Baseline thymidylate synthase expression according to histological subtypes of non-small cell lung cancer

Abstract

7521 Background: In non-small cell lung cancer (NSCLC) baseline thymidilate synthase (TS) levels are higher in squamous cell carcinoma (SCC) compared to adenocarcinoma (AC) and randomized clinical trials have shown a selective benefit for patients with non-squamous histology treated with pemetrexed, a TS-inhibiting agent. TS expression in undifferentiated large cell carcinoma (LCC) is unknown. Methods: TS expression at both mRNA (using tissue microdissection and qRT-PCR) and protein (through immunohistochemistry, IHC) levels was tested in 34 surgically resected LCC (stage I=20,II=6,IIIa=8) and compared with TS expression in surgical cases of SCC (n= 31) and AC (n=40). In addition other comparisons were made: a) TS protein expression with Ki-67 index; b) TS mRNA and E2F1 transcription factor mRNA; c) in all histotypes TS protein level with desmocollin-3 (DSC-3) immunostaining, a marker of squamous cell differentiation. TS expression level was assessed in a group of patients (n=22) with cytological diagnosis of NSCLC-NOS (not otherwise specified) and compared with TS data in tissue specimens obtained through subsequent bronchial biopsy or surgical resection. Results: Significantly higher median TS levels in LCC compared to AC (p<0.001 for both mRNA and protein values) and SCC compared to AC (p=0.002 mRNA, p<0.001 protein) were detected. A strong correlation between TS mRNA and protein levels were found (p<0.001) in SCC and AC, but not in LCC. TS and both Ki-67 and E2F1 were significantly correlated in AC and SCC (p=0.003 and p=0.05, respectively), but in LCC no correlation was found. In LCC, significantly higher TS levels were observed in DSC3-positive compared to DSC3-negative tumors (p=0.02). A significant correlation between TS IHC scores in matched cytological and corresponding tissue specimens was observed (p<0.001). Conclusions: This study demonstrates and confirms the: a) differential expression of TS among the NSCLC histotypes; b) lack of DSC-3 immunoreactivity in LCC is associated with lower TS expression; c) assessment of TS by IHC in cytological specimens correlates with the corresponding tissue TS expression. [Table: see text]