Prognostic value of perioperative ctDNA monitoring in patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemotherapy (NAC) and surgery.

Abstract

4094 Background: Recent results from a multicenter phase II clinical trial (jRCTs031200094) demonstrated that neoadjuvant FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) improves survival outcomes of patients with resectable ESCC. In this analysis, we evaluated the value of circulating tumor DNA (ctDNA) dynamics after FLOT and curative-intent surgery to predict treatment response and long term outcomes. Methods: The jRCTs031200094 clinical study enrolled 37 patients with ESCC to receive neoadjuvant FLOT followed by curative-intent surgery. Plasma samples were collected NAC, post-NAC (prior to surgery), and within 2–12 weeks post surgery [molecular residual disease (MRD) window]. A clinically validated, personalized, tumor-informed mPCR-NGS assay (Signatera, Natera, Inc.) was used on the banked specimens for ctDNA detection. Survival analyses were performed to calculate progression-free survival (PFS) stratified by ctDNA status at the post-NAC and post surgery timepoints. Results: This retrospective analysis included the 34 patients with ESCC and available ctDNA results. Patients had a median age of 66 years (range: 44–80), and the majority were male (79% [27/34]). Tumor locations included the middle (53%, 18/34), lower (41%, 14/34), and upper esophagus (5.9%, 2/34). The clinical stage distribution was 8.8% (3/34) stage I, 21% (7/34) stage II, 56% (19/34) stage III, and 15% (5/34) stage IV. R0 resection was achieved in 94% (29/31) of resected patients; 3 patients did not undergo esophagectomy due to disease progression or patient preference. Baseline ctDNA positivity was observed in 97.1% (33/34) of patients. Among 33 patients with ctDNA data available at the post-NAC timepoint, ctDNA-positivity was associated with significantly inferior PFS (HR: 3.17, 95% CI: 1.22-8.21; P=0.018), higher rate of lymph node positivity and higher tumor regression grade (TRG). Of the 29 patients with ctDNA data in the MRD window 31.3% (9/29) were ctDNA-positive and ctDNA-positivity in the MRD window was associated with significantly inferior PFS (HR: 5.89; P=0.001) and overall survival (OS; HR: 7.23; P=0.019). In addition, ctDNA dynamics in response to NAC and surgery were highly predictive of long term outcomes. Sustained clearance after NAC correlated with 80% 24m PFS. Inferior survival was observed in patients who remained ctDNA positive after NAC but cleared after surgery (HR 3.17) and in patients without clearance after surgery (HR 7.63). Conclusions: This study demonstrates prognostic and predictive value of single timepoint and longitudinal ctDNA status in the neoadjuvant and postsurgical management of patients with ESCC. Persistent ctDNA positivity following NAC and in the MRD window was strongly associated with inferior PFS, and early ctDNA clearance conferred the most favorable outcomes. Clinical trial information: jRCTs031200094.