DAILY: A prospective single arm study evaluating the impact of vitamin D, aspirin, exercise, and diet in colorectal cancer patients with ctDNA-defined minimal residual disease.

Abstract

e15534 Background: The successful utilization of circulating tumor DNA (ctDNA) for the identification of micrometastatic disease has fueled the exploration of therapeutic options in colorectal cancer (CRC). While ongoing studies are evaluating the efficacy of novel medical therapies in CRC patients with minimal residual disease (MRD), the influence of lifestyle factors is not well characterized. Epidemiology data is consistent that diet, vitamin D, aspirin, and exercise are associated with reduced risk of CRC recurrence; evidence from prospective clinical trials, however, is lacking. In this study, we evaluated the impact of lifestyle modifications in CRC patients with ctDNA-defined MRD following curative intent therapy. Methods: In this prospective single arm phase 2 pilot study, CRC patients with ctDNA-defined MRD (detectable ctDNA without radiographic evidence of disease) following completion of all standard therapies underwent lifestyle interventions for 3 months. Patients were identified with a tissue informed assay (Signatera). Trial interventions included daily aspirin supplementation (325mg if ≥70kg or 81mg if ≤70kg), daily vitamin D (oral cholecalciferol 8000 IU/d on days 1-14 followed by 4000 IU/d on days 15-90), low saturated fat diet, and physical activity (150 minutes of moderate activity weekly). Optional Fitbits for activity tracking and biweekly telephone counseling sessions were provided to encourage compliance. The primary endpoint was 3-month ctDNA clearance and secondary endpoints included decrease in ctDNA variant allele fraction (VAF) at 3 months and 12-month recurrence free survival. Results: Among the 16 CRC patients with ctDNA-defined MRD enrolled, 14 were evaluable at the time of data cutoff with the following baseline characteristics: median age 57 years (range 35-70), median BMI 30.7 (range 24.5-40.5), MSS (100%), KRAS mutated (35.7%), and PIK3CA mutated (21.4%). The median baseline detectable ctDNA level was 0.41 MTM/mL (range 0.03-2.2). At 3 months, 1 patient achieved ctDNA clearance which persisted at the time of data cutoff. The remaining 13 patients did not achieve ctDNA clearance or a decrease in VAF. Radiographic recurrence occurred in 64% of patients at 3 months with liver being the most common site (67%). Conclusions: Detectable ctDNA may potentially accelerate the prospective clinical assessment of lifestyle interventions in CRC. In this study, lifestyle modifications resulted in persistent ctDNA clearance for only a minority of patients. Future clinical trials should incorporate additional modalities to improve the efficacy of ctDNA clearance, which is ultimately necessary for eventual cure. Clinical trial information: NCT05036109 .