Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer

This research study is comparing two standard of care treatment options based on blood test results for participants who have metastatic colon cancer. The names of the potential treatments involved in this study are: * Active surveillance * FOLFIRI treatment * Nivolumab treatment * Encorafenib/Binimetinib/Cetuximab treatment * Trastuzumab + Pertuzumab

Inclusion Criteria: * Participants must have histologically confirmed resected Stage III adenocarcinoma of the colon. Any T \[Tx, T1, T2, T3, or T4-\], N1-2M0. * Participants must have completely resected disease. In patients with tumor adherent to adjacent structures, en block RO resection must be documented. * Entire tumor must be in the colon (rectal involvement is excluded). * Participants must have completed standard adjuvant chemotherapy per the discretion of the treating physician. Standard therapy includes FOLFOX, CAPOX, or therapy with 5FU analog alone will be permitted if it constitutes appropriate standard therapy in the opinion of the treating physician. * Participants must not have received prior neoadjuvant chemotherapy. * Age ≥18 years. * ECOG performance status ≤1. * Life expectancy of greater than 3 months. * Participants must have normal organ and marrow function as defined below: * leukocytes ≥3,000/mcL * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/ mcL * total bilirubin within normal institutional limits. For patients with Gilbert's syndrome, total bilirubin must be ≤ 2 and documented as elevated indirect bilirubin. * AST(SGOT)/ALT(SGPT) ≤3 (AST) or ≤ 3 (ALT) × institutional upper limit of normal * creatinine within normal institutional limits OR * creatinine clearance ≥40 mL/min/1.73 m2 for participants with creatinine levels above institutional normal by Cockroft-Gault formula. * In order to be eligible for the ctDNA positive cohort, women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG). * The effects on the developing human fetus are unknown. For this reason and because 5FU, Capecitabine, Oxaliplatin, Irinotecan, Leucovorin, Nivolumab, and Cetuximab are known to be teratogenic, in order to be eligible for the ctDNA positive cohort, females of child-bearing potential (FOCBP) and males must be willing to abstain from heterosexual activity or use 2 forms of effective contraception (fail rate of less than 1% per year, hormonal or barrier method of birth control) from time of informed consent until 5 months (FOCBP) and 7 months (males) after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Women who are not of childbearing potential, ie, who are postmenopausal or surgically sterile as well as azoospermic men, do not require contraception. * Participants must have documentation of microsatellite instability status. Testing by NGS, PCR based assessment and Immunohistochemistry (IHC) are acceptable. Presence of deficient (d) DNA mismatch repair (dMMR) may be assessed by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicated dMMR. This may be done locally. * Participant's circulating tumor DNA (ctDNA) assay (Guardant Reveal-Guardant Health) must satisfy assay specific quality control metrics to generate a result. * In order to be eligible for the ctDNA positive cohort, patient must be ctDNA positive following adjuvant therapy using the CLIA certified Guardant Reveal assay. ctDNA positive will be defined as positive based on having a tumor derived signal in the cfDNA that passes calling threshold ("ctDNA detected"). * Ability to understand and the willingness to sign a written informed consent document. Trastuzumab and Pertuzumab Specific Inclusion Criteria for HER2 cohort * HER2 overexpression/amplification as shown by NGS sequencing, IHC/FISH or Tumor with 3+ by IHC or 2+ by IHC and HER2/cep17 ratio \>2 by FISH. * AST(SGOT) ≤ 1.25 and ALT(SGPT) ≤ 1.25 × institutional upper limit of normal * Participants of childbearing potential must use effective contraceptive methods during and for 7 months after the last dose of HER2-targeted therapy * History of other malignancies within the 5 years prior to study registration, except for the following: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin (\*malignancies occurring more than 5 years prior to study entry are permitted if curatively treated with surgery alone). * LVEF ≥ 55% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) within 12 weeks of treatment start. Exclusion Criteria: * Patients who are receiving additional investigational therapy or on another investigational protocol * Patients who have confirmed metastatic disease per CT. * Patients who are unable to get any standard adjuvant therapy * Patients who have received more than 6 months of standard adjuvant therapy at the time of study entry. * With the exception of standard of care adjuvant therapy, patient received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic biologic therapy (e.g., cetuximab, bevacizumab etc.), within 30 days prior to start of study treatment. * Patients who are MSI-high or have a BRAF V600E mutation are excluded from Arm 1 (FOLFIRI) and Arm 2 (Active Surveillance). * Patients with a BRAFV600E mutation and who are MSI-high are excluded from Arm 5 (ENCO/BINI/CETUX). * Has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * (ctDNA positive cohort only). Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 6 months for woman and 6 months for men, after the last dose of trial treatment. * Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. * Has an active infection requiring systemic therapy. Nivolumab Specific Inclusion Criteria for MSI-H Cohort: * Must have documentation of microsatellite instability status. NGS, PCR based assessment and Immunohistochemistry (IHC) are acceptable. Presence of deficient (d) DNA mismatch repair (dMMR) may be assessed by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicated dMMR. This may be done locally. * Patients must have detectable ctDNA (Guardant Reveal assay) post standard adjuvant therapy in order to be in this cohort. Nivolumab Specific Exclusion Criteria for MSI-H Cohort: * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other forms of immunosuppressive therapy within 7 days prior to the first dose of nivolumab treatment. Subject requiring systemic steroids are excluded from the trial. The use of physiologic doses of corticosteroids may be approved after discussion with the sponsor. * Has a known history of active TB (Bacillus tuberculosis) * Hypersensitivity to nivolumab or any of is excipients * Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. * Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. * Patients that require supplemental oxygen are excluded. * Patients who are known HIV+ positive are eligible if their CD4+ count is ≥ 350/μL for at least 3 months and they have an undetectable viral load. In addition, patient must be currently receiving Highly Active Antiretroviral Therapy (HAART) and have been on therapy for at least 3 months prior to study entry, under the care of an Infectious Diseases specialist. Patients should have no history of an AIDS-defining opportunistic infection. * Patients known hepatitis B and hepatitis C must be under the care of viral hepatitis expert consultant. Patients with hepatitis B are required to be treated with anti-HBV treatment (e.g., entecavir) and have an HBV viral load \