Significance of Folate Receptor Alpha and Thymidylate Synthase Protein Expression in Patients with Non–Small-Cell Lung Cancer Treated with Pemetrexed

• Published in: Journal of thoracic oncology Vol. 8; no. 1; pp. 19 - 30
• Main Authors: Christoph, Daniel C., Asuncion, Bernadette Reyna, Hassan, Biftu, Tran, Cindy, Maltzman, Julia D., O’Shannessy, Daniel J., Wynes, Murry W., Gauler, Thomas C., Wohlschlaeger, Jeremias, Hoiczyk, Mathias, Schuler, Martin, Eberhardt, Wilfried E., Hirsch, Fred R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2013; International Association for the Study of Lung Cancer
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Biomarker; Biomarkers, Tumor - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Membrane - metabolism; Cell Nucleus - metabolism; Cytoplasm - metabolism; Disease-Free Survival; Female; Folate Receptor 1 - metabolism; Folate receptor alpha; Glutamates - therapeutic use; Guanine - analogs & derivatives; Guanine - therapeutic use; Humans; Kaplan-Meier Estimate; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Male; Middle Aged; Non–small-cell lung cancer; Pemetrexed; Predictive Value of Tests; Proportional Hazards Models; ROC Curve; Statistics, Nonparametric; Thymidylate synthase; Thymidylate Synthase - metabolism; Young Adult; Non–small-cell lung cancer; Biomarker; Thymidylate synthase; Pemetrexed; Folate receptor alpha
• ISSN: 1556-0864; 1556-1380
• DOI: 10.1097/JTO.0b013e31827628ff

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. 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). 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). 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.