Abstract 1657: Prediction of pathologic complete response to neoadjuvant therapy for esophageal adenocarcinoma using copy number alterations
Authors: Qian David C. , Lefferts Joel A. , Zaki Bassem I. , Mishyn Pavlo , Brickley Elizabeth B. , Xue Yue , Lisovsky Mikhail 
Published: August 2019

Abstract
Background: Standard of care for locally advanced (stage II-III) esophageal adenocarcinoma is neoadjuvant chemoradiation followed by esophagectomy. Pathologic complete response (pCR) to neoadjuvant therapy occurs in 25-30% of patients. Three-year overall and progression-free survival of patients with pCR are nearly double those of incomplete responders (86% and 80% versus 48% and 39%, respectively). Therefore accurate prediction of pCR prior to esophagectomy can potentially spare patients the intraoperative risks and postoperative changes in quality of life associated with surgery. However, no well-established biomarkers of pCR currently exist.
Methods: Paired pre-treatment biopsies and post-chemoradiation resections from patients with stage II-III esophageal adenocarcinoma between 2003 and 2017 were retrieved at a single institution. pCR was defined as absence of cancer cells in the treated specimen, while pathologic poor response (pPR) was defined as greater than 10% of tumor cells remaining in the specimen. In total, 27 pCR and 25 pPR resections were identified along with 20 and 12 of their corresponding DNA samples from pre-treatment biopsies that passed quality control on the OncoScan platform to call copy number alteration events. Within every cytogenetic band in the human genome, the quantity of bases gained by each sample was computed as the sum of gained genomic segment lengths weighted by the surplus copy number of each segment. These cytogenetic band gains were compared between pCR and pPR samples. An independent validation dataset of 47 patients with stage II-III esophageal adenocarcinoma was obtained from The Cancer Genome Atlas (TCGA).
Results: In 3-fold cross-validation, genomic gains in chromosome 14q11 and chromosome 19p13 displayed the most significant difference between pCR and pPR samples in all 3 training sets. Across the test sets, average AUC for correctly predicting pCR/pPR status was 0.829. Selecting 1.1 megabases as the cutoff that optimizes tradeoff between sensitivity and specificity in the discovery dataset also stratified survival in TCGA. Among TCGA patients, those possessing genomic gains in chr14q11 and chr19p13 that exceed 1.1 megabases had superior 5-year overall survival (44% versus 0%, HR = 0.324, P = 0.0249) with median survival of 46 months versus 20 months.
Conclusion: Genomic gains in 14q11 and 19p13 may be a valuable biomarker for inference of pCR/pPR among patients with esophageal adenocarcinoma. To our knowledge, it is the first such biomarker with demonstrated utility in an independent set of patients. Further prospective validation is warranted.
Citation Format: David C. Qian, Joel A. Lefferts, Bassem I. Zaki, Pavlo Mishyn, Elizabeth B. Brickley, Yue Xue, Mikhail Lisovsky. Prediction of pathologic complete response to neoadjuvant therapy for esophageal adenocarcinoma using copy number alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1657.