This phase III trial studies combination chemotherapy and atezolizumab to see how well it works compared with combination chemotherapy alone in treating patients with stage III colon cancer and deficient deoxyribonucleic acid (DNA) mismatch repair (dMMR). Drugs used in combination chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy with atezolizumab may work better than combination chemotherapy alone in treating patients with dMMR colon cancer.

PRIMARY OBJECTIVE:

I. To determine whether atezolizumab combined with fluorouracil (FOLFOX) and its continuation as monotherapy can significantly improve disease-free survival (DFS) compared to FOLFOX alone in patients with stage III colon cancers and deficient DNA mismatch repair (dMMR).

SECONDARY OBJECTIVES:

I. To determine whether atezolizumab combined with FOLFOX and its continuation as monotherapy can significantly improve overall survival compared to FOLFOX alone in patients with stage III colon cancers and dMMR.

II. To assess the adverse events (AE) profile and safety of each treatment arm, using the Common Terminology Criteria for Adverse Events (CTCAE) and patient related outcomes (PRO)-CTCAE (among patients aged >= 18 years).

QUALITY OF LIFE OBJECTIVE:

I. To determine the impact of the addition of atezolizumab to FOLFOX on patient-reported neuropathy, health-related quality of life (QOL), and functional domains of health-related QOL.

II. To access the efficacy of atezolizumab adjusting for baseline QOL and fatigue measurements.

POTENTIAL CORRELATIVE SCIENCE OBJECTIVES:

I. To determine if the "immunoscore" can predict the efficacy of atezolizumab for disease-free survival among patients with stage III colon cancer.

II. To assess whether circulating immune cell populations can predict the efficacy of atezolizumab as adjuvant therapy for stage III colon cancer.

III. To explore the associations of genomic alterations identified in cell-free (cf)DNA with DFS in patients treated with FOLFOX with or without atezolizumab.

IV. To assess whether soluble markers of systemic inflammation in blood can predict the efficacy of atezolizumab as adjuvant therapy for stage III colon cancer.

V. To assess the relationship between baseline plasma 25(OH) D levels, change in 25(OH)D levels, and DFS and overall survival (OS) in patients with stage III colon cancer receiving FOLFOX +/- atezolizumab.

VI. To determine the ability of using fecal microbiota and their metabolic products to predict survival benefit from anti-PD-L1 antibody therapy in dMMR colon cancer patients.

VII. To determine if hypermutation or hyper-indel status is associated with response to atezolizumab.

VIII. To determine if unique messenger ribonucleic acid (mRNA) expression signatures are predictive of disease-free survival among patients receiving adjuvant chemotherapy for stage III colon cancer.

IX. To determine if the efficacy of atezolizumab differs among dMMR cancers due to germline MMR mutation (MLH1, MSH2, MSH6, PMS2) versus those with MLH1 hypermethylation and CIMP in patients with stage III colon cancer.

X. To identify overall mutational burden and number of putative tumor neoantigens in colon carcinoma specimens.

XI. To determine changes in growth patterns compared to baseline (relative to age-specific standards for height and weight). (Patients aged 12 to < 18 years to evaluate the impact of atezolizumab on growth and development patterns in this population) XII. To determine changes in development patterns compared to baseline (relative to onset of menarche [for females] and pubertal changes). (Patients aged 12 to < 18 years to evaluate the impact of atezolizumab on growth and development patterns in this population)

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes starting on day 1 of cycle 1 or 2. Treatment repeats every 14 days for up to 25 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) every 6 months for the first 2 years, then for years 3-5 or until evidence of relapse, whichever comes first. Patients may also undergo blood sample collection throughout the trial.

ARM II: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI every 6 months for the first 2 years, then for years 3-5 or until evidence of relapse, whichever comes first. Patients may also undergo blood sample collection throughout the trial.

After completion of study treatment, patients are followed up for recurrence every 6 months for 2 years, then annually for 3 years. Patients are also followed up for survival every 6 months for up to 8 years.

Inclusion Criteria:

• Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C); tumors must be deemed to originate in the colon including tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve)

• Presence of deficient (d) DNA mismatch repair (dMMR); MMR status must be assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR; dMMR may be determined either locally or by site-selected reference lab; Note: loss of MLH1 and PMS2 commonly occur together; formalin-fixed paraffin-embedded (FFPE) tumor tissue is required for subsequent retrospective central confirmation of dMMR status

• Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to participate; patients whose tumors show MSI-H by PCR-based assay are not eligible to participate unless they also have MMR testing by IHC and are found to have dMMR (i.e. loss of one or more MMR proteins)

• Patients who are known to have Lynch syndrome, have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), and have been shown to be dMMR by IHC are eligible to participate

• Tumors must have been completely resected; in patients with tumor adherent to adjacent structures, en bloc R0 resection must be documented in the operative report or otherwise confirmed by the surgeon; near or positive radial margins are acceptable so long as en bloc resection was performed; proximal or distal margin positivity is not permitted

• Entire tumor must be in the colon (rectal involvement is an exclusion); surgeon confirmation that entire tumor was located in the colon is required only in cases where it is important to establish if the tumor is a colon versus (vs.) rectal primary; patients with more than one primary colon adenocarcinoma are eligible if the qualifying stage III tumor is confined to the colon, and not rectum, and the other cancers of lower stage are removed in the en bloc R0 resection

• Based upon the operative report and other source documentation, the location of the primary tumor will be categorized as proximal or distal to the splenic flexure (included with distal), and further categorization will be as follows: cecum/ascending, transverse, descending, sigmoid colon, or rectosigmoid colon

• No evidence of residual involved lymph node disease or metastatic disease at the time of registration based on clinician assessment of imaging; the treating physician will determine if incidental lesions on imaging require workup to exclude metastatic disease; if based on review of images, the treating physician determines the patient to be stage III, then the patient is eligible

• No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for the current colon cancer except for one cycle of mFOLFOX6

• Age >= 12 years

• Performance Status:

  • Patients < 16 years of age: Lansky >= 50%
  • Patients 16 to < 18 years of age: Karnofsky >= 50%
  • Patients >= 18 years of age: Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• This study involves: 1) an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown; and 2) an agent that has known genotoxic, mutagenic, and teratogenic effects; therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required; a female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)

• Absolute neutrophil count (ANC) >= 1500 mm^3

• Platelet count >= 100,000 mm^3; platelets >= 75,000 required for patients who received cycle 1 of mFOLFOX6 prior to registration

• Creatinine =< 1.5 x upper limit of normal (ULN) or

• Calculated creatinine clearance >= 45 mL/min by Cockcroft-Gault equation

  • Alternatively, for patients < 18 years of age, maximum serum creatinine =< the below age-gender-specific norms:

    • 12 years: 1.2 (male and female)
    • 13 to < 16 years: 1.5 (male), 1.4 (female)
    • 16 to < 18 years: 1.7 (male), 1.4 (female)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) except in the case of Gilbert disease

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)

• Thyroid-stimulating hormone (TSH) within normal limits (WNL); supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible

• No active known autoimmune disease, including colitis, inflammatory bowel disease (i.e. ulcerative colitis or Crohn's disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency

• No known active hepatitis B or C

  • Active hepatitis B can be defined as:

    • Hepatitis B virus surface antigen (HBsAg) detectable for > 6 months;
    • Serum hepatitis B virus (HBV) DNA 20,000 IU/ml (105 copies/ml); lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B
    • Persistent or intermittent elevation in ALT/AST levels
    • Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation

  • Active hepatitis C can be defined as:

    • Hepatitis C antibody (AB) positive AND
    • Presence of hepatitis C virus (HCV) RNA

• Excluded if known active pulmonary disease with hypoxia defined as:

  • Oxygen saturation < 85% on room air, or
  • Oxygen saturation < 88% despite supplemental oxygen

• No grade >= 2 peripheral motor or sensory neuropathy

• Patients positive for human immunodeficiency virus (HIV) are eligible only if they meet all of the following:

  • A stable regimen of highly active anti-retroviral therapy (HAART)
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
  • A CD4 count above 250 cells/mcL, and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based tests

• No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study

• No systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration

• No known history of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins

• No known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation

• No known allergy to 5-fluorouracil, oxaliplatin, or leucovorin