Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response

• Published in: Clinical cancer research Vol. 23; no. 11; pp. 2673 - 2680
• Main Authors: Schneider, Bryan J., Shah, Manish A., Klute, Kelsey, Ocean, Allyson, Popa, Elizabeta, Altorki, Nasser, Lieberman, Michael, Schreiner, Andrew, Yantiss, Rhonda, Christos, Paul J., Palmer, Romae, You, Daoqi, Viale, Agnes, Kermani, Pouneh, Scandura, Joseph M.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.06.2017
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Azacitidine - administration & dosage; Bioindicators; Biomarkers; Bisulfite; Cancer; Chemotherapy; Cisplatin - administration & dosage; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - genetics; Dose-Response Relationship, Drug; Epigenesis, Genetic - genetics; Epigenetics; Epirubicin; Epirubicin - administration & dosage; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophagus; Experimental design; Female; Fluorouracil - administration & dosage; Genes; Humans; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds - administration & dosage; Oxaliplatin; Patients; Priming; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Surgery; Toxicity; Tumor suppressor genes; Tumor Suppressor Proteins - drug effects; Tumor Suppressor Proteins - genetics
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-1896

Purpose: Epigenetic silencing of tumor suppressor genes (TSG) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pretreatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally advanced esophageal/gastric adenocarcinoma (EGC). Experimental Design: Eligible patients had untreated, locally advanced, resectable EGC, ECOG 0–2, and adequate organ function. 5-Azacitidine (V, 75 mg/m2) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E, 50 mg/m2; O, 130 mg/m2; X, 625 mg/m2 twice daily for 21 days). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection. Results: All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and 5 had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. Conclusions: Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m2 for 5 days followed by EOX chemotherapy every 21 days. Clin Cancer Res; 23(11); 2673–80. ©2016 AACR.