1040 - Tumor-Informed Circulating Tumor DNA for Prediction of Organ Preservation and Enhanced Surveillance in Locally Advanced Rectal Cancer: A Real-World Cohort
Presenter(s)
R. Ravella1, E. K. Liu1, A. Bercz2, F. J. Arturi1, A. Adames1, A. Tin3, N. Schauer3, R. Lentz3, V. M. Williams1, J. J. Cuaron1, M. Zinovoy1, M. Reyngold1, M. Weiser4, J. Garcia-Aguilar4, C. H. Crane1, A. Cercek5, D. A. Roth O’Brien1, J. J. Smith6, M. Gönen7, and P. B. Romesser1; 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 2Department of Surgery, The Mount Sinai Hospital, New York, NY, 3Natera, Inc., Austin, TX, 4Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 5Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 6Department of Colon and Rectal Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 7Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
Purpose/Objective(s): Watch-and-wait (WW) after complete clinical response (cCR) to neoadjuvant therapy (NAT) enables organ preservation in locally advanced rectal cancer (LARC). Post-NAT selection for WW and continued surveillance relies on endoscopy/MRI which may not detect microscopic residual disease. We hypothesized that ctDNA-based detection of molecular residual disease after NAT predicts treatment failure and ctDNA monitoring may complement endoscopic/MRI surveillance.
Materials/Methods: Patients with LARC were treated at a single institution with NAT followed by upfront total mesorectal excision (TME; n=32) or WW (n=25) and underwent ctDNA monitoring using a clinically validated, personalized, tumor-informed 16-plex PCR-NGS sequencing assay (SignateraTM, Natera, Inc). NAT regimens included chemoradiotherapy (CRT) with induction/consolidation chemotherapy (n=39), CRT alone (n=8), or systemic therapy alone (n=10). In this real-world cohort, ctDNA was collected per routine care at the discretion of the treating physicians. Performance was assessed for ctDNA tests drawn =12 weeks after NAT completion, within ±3 months of clinical failure (local regrowth, local recurrence, or distant recurrence), and throughout surveillance for patients without failure. Local regrowth was defined as pelvic tumor reappearance during WW after confirmed cCR, while local recurrence was defined as pelvic tumor recurrence after TME.
Results: A total of 207 plasma samples from 57 patients were analyzed. Median follow-up was 82 months (range 24-255). ctDNA drawn =12 weeks after NAT completion was available for 14 WW patients; 13 were ctDNA-negative and achieved cCR, and one was ctDNA-positive who achieved cCR but had de novo metastatic disease. In WW patients with ctDNA testing available within ±3 months of clinical failure, ctDNA detected failure with 100% sensitivity (14/14; 95% CI 77–100), including 6/6 local regrowths, 1/1 local recurrence after TME, and 7/7 distant recurrences. All WW patients without failure were serially ctDNA negative (12/12, 100% specificity; 95% CI 74–100). In the TME cohort, ctDNA detected failure with 100% sensitivity (14/14; 95% CI 77–100), including 2/2 local recurrences and 12/12 distant recurrences, and remained negative in all patients without recurrence (12/12, 100% specificity; 95% CI 74–100).
Conclusion: In a real-world LARC cohort, tumor-informed ctDNA was concordant with post-NAT response among patients selected for WW and identified clinical failure with 100% sensitivity when sampled within ±3 months of the event. Persistent ctDNA negativity predicted sustained clinical response with 100% specificity. These data suggest that serial tumor-informed ctDNA testing may add to endoscopy/MRI to (i) identify patients most likely to achieve durable organ preservation and (ii) enhance surveillance by detecting relapse earlier than conventional imaging and endoscopic surveillance.