Early stage colon cancer: Current treatment standards, evolving paradigms, and future directions

Table 4 Evolving tools and biomarkers which may help precise patient selection for adjuvant therapy and therapy personalization in early stage colon cancer

Biomarker/tool	Clinical significance	Potential use and relevance	Ref.
ctDNA	Prognostic	ctDNA detection in the bloodstream after surgical resection and adjuvant chemotherapy provides direct evidence of residual micro-metastatic disease and correlates with a very high risk of cancer recurrence in resected stage II and III patients. Sensitivity, specificity, positive and negative predictive values are 48%, 100%, 100% and 91%, respectively. Reported studies suggest that ctDNA can potentially serve as a real time marker of adjuvant therapy efficacy in stage II and III patients.	[110-115]
Immunoscore	Prognostic	High immunoscore is associated with favorable prognosis in both stage II and III patients independent of patient T stage, N stage and microsatellite instability. High-risk stage II patients with high Immunoscore had similar time to recurrence compared with average risk stage II patients in a recent report.	[118-122]
dMMR	Prognostic and predictive	Associated with favorable prognosis in stage II and possibly low-risk (IDEA defined) stage III patients. Predicts lack of benefit and possibly harm with 5-FU based adjuvant chemotherapy in both stage II and III patients.	[124-137]
KRAS and BRAFV600E mutation	Prognostic	KRAS and BRAFV600E mutations have been reported to be associated with a worse prognosis in several large retrospective studies, in both stage II and III patients. dMMR status attenuates adverse prognostic impact of BRAFV600E mutation, possibly except in IDEA defined high-risk stage III CC.	[133,137 -141]
Genomic profiling (Oncotype Dx Colon Cancer®)	Prognostic	Prognostic discrimination capacity is insufficient to guide therapy in routine clinical practice.	[142-147]
PIK3CA mutations	Predictive	Retrospective analysis suggests an association between the use of aspirin and improved survival among the patients with mutated-PIK3CA colorectal cancer including stage I-III patients.	[152]
CDX2 expression	Prognostic and predictive	Retrospective analysis suggested lack of CDX2 expression was associated with worse outcome in stage II and III CC. Lack of CDX2 expression appears to be predictive of benefit from adjuvant chemotherapy in stage II patients.	[153]
CMS	Prognostic	CMS1 tumors have a good prognosis, the CMS4 tumors have a poor prognosis, and the CMS2 and CMS3 types have an intermediate prognosis. Not validated to guide therapy in routine clinical practice.	[148-151]

ctDNA: Circulating tumor DNA; dMMR: Deficient mismatch repair status; CC: Colon cancer; CMS: Consensus molecular subtypes.