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.
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/m2twice 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/m2for 5 days followed by EOX chemotherapy every 21 days.Clin Cancer Res; 23(11); 2673-80. ©2016 AACR.
Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, New York, New York. bryansch@med.umich.edu.
Bryan J
BJ
Schneider
Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, New York, New York.
Manish A
MA
Shah
Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, New York, New York.
Kelsey
K
Klute
Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, New York, New York.
Allyson
A
Ocean
Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, New York, New York.
Elizabeta
E
Popa
Department of Thoracic Surgery, Weill Cornell Medical College, New York, New York.
Nasser
N
Altorki
Department of Surgery, Weill Cornell Medical College, New York, New York.
Michael
M
Lieberman
Department of Pathology, Weill Cornell Medical College, New York, New York.
Andrew
A
Schreiner
Department of Pathology, Weill Cornell Medical College, New York, New York.
Rhonda
R
Yantiss
Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York.
Paul J
PJ
Christos
Clinical Trials Office, Weill Cornell Medical College, New York, New York.
Romae
R
Palmer
Memorial Sloan-Kettering Cancer Center, New York, New York.
Daoqi
D
You
Memorial Sloan-Kettering Cancer Center, New York, New York.
Agnes
A
Viale
Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, New York, New York.
Pouneh
P
Kermani
Division of Hematology/Oncology, Department of Internal Medicine, Weill Cornell Medical College, New York, New York.|Division of Regenerative Medicine, Department of Internal Medicine; Weill Cornell Medical College, New York, New York.
Joseph M
JM
Scandura
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001374:Azacitidine / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage; D019175:DNA Methylation / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000235:genetics*; D015251:Epirubicin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000235:genetics
D009944:Organoplatinum Compounds; D025521:Tumor Suppressor Proteins; D000077150:Oxaliplatin; D015251:Epirubicin; D001374:Azacitidine; D002945:Cisplatin; D005472:Fluorouracil