Circulating Cell-Free Tumor DNA Testing in Guiding Treatment for Patients With Advanced or Metastatic Colorectal Cancer

Inclusion Criteria:

* Patients must have histologically or cytologically confirmed colorectal cancer.
* Patients must have advanced or metastatic disease with no curative options.
* Patients must have radiographically evaluable disease.
* Patients must have had at least 2 prior therapies for mCRC (including fluorouracil \[5-FU\], oxaliplatin, irinotecan, bevacizumab; cetuximab/panitumumab \[for RAS wild type (WT) patients\]) and have either progressed on or intolerant to these agents or use of these agents is contraindicated.
* Patients must be clinically eligible for either regorafenib or TAS-102 as per their treating physician.
* Patients must have a negative serum pregnancy test done less than are equal to 14 days prior to randomization for women of childbearing potential only. Women of child bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry for the duration of study participation.
* Patients must have ability to complete questionnaire(s) by themselves or with assistance.
* Patients must have ability to provide informed written consent.
* Patients must be willing to return to enrolling institution for follow-up as per study schedule.
* Patients must be willing to provide blood samples for correlative studies.
* Any of the following: Pregnant or nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception.
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.

Exclusion Criteria:

* Patient who have received prior TAS-102 are eligible to enroll on the study if they can receive regorafenib and vice-versa. Otherwise these patients will be excluded from the study.
* Congestive heart failure \> New York Heart Association (NYHA) class 2, unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months) or myocardial infarction less than 3 months prior to randomization.
* Ongoing infection \> grade 2 CTCAE version 4.0.
* Symptomatic metastatic brain or meningeal tumors unless the patient is \> 3 months from definitive therapy, has a negative imaging study within 4 weeks of randomization and is clinically stable with respect to brain lesions at the time of randomization (Note: patient must not be undergoing acute steroid therapy or taper \[chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies\]).
* Renal failure requiring hematological or peritoneal dialysis.
* Patients unable to swallow oral medications.