Assessment of folate receptor-α and epidermal growth factor receptor expression in pemetrexed-treated non-small-cell lung cancer patients.

INTRODUCTION: Folate receptor-α regulates cellular uptake of folates and antifolates (eg, pemetrexed) and is frequently expressed in pulmonary adenocarcinoma. EGFR is an established therapeutic target in NSCLC. Therapies targeting FRA or EGFR are available. The association between FRA and EGFR expression in advanced NSCLC has not been explored. Combining therapeutic FRA antibodies with an EGFR inhibitor might be beneficial, if both of the targets are significantly coexpressed. PATIENTS AND METHODS: Specimens from 160 advanced NSCLC patients receiving pemetrexed-based chemotherapy were assessed for membranous FRA and EGFR protein expression using immunohistochemistry and the Hybrid (H)-score. EGFR (exons 18-21) and Kirsten RNA-associated rat sarcoma 2 virus (exon 2) mutations were determined. Results were correlated to patients' clinicopathological data, progression-free survival (PFS), and overall survival (OS). RESULTS: Forty-seven patients (29%) had tumors with strong FRA and EGFR expression, but no statistically significant correlation was seen between protein levels of FRA and EGFR. High membranous FRA expression (H-score ≥ 20) was associated with prolonged PFS (5.5 vs. 3.4 months; hazard ratio [HR], 0.6060; P = .0254) and improved OS (12.1 vs. 6.4 months; HR, 0.5726; P = .0076). CONCLUSION: Survival times are improved in NSCLC patients whose tumors show strong membranous FRA expression. No statistical correlation between membranous FRA and EGFR expression was demonstrated in advanced NSCLC, but 47 patients (29%) had higher expression of both of the receptors and could be suitable for combined targeted therapies.

Thymidylate synthase protein expression by IHC and gene copy number by SISH correlate and show great variability in non-small cell lung cancer.

INTRODUCTION: Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to TS-targeting drugs, e.g., pemetrexed. METHODS: TS protein expression (PE) and gene copy number (GCN) were assayed using immunohistochemistry and silver in situ hybridization, respectively, on primary tumors of 189 resected non-small cell lung patients. Associations with pathological and clinical features and prognosis were explored. RESULTS: Median immunohistochemistry H-score was 220 (range, 10-380) on a 0 to 400 scale; 17% of the patients had a TS expression of 300 or more. TS PE expression did not significantly differ by histology and did not significantly associate with disease-free survival (DFS) or overall survival (OS). However, there was a tendency for increased DFS (p = 0.12) and OS (p = 0.12) in PE positive (>median) squamous-cell carcinoma (SCC) patients. Median GCN was 2.5 genes/nucleus (range, 1.4-9.6); 29% of patients had GCN of 3 or more, 7% of 4 or more and 0.8% amplification. GCN differed by histology (p = 0.015); 50% of SCCs having GCN more than 2.5 versus 32% of adenocarcinomas. There was no significant relationship between TS GCN and DFS or OS; however, a trend toward better DFS (p = 0.18) and OS (p = 0.10) with increased GCN in SCCs was observed. TS GCN was significantly correlated with PE (r = 0.30, p = 0.0009). CONCLUSIONS: TS PE and GCN vary widely in non-small cell lung and correlate significantly with each other. TS GCN is higher in SCCs, whereas TS PE does not associate with histological subtypes, clinical features, or survival. Variability of TS PE and GCN may indicate potential benefit from pemetrexed therapy in selected SCC patients.