Correlation of mid-chemoradiation ctDNA results and clinical complete response to total neoadjuvant therapy (TNT) for locally advanced rectal adenocarcinoma.
Authors: Seth Felder, Russell F Palm, Sarah E. Hoffe, James Costello, Harshna Vadvala, Iman Imanirad, Tiago Biachi de Castria, Richard D. Kim, Amalia Stefanou, Sophie Dessureault, Julian Sanchez, Kujtim Latifi, Jessica M. Frakes
Journal: Journal of Clinical Oncology (2025)

263 Background: The total neoadjuvant therapy (TNT) paradigm for locally advanced rectal cancer (LARC) is evolving with intensification and de-escalation neoadjuvant therapies. Chemoradiation (CRT) followed by consolidation chemotherapy offers the highest rate of organ preservation. Circulating tumor DNA (ctDNA) response during TNT may serve as a biomarker that allows for therapy personalization to better select candidates for rectal organ preservation (Watch-and-Wait, WW). Methods: We enrolled patients with mismatch repair proficient LARC eligible for TNT on a prospective protocol (NCT05108428). Patients underwent CRT to 50.4 Gy with a mid-treatment evaluation (27 Gy) on a MRI-linac followed by 8 cycles of consolidation FOLFOX. A sequential MRI-guided adaptive radiotherapy boost to 59.4 Gy was delivered if rectal tumor volume reduced &gt; 30% at 27 Gy. Standard restaging with diagnostic MRI and endoscopy occurred after TNT to evaluate organ preservation candidacy. ctDNA was obtained at diagnosis, mid-CRT (27 Gy), completion of TNT, and regular intervals in surveillance. ctDNA analysis was performed using a clinically validated, personalized, tumor-informed assay (Signatera, Natera, Inc.). Descriptive statistics for clinical response for mid-treatment assessment are reported. Additional clinical outcomes will be reported as follow up matures. Results: A total of 20 patients were enrolled (70% male, 70% cN+) with average age of 58 (range: 30-86) and 40% with threatened or involved radial margin. Average follow up is 12 months (range: 4-24 months) from date of completion of TNT. Average initial tumor volume was 26cc (range: 8.6cc- 66.8cc) with an average tumor reduction of 68.5% at 27 Gy. Volumetric change based on mid treatment MRI &gt;30% did not predict WW eligibility (2 patients with &lt;30% volumetric change maintains clinical complete responses). All patients demonstrated positive ctDNA at diagnosis (average 7.08 MTM/mL, range: 0.08 MTM/mL -77.96 MTM/mL). 25% of patients had elevated CEA at diagnosis. Conversion to negative ctDNA at mid-CRT occurred in 53% of patients. 57% of patients with a positive ctDNA at this timepoint underwent formal oncologic mesorectal excision with adenocarcinoma confirmed in the specimens. 25% of patients with negative ctDNA at this timepoint underwent a local excision, with no histologic invasive cancer in both specimens. We observed a 100% rectal organ preservation rate when early conversion to negative ctDNA at the 27 Gy of CRT timepoint. Conclusions: ctDNA clearance during CRT may be a good early predictor for patients that may be a candidate for a WW protocol. This biomarker may also guide consolidation therapy escalation (FOLFIRINOX) or de-escalation (chemotherapy omission) for select patients. Longer follow up is needed to correlate with clinical outcomes and future studies with more patients is needed. Clinical trial information: NCT05108428 .