Significance of folate receptor alpha and thymidylate synthase protein expression in patients with non-small-cell lung cancer treated with pemetrexed.

Abstract

INTRODUCTION:

Folate receptor alpha (FRA) regulates cellular uptake of folates and antifolates. Information about FRA protein expression in metastatic non-small-cell lung cancer (NSCLC) is limited. We investigated FRA as a biomarker for pemetrexed-based chemotherapy and compared it with thymidylate synthase (TS), the main target of pemetrexed.

METHODS:

Pretreatment tumor specimens from 207 patients with advanced NSCLC were assessed for FRA and TS protein expression by immunohistochemistry using the H-score (range, 0-300) and correlated to patients' clinicopathological data, radiographic response, progression-free survival (PFS), and overall survival (OS).

RESULTS:

Low total (cytoplasmic and nuclear) TS protein expression (H-score < 210) was associated with improved PFS (median: 5.6 versus 3.5 months; hazard ratio [HR] = 0.6379, p = 0.0131) and prolonged OS (median: 22.5 versus 11.5 months; HR = 0.5680,p = 0.0107). An association between lower TS levels and response to pemetrexed-based therapy was found-mean H-score 187 ± 5, median 180 for responders versus mean H-score 201 ± 4, median 210, for non-responders, p = 0.0244. High intracellular FRA expression (H-score ≥110) was associated with prolonged OS (28.9 versus 11.7 months, HR = 0.5316, p = 0.0040) and a trend for association with PFS (5.6 versus 4.1 months, HR = 0.7395, p = 0.0801) was noted. Membranous FRA expression was seen in 83% of patients, moreover, high membranous expression (H-score ≥20) was associated with improved PFS (5.6 versus 3.7 months, HR = 0.6445, p = 0.0306) and OS (22.1 versus 11.5 months, HR = 0.5378, p = 0.0131).

CONCLUSIONS:

A large number of NSCLC patients have high expression of FRA and/or a low level of TS expression. Expression levels of FRA and TS were associated with clinical benefit from pemetrexed therapy.

• Authors: Daniel C Christoph, Bernadette Reyna Asuncion, Biftu Hassan, Cindy Tran, Julia D Maltzman, Daniel J O'Shannessy, Murry W Wynes, Thomas C Gauler, Jeremias Wohlschlaeger, Mathias Hoiczyk, Martin Schuler, Wilfried E Eberhardt, Fred R Hirsch
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 8 Issue 1 Pg. 19-30 (Jan 2013) ISSN: 1556-1380 [Electronic] United States
• PMID: 23242435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Folate Receptor 1
• Glutamates
• Pemetrexed
• Guanine
• Thymidylate Synthase

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Cell Membrane (metabolism)
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• Disease-Free Survival
• Female
• Folate Receptor 1 (metabolism)
• Glutamates (therapeutic use)
• Guanine (analogs & derivatives, therapeutic use)
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (drug therapy, metabolism)
• Male
• Middle Aged
• Pemetrexed
• Predictive Value of Tests
• Proportional Hazards Models
• ROC Curve
• Statistics, Nonparametric
• Thymidylate Synthase (metabolism)
• Young Adult