Identification of serum microRNAs predicting the response of esophageal squamous-cell carcinoma to nivolumab

Abstract

Background Nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, showed promising activity for the treatment of advanced esophageal squamous-cell carcinoma in a phase II study (ONO-4538-07; JapicCTI­No.142422). We explored serum microRNA (miRNA) candidate predictive markers of the response to nivolumab. Methods In the phase II study, 19 patients received nivolumab (3 mg/kg IV Q2W) at National Cancer Center Hospital. The expression of 2565 serum miRNAs before and during treatment was analyzed using a 3D-Gene Human miRNA Oligo Chip (Toray Industries, Inc.). Immune-related response evaluation criteria used to evaluate response and miRNA expression were compared between responders and non-responders. The top 20 miRNAs by accuracy in receiver operating characteristic curve analysis were identified by leave-one-out cross-validation, and those with the area under curve values > 0.8, cross-validated accuracy > 0.8, and a 0.5 difference in the average log2 expression level between responders and non-responders were further analyzed. Results Of the 19 patients, five responded to nivolumab. We identified miRNAs related to the response to nivolumab, including one detected in the serum before treatment (miR-1233-5p; AUC = 0.895) and three present after treatment (miR-6885-5p, miR-4698 and miR-128-2-5p; AUC = 0.93, 0.97 and 0.93, respectively). Conclusions Candidate miRNAs capable of predicting the response to nivolumab were identified in the serum of patients with advanced esophageal squamous-cell carcinoma in ONO-4538-07.

Impact of noncoding RNAs on cancer directed immune therapies: Now then and forever

“…On other hand, down regulation of miR‐320b and miR‐375 was associated with delayed response for nivolumab treatment 143 . In similar line, high level of miR‐1233‐5p was associated with poor response of advanced esophageal squamous cell carcinoma for nivolumab 144 . Similarly overexpression of miR‐222 was correlated with lower therapeutic efficacy of ipilimumab (anti‐CTLA4) 145 in metastatic melanoma.…”

Targeting non-coding RNAs to overcome cancer therapy resistance

“…A phase 2 study that explored the efficacy of nivolumab, a PD-1 inhibitor, in esophageal squamous cell carcinoma revealed that serum miR-1233-5p levels (AUC = 0.895) before nivolumab treatment and miR-6885-5p, miR-4698, and miR-128-2-5p levels (AUC of 0.93, 0.97, and 0.93, respectively) after treatment initiation predicted response to ICI. 134 Though this was a small study, the evidence indicates the usability of ncRNAs for future prospective clinical trials. By investigating the differences of pretreatment circulating miRNAs between responders and non-responders in patients with NSCLC who received anti–PD-1 immunotherapy, Shukuya et al developed a response-predicting miRNA signature that consists of miR-199a-3p, miR-21-5p, and miR-28-5p.…”

The Pathologic and Molecular Landscape of Esophageal Squamous Cell Carcinogenesis

“…Sudo and colleagues [97] propose a panel of six miRNA as a serologic test to diagnose ESCC at early stage: in their results, serologic levels of miR-8073, miR-3196 and miR-744-5p were higher, while serological levels of miR-6820-5p, miR-6794-5p and miR-6799-5p were lower in ESCC patients than in controls. Finally, levels of circulating miR-1233, miR-6885-5p, miR-4698 and miR-128-2-5p have predictive significance, being associated with response to nivolumab [98].…”