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
Bryan J Schneider, Manish A Shah, Kelsey Klute, Allyson Ocean, Elizabeta Popa, Nasser Altorki, Michael Lieberman, Andrew Schreiner, Rhonda Yantiss, Paul J Christos, Romae Palmer, Daoqi You, Agnes Viale, Pouneh Kermani, Joseph M Scandura, Bryan J Schneider, Manish A Shah, Kelsey Klute, Allyson Ocean, Elizabeta Popa, Nasser Altorki, Michael Lieberman, Andrew Schreiner, Rhonda Yantiss, Paul J Christos, Romae Palmer, Daoqi You, Agnes Viale, Pouneh Kermani, Joseph M Scandura
Abstract
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.
Conflict of interest statement
Conflicts of Interest: No author reported relevant financial interests in this manuscript with the following exceptions: Dr. Allyson Ocean received honoraria from Celgene while serving on the speaker bureau for nab-paclitaxel.
©2016 American Association for Cancer Research.
Figures
![Figure 1. VEOX Decreased DNA Methylation and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5425331/bin/nihms830324f1.jpg)
![Figure 2. Survival after VEOX Therapy](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5425331/bin/nihms830324f2.jpg)
Source: PubMed