Circulating tumor DNA as a marker of recurrence risk in locoregional esophagogastric cancers with pathologic complete response.
Authors: Lander Eric Michael , Huffman Brandon , Klempner Samuel J , Aushev Vasily N. , Izaguirre Carbonell Jesus , Ferguson Jenifer , Sharma Shruti , Jurdi Adham A , Liu Minetta C. , Eng Cathy , Gibson Michael K. 
Published: January 2023

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Background: Following neoadjuvant therapy and definitive surgery, up to one-third of patients (pts) with esophageal (E), gastroesophageal junction (GEJ), and gastric (G) adenocarcinoma with a pathologic complete response (pCR) (tumor regression grade 0 [TRG0]) will experience disease recurrence, while up to one-half of pts with a near-pCR (TRG1) experience disease recurrence. Our study aims to provide real-world evidence that postoperative circulating tumor DNA (ctDNA) is prognostic of recurrence in pts with pCR or near-pCR after curative-intent neoadjuvant treatment and surgery. Methods: We identified pts from 11 institutions with stages I-III esophagogastric cancers who completed neoadjuvant therapy and had TRG0 or TRG1 scores at the time of curative-intent surgery. Postoperative plasma samples were collected for ctDNA analysis within a 16-week molecular residual disease (MRD) window after definitive surgery and serially during routine clinical follow-up from 9/19/19 to 2/21/22. MRD by ctDNA was assessed using a personalized, tumor-informed ctDNA assay (bespoke Signatera mPCR-NGS assay). The primary outcome was recurrence-free survival (RFS), measured from the date of surgery to the first documented sign of radiographic recurrence. Survival analysis was performed using the maximum likelihood bias reduction method for Cox regression in R (version 4.1) package survival. Results: We obtained 250 blood samples from 42 pts with E (n=18), GEJ (n=16), and G (n=8) adenocarcinomas who received either neoadjuvant chemoradiation or chemotherapy. 11 pts had a pCR (TRG0), and 31 pts had a near-pCR (TRG1). For pts analyzed in the post-operative, 16-week MRD window (n=21), the presence of ctDNA correlated with a higher recurrence rate (66.7%; 2/3) compared to the absence of ctDNA (11.1%; 2/18). Detectable ctDNA was associated with a significantly shorter RFS (HR 23.0, 95% CI 2.0 – 268.1; p = 0.012). 38 pts had ctDNA analyzed at any post-MRD time point (>16 weeks after surgery) over a median follow-up of 22.3 months. With additional routine ctDNA testing at any post-MRD time point, the recurrence rate was 90.0% (9/10) in ctDNA-positive pts compared to 10.7% (3/28) in ctDNA-negative pts, exhibiting a further reduction in RFS (HR 44.4; 95% CI 5.4-366.3; p<0.001). The sensitivity and specificity of the ctDNA assay at any post-operative time point was 87.5% and 96.2%, respectively. Out of 10 ctDNA-positive pts, two (20%) converted from ctDNA-positive to ctDNA-negative with subsequent treatment. Conclusions: Within the subgroup of pts with favorable pathologic responses after neoadjuvant therapy (TRG 0-1), the presence of post-operative ctDNA identified pts with elevated recurrence risk. If validated in larger cohorts this approach may be used to select pts at risk for recurrence following neoadjuvant therapy, with potential implications for direction of adjuvant therapy.