Thymidylate Synthase and Folyl-polyglutamate Synthase are not Clinically Useful Markers of Response to Pemetrexed in Patients with Malignant Pleural Mesothelioma

Authors

Daniel Schwed-Lustgarten MD, Lehigh Valley Health NetworkFollow
Charuhas Deshpande MD, University of Pennsylvania
Charu Aggarwal MD, MPH, University of Pennsylvania
Liang-Chuan Wang PhD, University of Pennsylvania
Vassiliki Saloura MD, University of Chicago
Anil Vachani MD, University of Pennsylvania
Li-Ping Wang MD, University of Pennsylvania
Leslie Litzky MD, University of Pennsylvania
Michael Feldman MD, University of Pennsylvania
Jeanette Creaney PhD, University of Western Australia
Anna K. Nowak MD, PhD, University of Western Australia
Corey Langer MD, University of Pennsylvania
Simona Inghilleri PhD, University and Fondazione IRCCS Policlinico San Matteo - Italy
Giulia Stella MD, PhD, University and Fondazione IRCCS Policlinico San Matteo - Italy
Steven M. Albelda MD, University of Pennsylvania

Publication/Presentation Date

4-1-2013

Abstract

PURPOSE: Thymidylate synthase (TS) is a potential predictor of outcome after pemetrexed (Pem) in patients with malignant pleural mesothelioma (MPM), and assays measuring TS levels are commercially marketed. The goal of this study was to further evaluate the value of TS and to study another potential biomarker of response, the enzyme, folyl-polyglutamate synthase (FPGS), which activates Pem intracellularly.

METHODS: Levels of TS and FPGS were semi-quantitatively determined immunohistochemically using H-scores on tissue samples from 85 MPM patients receiving Pem as primary therapy. H-score was correlated with radiographic disease control rate (DCR), time to progression (TTP) and overall survival (OS). In addition, expression levels of TS and FPGS in MPM cell lines were determined using immunoblotting and correlated with their sensitivity to Pem-induced cell death.

RESULTS: H-scores from patients with disease control versus progressive disease showed extensive overlap. There were no significant correlations of DCR, TTP, or OS to either TS levels (p = 0.73, 0.93, and 0.59, respectively), FPGS levels (p = 0.95, 0.77, and 0.43, respectively) or the ratio of FPGS/TS using the median scores of each test as cutoffs. There was no correlation between TS or FPGS expression and chemosensitivity of mesothelioma cells to Pem in vitro.

CONCLUSIONS: Although previous retrospective data suggest that TS and FPGS expression might be potential markers of Pem efficacy in MPM, our data indicate these markers lack sufficient predictive value in individual patients and should not be used to guide therapeutic decisions in the absence of prospective studies.

Volume

8

Issue

4

First Page

469

Last Page

477

ISSN

1556-1380

Published In/Presented At

Lustgarten, D., Deshpande, C., Aggarwal, C., Wang, L., Saloura, V., Vachani, A., & ... Albelda, S. (2013). Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma. Journal Of Thoracic Oncology: Official Publication Of The International Association For The Study Of Lung Cancer, 8(4), 469-477. doi:10.1097/JTO.0b013e318283da3e

Disciplines

Chemicals and Drugs | Circulatory and Respiratory Physiology | Medical Biochemistry | Medical Cell Biology | Medical Molecular Biology | Medical Pharmacology | Medical Sciences | Medical Specialties | Medicine and Health Sciences | Oncology

PubMedID

23486267

LVHN link

http://search.ebscohost.com/login.aspx?direct=true&db=mnh&AN=23486267&site=ehost-live&scope=site

Department(s)

Department of Medicine

Document Type

Article