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 Journal Article
| Authors: | Schneider, B. J.; Shah, M. A.; Klute, K.; Ocean, A.; Popa, E.; Altorki, N.; Lieberman, M.; Schreiner, A.; Yantiss, R.; Christos, P. J.; Palmer, R.; You, D.; Viale, A.; Kermani, P.; Scandura, J. M. |
| Article Title: | 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 |
| 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. DNAmethylation 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. © 2016 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 23 |
| Issue: | 11 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-06-01 |
| Start Page: | 2673 |
| End Page: | 2680 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-16-1896 |
| PROVIDER: | scopus |
| PMCID: | PMC5425331 |
| PUBMED: | 27836862 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 July 2017 -- Source: Scopus |
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