Efficacy of adjuvant chemotherapy for non-small cell lung cancer assessed by metastatic potential associated with ACTN4
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Nami Miura1, Masahiro Kamita1, Takanori Kakuya1, Yutaka Fujiwara2, Koji Tsuta3, Hideaki Shiraishi2, Fumitaka Takeshita4, Takahiro Ochiya5, Hirokazu Shoji1, Wilber Huang6, Yuichiro Ohe2, Tesshi Yamada1, Kazufumi Honda1,7
1Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan
2Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
3Division of Pathology, National Cancer Center Hospital, Tokyo 104-0045, Japan
4Department of Functional Analysis, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo 104-0045, Japan
5Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan
6Abnova, Taipei 114, Taiwan
7Japan Agency for Medical Research and Development: AMED-CREST, AMED, Tokyo 100-0004, Japan
Kazufumi Honda, e-mail: [email protected]
Keywords: ACTN4 (actinin-4), predictive biomarker for adjuvant chemotherapy, early stage of non-small cell lung cancer (NSCLC), JBR.10
Received: December 25, 2015 Accepted: April 02, 2016 Published: April 21, 2016
Although several clinical trials have demonstrated the benefits of platinum-combined adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC), predictive biomarkers for the efficacy of such therapy have not yet been identified. Selection of patients with high metastatic ability in the early stage of non-small cell lung cancer (NSCLC) has the potential to predict clinical benefit of adjuvant chemotherapy (ADJ).
In order to develop a predictive biomarker for efficacy of ADJ, we reanalyzed patient data using a public database enrolled by JBR.10, which was a clinical trial to probe the clinical benefits of ADJ in stage-IB/II patients with NSCLC. The patients who were enrolled by JBR.10 were classified into 2 subgroups according to expression of the ACTN4 transcript: ACTN4 positive (ACTN4 (+)) and ACTN4 negative (ACTN4 (−)). In the ACTN4 (+) group, overall survival (OS) was significantly higher in the ADJ subgroup compared with the observation subgroup (OBS), indicating a significant survival benefit of ADJ. However, no difference in OS was found between ADJ and OBS groups in ACTN4 (−). Although ACTN4 expression level did not correlate with the chemosensitivity of cancer cell lines for cytotoxic drugs, the metastatic potential of A549 lung adenocarcinoma cells was significantly reduced by ACTN4 shRNA in in vitro assays and in an animal transplantation model. The clinical and preclinical data suggested that ACTN4 is a potential predictive biomarker for efficacy of ADJ in stage-IB/II patients with NSCLC, by reflecting the metastatic potential of tumor cells.
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