Clinical significance of topoisomerase‐II expression in patients with advanced non‐small cell lung cancer treated with amrubicin

Abstract

Background: Amrubicin chemotherapy is a treatment option for patients with non-small cell lung cancer (NSCLC) after third-line treatment in Japan. Although topoisomerase-II (Topo-II), a target of amrubicin, has been reported to be a prognostic or predictive marker for chemosensitivity and clinical outcomes in various types of malignancies, its effects in the Japanese population remain unknown. Methods: Data regarding 44 patients with advanced NSCLC treated with amrubicin between April 2004 and May 2014 were retrospectively analyzed. We evaluated the expression levels of Topo-II by immunohistochemical staining of tumor specimens obtained via biopsy or surgical resection. Results: The majority of enrolled patients were men (68%) with a median age of 67 (range, 43-78) years. The most common histological type was adenocarcinoma (70%). High Topo-II expression was observed in 13 (30%) of the 44 patients. The median progression-free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo-II expression and progression-free survival, patients with low Topo-II expression had significantly longer OS than did those with high Topo-II expression. Good performance status and low expression of Topo-II were all significantly associated with a favorable OS. Conclusion: Low expression of Topo-II was identified as an independent prognostic factor for longer survival in patients with NSCLC receiving amrubicin, a Topo-II inhibitor. Key pointsSignificant findings of the study:• The median progression-free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. • While there was no significant association between Topo-II expression and progression-free survival, patients with low Topo-II expression had significantly longer OS than did those with high Topo-II expression. • Good performance status and low expression of Topo-II were all significantly associated with a favorable OS.

Comprehensive expressional analysis of chemosensitivity‐related markers in large cell neuroendocrine carcinoma of the lung

“…Additionally, we revealed that high Topo‐II expression is an independent prognosticator of LCNEC in large samples after surgical resection, consistent with various malignancies, including SCLC 19–22 . Xue et al have shown that Topo‐II inhibition inhibits NSCLC growth, invasion, and migration in vitro and tumor growth in vivo, which supports our results that high expression of Topo‐II is a prognostic factor after surgical resection 23 .…”

“…In terms of the effect of Topo‐II expression on anticancer drug therapy, several previous reports have shown that high Topo‐II expression may contribute to a superior response to Topo‐II inhibitors in breast cancer and NSCLC 13,24–26 . Reportedly, patients with SCLC expressing high Topo‐II present longer progression free survival with amrubicin therapy than those with SCLC expressing low Topo‐II 13 ; however, this is not significant in NSCLC 22 . Currently, there is no data on whether high Topo‐II expression is correlated with the efficacy of Topo‐II inhibitors in LCNEC.…”

Impact of Polyallylamine Hydrochloride on Gene Expression and Karyotypic Stability of Multidrug Resistant Transformed Cells

“…It shows that targeting topo2-α may provide a treatment strategy for patients with laryngeal cancer [ 37 ]. Low expression of topo2-α increased survival of patients with non-small cell lung cancer treated with amrubicin, a topo2-α inhibitor [ 38 ]. Thus, a decreased expression of topo2-α in the RJK-PAA and RJKEB-PAA cells may be indicative for enhanced sensitivity of these cells to drugs.…”

DNA topoisomerases as molecular targets for anticancer drugs

“…In Japan, amrubicin has been approved for the treatment of patients with NSCLC and SCLC 172 . Furthermore, it is used as a therapy option in the chemotherapy of NSCLC after the 3rd-line treatment 170 . Phase II of clinical trials for the use of amrubicin plus pembrolizumab in the treatment of refractory SCLC (NCT03253068) is currently ongoing.…”

“…Amrubicin (9-amino-anthracycline; SM-5887) is a synthetic anthracycline derivative with potent antitumor activity based on the hTop II inhibition ( Figure 9(c) ). Cytotoxic activity of amrubicin results from the stabilisation of DNA–hTop II cleavable complexes 169 , 170 . Moreover, amrubicinol, an active amrubicin metabolite, is 5–220 times more cytotoxic than the original compound 171 .…”