The Surveillance Nonoperative Watch & Wait (SNOWW) Rectal Cancer Trial.

This will be a prospective multi-center observational study for adult patients with stage 2 or 3 rectal adenocarcinoma who will be treated with TNT and are potential candidates for WW management. Study eligibility will be determined prior to the initiation of TNT by individual site investigators with the expectation that both the patient and investigator will be involved in multidisciplinary cancer decision-making. The rectal cancer tissue samples that were used to make the cancer diagnosis will also be used by our collaborative sponsor (Natera, Inc) to develop a tissue-informed and patient-specific ctDNA profile for each study patient. Patient blood samples will then be collected before the start of TNT, during TNT, after the completion of TNT, and for WW patients, at the time of every scheduled endoscopic surveillance exam, as recommended by the NCCN, and when non-scheduled endoscopic exams are performed. Figure 1. The patients will be prospectively followed for 2 years after the initiation of W\&W or until cancer regrowth is suspected or confirmed and treatments other than WW are implemented. Patients who have cancer regrowth and then salvage surgery will be followed until their first postoperative cancer re-staging examination. Patients who have cancer regrowth and do not have salvage surgery will be followed. until this decision to not pursue salvage surgery is made.

The study surgeons and their patients will have access to their ctDNA test results. The study surgeon and other members of the patients' cancer care team will be advised to consider these results in their patient care decision-making and to document how each ctDNA effected decision making, if at all. The study surgeon will be responsible for ensuring that their patients are aware of the limitations of ctDNA testing and the NCCN recommendations for its use in WW management of rectal cancer.

To evaluate the impact of ctDNA on the shared decision-making process, the validated 9 Item Shared Decision-Making Questionnaire (SDM-Q-9) and the Control Preference Sale (CPS) will be administered to patients at the re-staging visit following TNT, when the decision to pursue WW or surgery is being considered. For patients managed with WW, the SDM-Q-9 will also be re-administered every time ctDNA is used in surveillance and whether a treatment decision is being actively reconsidered based on ctDNA results.

Additionally, the Shared Decision-Making Questionnaire- Physician Version (SDM-Q-Doc) will be completed by study surgeons at the re-staging visit following TNT, when the decision to pursue WW or surgery is being considered. For patients managed with WW, the SDM-Q-Doc will also be re-administered every time ctDNA is used in surveillance and whether a treatment decision is being actively reconsidered based on ctDNA results. This will allow assessment of surgeon perspectives on the decision-making process and how ctDNA influences clinical recommendations