This is a phase 2 pragmatic study to examine the utility of ctDNA-informed treatment management for participants with early-stage rectal cancer using the Signatera Genome assay. The primary aims are to 1) assess pathologic complete response (path CR) in the ctDNA informed management arm; 2) assess pathologic complete response (path CR) in the post total neoadjuvant therapy (TNT) standard of care (SOC) surgery arm; and 3) assess disease free survival (DFS) in the ctDNA informed management arm.

Two cohorts of participants will be enrolled: Cohort A (participants appropriate for receiving TNT) and Cohort B (TNT already performed at UC Davis Health or externally). At Time A after TNT is completed and based on ctDNA assay results, the clinical decision will be made to put participants into one of two arms: the ctDNA informed management arm (Watchful Waiting [WW] surveillance) or the post TNT SOC surgery arm; participants will be monitored for ctDNA positivity for up to 5 years.

Inclusion Criteria:

• Tumor tissue histologically confirming rectal adenocarcinoma that is available for Natera ctDNA assay.
• Cohort A only: Patients appropriate for receiving TNT including chemotherapy and chemoradiation.
• Cohort B only: TNT must have included at least 4 cycles of CAPEOX or 6 cycles of FOLFOX and at least 45 Gy in 25 fractions to the pelvis during chemoradiation.
• Patients ≥18 years of age at time of consent.
• Ability to understand and willingness to sign the informed consent form (ICF).
• Ability and stated willingness to adhere to the study visit schedule and protocol procedures/requirements.

Exclusion Criteria:

• Prior treatment for rectal cancer, except for cohort B.
• Evidence of distant metastatic disease on staging imaging (CT chest with abdominopelvic imaging by CT or MRI) within 8 weeks of enrollment.
• Patients on hemodialysis.
• Any condition that in the opinion of the investigator would interfere with the participant's safety or compliance while on trial