Genetic Testing in Screening Patients With Metastatic or Unresectable Colon or Rectal Cancer for a COLOMATE Trial

Inclusion Criteria: * Histological confirmation of adenocarcinoma of the colon or rectum that is metastatic and/ or unresectable * Progression, intolerance, or contraindication to a fluoropyrimidine (e.g., 5- fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody (bevacizumab, ziv-aflibercept, or ramucirumab), and an anti-PD-1 monoclonal antibody (nivolumab or pembrolizumab) if tumor has deficient mismatch repair proteins (dMMR) or is microsatellite instability-high (MSI-H) * For patients with KRAS and NRAS wild-type tumors, progression, intolerance, or contraindication to an anti-EGFR monoclonal antibody (cetuximab or panitumumab) * Note: If tissue is known to be positive for HER2 expression (IHC 3+) or the tumor has ERBB2 (HER2) amplification detected by a Clinical Laboratory Improvement Act (CLIA)-certified assay, prior treatment with anti-EGFR therapy is not required * At least one site of disease that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) that has not been previously irradiated; if the patient has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation * Life expectancy \>= 3 months per estimation of investigator * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 * Capable of understanding and complying with the protocol requirements and has signed the informed consent document * Satisfy at least one of the following two conditions: * Willing and able to provide blood sample for screening purposes * Guardant 360 testing completed =\< 60 days prior to registration Exclusion Criteria: * Evidence within the last 3 years of another malignancy which required systemic treatment. EXCEPTIONS: Non-melanotic skin cancer, carcinoma-in-situ of the cervix, or localized prostate cancer with a current PSA of \< 1.0mg/dL on 2 successive evaluations, at least 90 days apart, with the most recent evaluation no more than 4 weeks prior to registration * Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee * History of solid organ transplantation * Pregnant or planning to become pregnant within the next 12 months