Rates of Aerodigestive Cancer After Positive mt-sDNA and Colonoscopy Without Advanced Colorectal Neoplasia in Patients with a Prior Cancer History

Multitarget stool DNA (mt-sDNA) testing is widely used for colorectal cancer (CRC) screening, however the clinical implications of a positive mt-sDNA results with a subsequent negative colonoscopy remain unclear especially in patients with a history of non-CRC malignancy. This study aimed to characterize the long-term incidence of new or recurrent malignancy in these patients. This retrospective, single-center study was conducted at Memorial Sloan Kettering Cancer Center between 2014 and 2024. Patients included had a history of non-CRC malignancy, a positive mt-sDNA result, and a subsequent colonoscopy without advanced colorectal neoplasia. Exclusion criteria included prior CRC, inadequate follow-up, or ineligibility for mt-sDNA testing. The primary outcome was the incidence of new or recurrent cancer, classified by location and organ system. Aerodigestive tract involvement was defined to include the lungs, oropharynx, esophagus, stomach, liver, pancreas, bowel, and parotid gland. MSK-IMPACT® tumor sequencing was reviewed when available. Sixty-five patients met inclusion criteria. With a median follow-up of 28 months, 14 patients (22%) developed new or recurrent disease; 13 of these (93%) involved the aerodigestive tract. Malignancy-related events included primary gastric, lung, and hypopharyngeal cancers, as well as recurrent or metastatic disease involving aerodigestive and gastrointestinal organs. There were no significant differences in demographics or colonoscopy findings between groups. However, patients who remained disease-free were more likely to have never smoked (63% vs. 23%, p = 0.03). Of six patients with MSK-IMPACT® data, one had a KRAS mutation targeted by mt-sDNA. In this cohort, approximately one in five patients were subsequently diagnosed with a new primary malignancy or recurrent disease; these findings require further study, do not support changes in clinical surveillance, and highlight the need for careful discussion when ordering mt-sDNA testing in patients with prior non-CRC.