期刊
ONCOTARGET
卷 7, 期 41, 页码 67495-67506出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11317
关键词
methylation; azacitidine; CIMP; colorectal cancer; vimentin
资金
- Celgene Corporation, Summit, NJ
- National Institutes of Health Early Detection Research Network [UO1CA152756]
- National Institutes of Health Cancer Center Support Grant [P30CA016672]
- American Cancer Society [123436-RSG-12-159-01-DMC]
Purpose: Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. Experimental Design: This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m(2)/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks. Results: Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [ stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume (P<0.001) and higher levels of baseline methylation correlated with the obtainment of stable disease (P=0.04). Conclusions: Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Serum methylated vimentin may be associated with benefit from a regimen including a hypomethylation agent, although this study is not able to separate a potential prognostic or predictive role for the biomarker.
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