Potential of Circulating Tumor DNA in Stratifying Patients with Localized pMMR Colon Cancer to Neoadjuvant Therapy

Introduction: Neoadjuvant chemotherapy has potential benefit in patients with localized colon cancer with proficient mismatch repair (pMMR). However, patient selection is a major challenge. We explored whether pre-operative circulating tumor DNA (pre-op ctDNA) would be helpful in selecting high-risk patients for neoadjuvant chemotherapy. Methods: Pre-op ctDNA levels were determined using blood samples from patients undergoing potentially curative surgery for localized pMMR colon cancer. Associations between pre-op ctDNA and pathological stage, positive (R1) resection margins and disease recurrence were investigated. Predictive models for these outcomes using routinely available clinical factors with and without pre-op ctDNA were developed. Results: In total, 979 patients were included. Pre-op ctDNA was significantly associated with pathological stage, although no difference between patients with stage II and III disease was noted (positive patients: stage I 28% versus stage II 67% versus stage III 75%, p < 0.001). Pre-op ctDNA was also associated with R1 resection (positive patients: R0 59% versus R1 82%, p = 0.017). Patients with positive pre-op ctDNA had increased 3-year cumulative incidence of recurrence after surgery (23% [95% CI 18–28] versus 5.3% [95% CI 2.6–9.4]; p < 0.001), most of which occurred within 12 months of surgery. Although the addition of ctDNA to clinical predictive models did not improve prediction of pathological stage or R1 status, it had some value in identifying early recurrence after surgery. Conclusion: Pre-op ctDNA is associated with pathological stage, R1 resection, and recurrence after surgery in patients with localized pMMR colon cancer. However, its value in improving the selection of high-risk patients for neoadjuvant chemotherapy requires further investigation.