Correlation of Expression Levels of Copper Transporter 1 and Thymidylate Synthase with Treatment Outcomes in Patients with Advanced Non-small Cell Lung Cancer Treated with S-1/Carboplatin Doublet Chemotherapy

Abstract

Background: Copper transporter 1 (CTR1) is a critical determinant of the uptake and cytotoxic effect of the platinum<br />drugs carboplatin and cisplatin. Thymidylate synthase (TS) is an enzyme involved in DNA synthesis and is associated<br />with resistance of tumor cells to 5-fluorouracil. We investigated the correlation between CTR1 and TS expression levels<br />and treatment outcomes in patients with advanced non-small-cell lung cancer (NSCLC) treated with S-1/carboplatin<br />doublet chemotherapy. Methods: Twenty-nine patients were enrolled in this study. Tumor expression of CTR1 and<br />TS was measured immunohistochemically and analyzed for correlation with tumor response, progression-free survival<br />(PFS), and overall survival (OS). Results: Tumor response was significantly better in patients with CTR1High tumors<br />than in patients with CTR1Low tumors (64% vs. 18%, P = 0.02). Patients with TSLow tumors had a significantly longer OS<br />(median 21.2 vs. 8.5 months, P = 0.02), but not PFS, than patients with TSHigh tumors. When CTR1 and TS co-expression<br />was analyzed, patients with either CTR1High or TSLow tumors showed a significantly better tumor response (50% vs. 0%,<br />P = 0.01), longer PFS (median 4.2 vs. 2.1 months, P = 0.03), and longer OS (median 21.2 vs. 8.5 months, P = 0.01) than<br />patients with both CTR1Low and TSHigh tumors. Conclusions: Our study suggests that combined CTR1/TS expression<br />status has the potential to be an important predictor of good treatment outcomes in patients with advanced NSCLC<br />treated with S-1/carboplatin doublet chemotherapy.