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

Nicolson, Marianne C., Fennell, Dean A., Ferry, David, O'Byrne, Kenneth J., Shah, Riyaz, Potter, Vanessa, Skailes, Geraldine, Upadhyay, Sunil, Taylor, Paul, André, Valerie, Nguyen, Tuan S., Myrand, Scott P., Visseren-Grul, Carla, Das, Mayukh, & Kerr, Keith M. (2013) 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. Journal of Thoracic Oncology, 8(7), pp. 930-939.

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Abstract

INTRODUCTION In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated with pemetrexed, low thymidylate synthase (TS) expression is associated with better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level.

METHODS Treatment-naive patients with nonsquamous non-small-cell lung cancer (stage IIIB/IV) had four cycles of first-line chemotherapy with pemetrexed/cisplatin. Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability. TS expression (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), and quantitative reverse-transcriptase polymerase chain reaction. Cox regression was used to assess the association between H-scores and progression-free/overall survival (PFS/OS) distribution estimated by the Kaplan-Meier method. Maximal χ analysis identified optimal cutpoints between low TS- and high TS-expression groups, yielding maximal associations with PFS/OS.

RESULTS The study enrolled 70 patients; of these 43 (61.4%) started maintenance treatment. In 60 patients with valid H-scores, median (m) PFS was 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS was 9.6 (95% CI, 7.3-15.7) months. Higher nuclear TS expression was significantly associated with shorter PFS and OS (primary analysis IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At the optimal cutpoint of nuclear H-score (70), mPFS in the low TS- versus high TS-expression groups was 7.1 (5.7-8.3) versus 2.6 (1.3-4.1) months (p = 0.0015; hazard ratio = 0.28; 95%CI, 0.16-0.52; n = 40/20). Trends were similar for cytoplasm H-scores, quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints (OS, response, and disease control).

CONCLUSIONS The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts. © 2013 by the International Association for the Study of Lung Cancer.

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ID Code: 65230
Item Type: Journal Article
Refereed: No
Additional URLs:
Keywords: Non-small-cell lung cancer, Pemetrexed, Thymidylate synthase expression, Translational research, cisplatin, cyanocobalamin, dexamethasone, folic acid, messenger RNA, thymidylate synthase, adult, advanced cancer, aged, article, cancer chemotherapy, cancer patient, cancer staging, confidence interval, cytoplasm, disease course, double blind procedure, drug tolerability, female, human, human tissue, immunohistochemistry, Kaplan Meier method, lung non small cell cancer, maintenance therapy, major clinical study, male, multicenter study, multiple cycle treatment, overall survival, phase 2 clinical trial, priority journal, progression free survival, proportional hazards model, prospective study, protein blood level, protein expression, reverse transcription polymerase chain reaction, treatment outcome, vitamin supplementation
DOI: 10.1097/JTO.0b013e318292c500
ISSN: 1556-0864
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: © 2013 by the International Association for the Study of Lung Cancer
Deposited On: 09 Dec 2013 06:45
Last Modified: 10 Dec 2013 00:29

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