Selection of patients with high metastatic ability of non-small cell lung cancer (NSCLC) has the potential to predict the clinical benefit of adjuvant chemotherapy (ADC). ACTN4 is an oncogene associated with cancer metastasis. To demonstrate the clinical utility of a predictive biomarker for the efficacy of ADC for NSCLC, we analyzed clinical and preclinical data.
In Step 1, we reanalyzed the impact of ACTN4 on the efficacy of ADC from clinical information and mRNA profiles from the public database of a randomized phase III trial of adjuvant vinorelbine plus cisplatin after complete resection of stage IB or II NSCLC (JBR.10), which was a clinical trial probing the clinical benefits of ADC in stage IB/II patients with NSCLC. In Step 2, we measured ACTN4 protein levels in patients with completely resected stage II or IIIA lung adenocarcinoma at the National Cancer Center Hospital (NCCH) from 2008 to 2011 using immunohistochemistry (IHC). We then retrospectively compared survival between ADC treated with platinum doublet and observation (OBS) groups. In Step 3, we investigated the biological functions of ACTN4 with the A549 lung adenocarcinoma cell line, which has gene amplification of ACTN4.
In Step 1, the 133 patients enrolled in JBR.10 were divided into two groups by expression of the ACTN4 transcript: an ACTN4-positive (ACTN4(+)) group (n = 25) and an ACTN4-negative (ACTN4(-)) group (n = 108). In the ACTN4(+) group, overall survival (OS) was significantly longer in ADC subjects (n = 15) compared with OBS (n = 10) (hazard ratio [HR] = 0.27; p = 0.042). However, no differences in OS were noted between ADC (n = 56) and OBS (n = 52) subjects in the ACTN4(-) group. In Step 2, 148 eligible patients were classified into two groups based on IHC findings. In the ACTN4-IHC(+) group (n = 75), mean survival was longer in the ADC patients (n = 22) than in OBS patients (n = 53) (HR = 0.307; p = 0.028). In contrast, the ACTN4-IHC(-) group (n = 73) showed no tangible survival benefit with ADC. In Step 3, the metastatic potential of A549 was significantly reduced by ACTN4 shRNA.
Clinical data and biological assays suggested ACTN4 as a potential predictive biomarker for the efficacy of ADC in patients with NSCLC.
Clinical trial identification
Legal entity responsible for the study
All authors have declared no conflicts of interest.