Localized colorectal cancer is highly treatable, primarily by surgery. Resection results in a cure in approximately 50% of patients.⁴ However, 40-50% of patients diagnosed initially with localized CRC will eventually develop metastatic disease. For the nearly one-quarter of those patients who present with metastatic colorectal cancer, treatment can be far more difficult than localized disease, resulting in almost one million deaths per year.^5,6,7 While family and personal medical history (including genetics, inflammatory bowel disease, chronic ulcerative colitis, Crohn’s disease, diabetes, colon polyps, and cholecystectomy) contribute to risk for CRC, much of the recent increase in global incidence is driven by lifestyle factors (including obesity, physical inactivity, alcohol consumption, tobacco use, and diet).^7,8,9

CRC progression is a stepwise histological sequence, most commonly initializing with a transformation from adenoma to carcinoma over a period of ~10 years.¹⁰ CRC evolves from benign to malignant lesions, some key driver genes acquire a series of mutations over time. Depending on the origin of these mutations, CRC can be classified as sporadic (driver point mutations, 70-75%), hereditary (known inherited mutations, 5%) or familial (unknown inherited mutations, 20-25%).^11,12 Key altered pathways include WNT, MAPK/PI3K, RTK-RAS, TGF-β and key driver genes include APC, KRAS, BRAF, PIK3CA, SMAD4, and TP53.^11-14 The frequency of deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) is ~15% of all CRC cases, while stage IV dMMR/MSI-H tumors account for ∼2–4% of all metastatic CRCs. ¹⁵ CRCs can be classified into 4 major consensus molecular subtypes according to their mutation pattern and gene expression profiles, each with different prognosis and therapeutic sensitivities. Tumors arising from the left vs the right sides of the colorectum are clinically and molecularly distinct; sidedness impacts prognosis and can influence therapeutic options.

CRC may be asymptomatic or heralded by symptoms of fatigue, blood in the stool, abdominal pain, changes in bowel habits, or obstructive symptoms.^8,16 The three characteristics that form the basis for the TNM staging system of CRC include^4,17: 

• The degree of penetration of the tumor (T) through the bowel wall.
• The presence or absence of nodal (N) involvement.
• The presence or absence of distant metastases (M).

Staging is based on the American Joint Committee on Cancer’s TNM classification 

Staging guides treatment strategies.¹⁸ Stages I-IIIA are resectable and stages IIIB-IVC are locally advanced or metastatic. Currently targeted therapies (including BRAF, EGFR, HER2, NTRK, and Multikinase inhibitors), checkpoint therapies (including PD-1, PD-L1, and CTLA-4 inhibitors), and chemotherapies are used as standard of care. 

A quarter to a half of patients develop liver metastasis over the course of the disease, although rates can be as high as 62% in the 3L setting.¹⁹ These patients experience low response rates and shorter median overall survival.²⁰ Chemotherapy and bevacizumab safety profiles can be intolerable for some patients. Median overall survival for standard of care is only ~1 year in 2L, and less in 3L​ patients. There is no targeted therapy options or critical genomic profiling that would aid in treatment decision-making in the adjuvant setting and actionability of genomic profiling in early- stage CRC is limited.^20,21

As the complicated signaling pathways and network cross-talk involved in CRC tumorigenesis are better understood, agents that target these emerging key biomarkers including TGF-b, PIK3CA, PTEN, HER2, KRAS G12C, LAG3, and CTLA-4 will allow for earlier detection, more effective treatments, and less toxic therapies.^22,23 Methylation-based liquid biopsy tests have the potential to improve several clinical applications including early detection and monitoring.^24,25