA Jr, André T. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol. 2020;38(1):11–9. https://doi.org/10.1200/jco.19.02107.

Article  CAS  PubMed  Google Scholar 

André T, Shiu K-K, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207–18. https://doi.org/10.1056/NEJMoa2017699.

Article  PubMed  Google Scholar 

Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fourchardiere C, Rivera F, Elez E, Le DT, Yoshino T, Zhong WY, Fogelman D, Marinello P, Andre T. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;23(5):659–70. https://doi.org/10.1016/s1470-2045(22)00197-8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015;385(9980):1843–52. https://doi.org/10.1016/S0140-6736(14)62004-3.

Article  CAS  PubMed  Google Scholar 

Koeberle D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D, Matter K, Winterhalder R, Borner M, Anchisi S, Moosmann P, Kollar A, Saletti P, Roth A, Frueh M, Kueng M, Popescu RA, Schacher S, Hess V, Herrmann R. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol. 2015;26(4):709–14. https://doi.org/10.1093/annonc/mdv011.

Article  CAS  PubMed  Google Scholar 

Aparicio T, Ghiringhelli F, Boige V, Le Malicot K, Taieb J, Bouche O, Phelip JM, Francois E, Borel C, Faroux R, Dahan L, Jacquot S, Genet D, Khemissa F, Suc E, Desseigne F, Texereau P, Lepage C, Bennouna J, Investigators P. Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9). J Clin Oncol. 2018;36(7):674–81. https://doi.org/10.1200/JCO.2017.75.2931.

Article  CAS  PubMed  Google Scholar 

Hegewisch-Becker S, Graeven U, Lerchenmuller CA, Killing B, Depenbusch R, Steffens CC, Al-Batran SE, Lange T, Dietrich G, Stoehlmacher J, Tannapfel A, Reinacher-Schick A, Quidde J, Trarbach T, Hinke A, Schmoll HJ, Arnold D. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015;16(13):1355–69. https://doi.org/10.1016/S1470-2045(15)00042-X.

Article  CAS  PubMed  Google Scholar 

Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, von Moos R, Viéitez JM, Bouché O, Borg C, Steffens C-C, Alonso-Orduña V, Schlichting C, Reyes-Rivera I, Bendahmane B, André T, Kubicka S. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37. https://doi.org/10.1016/S1470-2045(12)70477-1.

Article  CAS  PubMed  Google Scholar 

Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, Chevalier S, Allegra CJ. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014;50(2):320–31. https://doi.org/10.1016/j.ejca.2013.09.013.

Article  CAS  PubMed  Google Scholar 

Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506. https://doi.org/10.1200/jco.2012.42.8201.

Article  PubMed