Table 1.

Summary of literature addressing the association of CMS(-like) subtypes with therapy response.

Therapy composition	Reference	Trial/Cohort	Samples	Stage	Treatment	Main results
Chemotherapy only	Roepman et al.71	Local cohort	222	Stage III	No adjuvant therapy vs. 5-FU-based therapy	Epithelial B-type benefits from chemotherapy, mesenchymal C-type does not.
	Song et al.141	NASBP C-07	1729	Stage II and III	Leucovorin and 5-FU ± Oxaliplatin	Addition of oxaliplatin only benefits CMS2(-like) patients
	Okita et al.145	Local cohort	193	Metastatic	Irinotecan-based vs. Oxaliplatin-based	CMS4 benefits from irinotecan-based therapy
	Allena, Dunnea et al.142	Local cohort Marisa et al.68	156, 479	Stage II and III	No adjuvant therapy vs. 5-FU-based therapy	Only stage II and III CMS2 and stage III CMS3 benefit from adjuvant chemotherapy
Cetuximab	De Sousa e Meloa, Wanga et al.66, Sadanandam et al.67	Khambata-Forda, Garretta et al.132	110	Metastatic	No therapy vs. cetuximab mono therapy	No benefit for cetuximab in KRAS wildtype mesenchymal CCS3/stem-like subtypes, only in CCS1/TA-like epithelial subtypes.
Chemo- plus targeted therapy	Mooi et al.74	AGITG MAX	237	Metastatic	Capecitabine vs. Capecitabine + Bevacizumab (± Mitomycin)	Bevacizumab use only benefits CMS2 and possibly CMS3.
	Smeets et al.134	ANGIOPREDICT, CAIRO149	204, 205	Metastatic	Fluoropyrimidine-based chemotherapy ± Bevacizumab	CIN-intermediate/high (enriched for CMS2 & CMS4) benefit from bevacizumab, CIN-low (enriched for CMS1 & CMS3) do not.
	Trinh et al.137	CAIRO213	311	Metastatic	Capecitabine + Oxaliplatin + Bevacizumab ± Cetuximab	Benefit cetuximab only observed in KRAS wildtype epithelial (CMS2 & CMS3) group, not in mesenchymal (CMS4) group.
	Stintzing et al.135,136	FIRE3	315	Metastatic	FOLFIRI + Bevacizumab or + Cetuximab	Cetuximab yields more benefit than bevacizumab in CMS4.
	Lenz et al.75	CALGB/SWOG 80405	581	Metastatic	~75% FOLFOX, ~25% FOLFIRI + Bevacizumab or + Cetuximab	Bevacizumab yields more benefit than cetuximab in CMS1. Cetuximab yields more benefit than bevacizumab in CMS2.

Main characteristics of studies are listed, as well as the most notable outcomes. Superscripted numbers refer to original publication.

vs. versus.

^aIndicates shared first authorship.