Circulating tumor DNA as a marker of recurrence risk in locoregional esophagogastric cancers with pathologic complete response.

person Eric Michael Lander Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN info_outline Eric Michael Lander, Brandon Huffman, Samuel J Klempner, Vasily N. Aushev, Jenifer Ferguson, Shruti Sharma, Adham A Jurdi, Minetta C. Liu, Cathy Eng, Michael K. Gibson

Authors person Eric Michael Lander Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN info_outline Eric Michael Lander, Brandon Huffman, Samuel J Klempner, Vasily N. Aushev, Jenifer Ferguson, Shruti Sharma, Adham A Jurdi, Minetta C. Liu, Cathy Eng, Michael K. Gibson Organizations Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, Dana-Farber Cancer Institute, Boston, MA, Mass General Cancer Center, Boston, MA, Natera, Inc., Austin, TX, Natera, Inc, Austin, TX, Vanderbilt-Ingram Cancer Center, Nashville, TN Abstract Disclosures Research Funding Conquer Cancer Foundation of the American Society of Clinical Oncology Conquer Cancer Foundation of the American Society of Clinical Oncology, U.S. National Institutes of Health Background: Following neoadjuvant therapy and definitive surgery, up to one-third of patients (pts) with gastroesophageal adenocarcinoma with a pathologic complete response (pCR; tumor regression grade 0 [TRG0]) will recur, while up to one-half of pts with a near-pCR (TRG1) experience recurrence. Our study aims to evaluate postoperative circulating tumor DNA (ctDNA) as a prognosticator of recurrence in pts with pCR or near-pCR after curative-intent neoadjuvant chemotherapy (NAC) or chemoradiation (CRT) and surgery. Methods: We retrospectively 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 follow-up from 9/19/19 to 2/21/22. MRD by ctDNA was assessed using a personalized, tumor-informed ctDNA assay (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. Results: We obtained 250 blood samples from 45 pts with esophageal (N=18), gastroesophageal junction (N=17), and gastric (N=10) adenocarcinomas who received either NAC or CRT. The median follow-up for this cohort was 22.8 months (range: 0.3-81.7 months). Despite pts achieving pCR (N=12) or near-pCR (N=33), ctDNA-positivity in the 16-week MRD window (N=21) correlated with higher rates of recurrence (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). 35 pts had ctDNA analyzed at any post-surgical time point, where the recurrence rate was 87.5% (7/8) in ctDNA-positive pts compared to 7.4% (2/27) in ctDNA-negative pts, exhibiting a further reduction in RFS (HR 44.8; 95% CI 5.4-369.7; p<0.0001). Out of 8 ctDNA-positive pts, two (25%) converted from ctDNA-positive to ctDNA-negative with subsequent treatment. Conclusions: Within the subgroup of pts with esophagogastric adenocarcinoma and favorable pathologic responses (TRG 0-1) following neoadjuvant treatment, the presence of post-operative ctDNA identified pts with elevated recurrence risk. If validated in larger cohort studies, testing for ctDNA may be a useful biomarker to select pts at risk for recurrence with potential to inform prospective clinical trials for direction of adjuvant therapy.