Phase II/III Study of Circulating Tumor DNA as a Predictive Biomarker in Adjuvant Chemotherapy in Patients With Stage IIA Colon Cancer (COBRA)

• The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Histologically/pathologically confirmed stage IIA adenocarcinoma of the colon (T3, N0, M0) with at least 12 lymph nodes examined at the time of surgical resection.

• Appropriate for active surveillance (i.e., no adjuvant chemotherapy) at the discretion of and as documented by the evaluating oncologist based on current practice patterns.

• The distal extent of the tumor must be \>= 12 cm from the anal verge on pre-surgical endoscopy (i.e., excluding rectal adenocarcinomas warranting treatment with chemoradiation). If the patient did not undergo a pre-surgical endoscopy, then the distal extent of the tumor must be \>= 12 cm from the anal verge as determined by surgical examination or pre-operative imaging.

• The patient must have had an en bloc complete gross resection of tumor (curative resection) as definitive surgical cancer treatment within 14 to 60 days of study randomization. Patients who have had a two-stage surgical procedure to first provide a decompressive colostomy and then, in a later procedure, to have the definitive surgical resection, are eligible.

• Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling.

• Absolute neutrophil count (ANC) must be \>= 1200/mm\^3 (within 28 days before randomization).

• Platelet count must be \>= 100,000/mm\^3 (within 28 days before randomization); and

• Hemoglobin must be \>= 9 g/dL (within 28 days before randomization).

• Total bilirubin must be =\< ULN (upper limit of normal) for the lab (within 28 days before randomization) unless the patient has a chronic grade 1 bilirubin elevation due to Gilbert?s disease or similar syndrome involving slow conjugation of bilirubin; and

• Alkaline phosphatase must be \< 2.5 x ULN for the lab (within 28 days before randomization); and

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be \< 1.5 x ULN for the lab (within 28 days before randomization).

• Serum creatinine =\< 1.5 x ULN for the lab or measured or calculated creatinine clearance \>= 50 mL/min using the Cockcroft-Gault formula for patients with creatinine levels \> 1.5 x ULN for the lab (within 28 days before randomization).

• Pregnancy test (urine or serum according to institutional standard) done within 14 days before randomization must be negative (for women of childbearing potential only).

• Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring of international normalized ratio (INR) if they are randomized to Arm 2 and receive capecitabine.