Thymidylate Synthase Expression and Outcome of Patients Receiving Pemetrexed for Advanced Nonsquamous Non–Small-Cell Lung Cancer in a Prospective Blinded Assessment Phase II Clinical Trial

• DOI: 10.1097/jto.0b013e318292c500
• Publication Date: 2013-05-30T11:19:49Z
• Authors: Marianne C. Nicolson; Dean A. Fennell; David Ferry; Kenneth O'Byrne; Riyaz Shah; Vanessa Potter; Geraldine Skailes; Sunil Upadhyay; Paul Taylor; Valerie André; Tuan S. Nguyen; Scott P. Myrand; Carla Visseren-Grul; Mayukh Das; Keith M. Kerr
• Keywords: Pemetrexed; Tolerability; Performance status

In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated pemetrexed, low thymidylate synthase (TS) expression is associated better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level.Treatment-naive (stage IIIB/IV) had four cycles first-line chemotherapy pemetrexed/cisplatin. Nonprogressing continued on pemetrexed maintenance until progression or maximum tolerability. TS (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), quantitative reverse-transcriptase polymerase chain reaction. Cox regression used to assess between H-scores progression-free/overall survival (PFS/OS) distribution estimated Kaplan-Meier method. Maximal χ² analysis identified optimal cutpoints TS- high TS-expression groups, yielding maximal associations PFS/OS.The enrolled 70 patients; these 43 (61.4%) started treatment. 60 valid H-scores, median (m) PFS 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS 9.6 CI, 7.3-15.7) months. Higher nuclear significantly shorter OS (primary IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At cutpoint H-score (70), mPFS versus groups 7.1 (5.7-8.3) 2.6 (1.3-4.1) months (p = 0.0015; 0.28; 0.16-0.52; n 40/20). Trends were similar for cytoplasm reaction other endpoints (OS, response, disease control).The primary endpoint met; longer PFS. Further randomized studies are needed explore IHC as a potential biomarker outcomes treatment larger patient cohorts.