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Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance

- ctDNA-POSITIVE: FOLFIRI Protocol

* FOLFIRI chemotherapy via intravenous infusion on days 1-3 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks).
* infusions will consist of the drugs
* 5-Fluorouracil
* Irinotecan
* Leucovorin

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance

-- Active surveillance.

* Observation and monitoring with imaging (every 3 months), tumor markers, and ctDNA draws every 1 month for the initial 6 months.
* After 6 months, followed with ctDNA, tumor markers, and scans every 3 months for the first 3 years and every 6 months thereafter.

Additional scans and tumor markers will be at the discretion of the clinician. .

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into 1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance

- Observation and monitoring with imaging, tumor markers, and ctDNA collections every 3 months for the first 3 years and every 6 months thereafter.

Additional scans and tumor markers will be at the discretion of the clinician

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests.

If these tests show that the participant is eligible to participate in the research study and is ctDNA positive and MSI-H, the participant will not be randomized and will be placed into the group: ctDNA positive, MSI-H: Nivolumab

-ctDNA-Positive, MSI-H: Nivolumab Protocol

* Nivolumab treatment via intravenous infusion on day 1 of each cycle. Cycle is 28 days long. This will occur for up to 12 cycles (48 weeks).
* infusions will consist of the drug Nivolumab

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests.

If these tests show that the participant is eligible to participate in the research study and is ctDNA positive and has a BRAF mutation, the participant will not be randomized and will be placed into the group: ctDNA positive, BRAF mutant: Encorafenib/Binimetinib/Cetuximab

-ctDNA-Positive, MSI-H: Encorafenib/Binimetinib/Cetuximab Protocol

* Encorafenib/Binimetinib treatment is received orally every day and Cetuximab via intravenous infusion on day 1 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks).
* infusions will consist of the drug Cetuximab

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. Participants that are eligible to receive Trastuzumab and Pertuzumab will be placed in this HER2 cohort: ctDNA-positive \& HER2 amplification and MSS Trastuzumab and Pertuzumab. Trastuzumab is received via intravenous administration, and Pertuzumab treatment is received intravenously by infusion. Cycle is 21 days. This will occur for up to 8 cycles.

FOLFIRI cycle will be two weeks (14 days) long, with FOLFIRI administered on Days 1-3. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of FOLFIRI chemotherapy.

FOLFIRI Protocol

Will be followed with observation and monitoring with imaging, tumor markers, and ctDNA collections

ACTIVE SURVEILLANCE

Nivolumab cycle will be four weeks (28 days) long, with Nivolumab administered on day 1. Participants will receive up to 12 four-week cycles (for a total of 48 weeks) of Nivolumab treatment.

Nivolumab Protocol

Encorafenib/Binimetinib will be taken orally every day and Cetuximab will be administered intravenously on day 1 of each cycle. Cycles are 14 days long. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of Encorafenib/Binimetinib/Cetuximab.

Encorafenib/Binimetinib/Cetuximab Protocol

Trastuzumab (Herceptin) is received by intravenous administration and Pertuzumab is received intravenously by infusion on Day 1 of each cycle. Cycles are 21 days long. Participants will receive up to 8 cycles of Trastuzumab and Pertuzumab.

Trastuzumab + Pertuzumab

Aparna Parikh, MD

Rona Yaeger, MD

Manish Shah, MD

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

The FDA (the U.S. Food and Drug Administration) has approved FOLFIRI, comprised of Irinotecan, Leucovorin, and 5-Fluorouracil, as a treatment option for metastatic colon cancer in the Stage IV setting.

* After diagnosis and surgical removal of tumors, individuals with metastatic colon cancer commonly receive what is called adjuvant chemotherapy treatment, commonly utilizing treatment plans called FOLFOX, CAPOX, or therapy with 5-Fluorouracil.
* If all the cancer is not killed, the investigators may be able to detect tumor in the blood called circulating tumor DNA (ctDNA). This is genetic material unique to metastatic colon cancer that may be present in the blood stream, and it can be identified through a ctDNA blood test. If ctDNA is present in the blood stream, it is commonly called micro-metastatic disease (meaning disease that can't be seen detected by CT scans but may be there in the blood). Cancer researchers believe that ctDNA in the blood stream may be an indicator that cancer is more likely to recur.
* After initial adjuvant chemotherapy, it is standard for individuals to begin active surveillance, where they do not receive further treatment but instead undergo frequent tumor imaging scans to see if their cancer is stable, growing, or coming back. The investigators plan to see if additional therapy, where FOLFIRI (comprised of Irinotecan, Leucovorin, and 5-Fluorouracil) is administered can decrease recurrence. Typically, FOLFIRI is given when the disease is visibly recurrent.

  * In addition, the investigators plan to include study groups of adjuvant nivolumab treatment and adjuvant Encorafenib/Binimetinib/Cetuximab treatment to see if these treatments can decrease recurrence. The FDA has not approved either of these as a treatment options for metastatic colon cancer in the Stage IV setting.
  * Patients who have a greater than normal number of genetic markers called microsatellites are called MSI-H. Because tumor cells with these features tend to have more genetic mutations than tumor cells without them, they are more likely to be recognized by the immune system. Nivolumab is an anti-PD-1 antibody. It works by attaching to and blocking a molecule called PD-1. PD-1 is a protein that is present on different types of cells in your immune system and controls parts of your immune system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1 from shutting down the immune system, thus potentially allowing immune cells to recognize and destroy cancer cells.
  * Encorafenib in combination with binimetinib and cetuximab is one of the first effective regimens to target the BRAF V600E-mutation in colon cancer. When this mutation is present, it switches on pathway called the MAPK pathway which stimulates cell division and leads to uncontrolled cell growth. Encorafenib, binimetinib and cetuximab target different parts of this important signaling pathway in tumor cells with this mutation and slows down their growth and communication

However, in this research study, the investigators are

* determining whether there are differences in cancer recurrence in ctDNA positive participants treated with additional therapy versus put on active surveillance.
* determining whether there are differences in health in ctDNA positive participants treated with additional therapy versus put on active surveillance.
* examining whether patients who undergo further therapy experience changes in the ctDNA levels.

Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer

Early Identification and Treatment of Occult Metastatic Disease in Stage III Colon Cancer

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research

Disease-free survival (DFS) between ctDNA-positive patients treated with additional treatment of FOLFIRI and ctDNA-positive patients who are untreated

Compare the clearance rate of ctDNA in ctDNA-positive patients between patients treated with additional treatment of FOLFIRI and those who are untreated

Overall survival (OS) between ctDNA-positive patients treated with additional adjuvant therapy (Arm 1) and ctDNA-positive patients who are untreated (Arm 2)

Determine clearance rate of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort

Determine the disease-free survival (DFS) of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort

Determine the clearance rate of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab in an exploratory BRAF V600E cohort.

Determine the disease-free survival DFS of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab, in an exploratory BRAF V600E cohort.

Examine the correlation of ctDNA clearance as a surrogate marker for disease burden

Compare lead time to recurrence and sensitivity of predicting recurrence between ctDNA and tumor markers

Determine the DFS ctDNA-positive patients treated Herceptin/Perjeta

Determine the clearance rate of ctDNA-positive patients treated Herceptin/Perjeta

Spots Global Cancer Trial Database for nivolumab protocol