P66.07 ASCL1 and DLL3 Expression and Their Clinicopathological Implications in Surgically Resected Pure Small Cell Lung Cancer

Abstract

Small cell lung cancer (SCLC) is one of the most aggressive malignancies characterized by neuroendocrine (NE) differentiation. Our previous data revealed the achaete-scute homolog 1 (ASCL1) gene was a transcription factor in NE differentiation and highly expressed in SCLC. The Delta-like protein 3 (DLL3), as a direct downstream target of ASCL1, is involved in NE differentiation and carcinogenesis of SCLC. A DLL3-targeted antibody-drug conjugate, rovalpituzumab tesirine (Rova-T) has recently been developed for treatment of SCLC. This study was to investigate the relationship between ASCL1 and DLL3 protein expression and their clinicopathological implications in surgically resected pure SCLC. 247 surgically resected pure SCLC samples with limited clinical stage and follow-up data were retrieved in this retrospective study. ASCL1 and DLL3 protein expression was detected by immunohistochemistry staining in SCLC tissue microarrays. The correlation between ASCL1 and DLL3 protein expression as well as their clinicopathological features were analyzed by chi-square test. Disease-free survival (DFS) and overall survival (OS) in SCLC patients with ASCL1/DLL3 low and high expressions were compared by Kaplan-Meier method and Log-rank test. Among the 247 surgically resected pure SCLC patients, 175 (70.9%) were male and 202 (81.8%) were less than 65 years. According to the AJCC Cancer Staging Manual (seventh edition), 78 (31.6%) were stage I, 68 (27.5%) were stage II, and 101 (40.9%) were stage III. ASCL1 expression was localized in the nucleus of SCLC tumor cells, and 105 (42.5%) patients showed high expression. ASCL1 high expression was associated with clinical stage (p=0.019) and nerve invasion (p=0.030). DLL3 expression was localized in the cytoplasm and membrane of tumor cells, and DLL3 high expression was observed in 188 (72.8%) patients. DLL3 high expression was correlated with vascular invasion (p=0.045). ASCL1 expression was positively associated with DLL3 expression (p=0.030). In addition, DLL3 expression has a strong association with expression of classic NE markers, Synapsin (Syn) and Chromogranin A (CgA). Survival analysis revealed that patients with ASCL1 high expression have a worse OS (p=0.047), whereas further multivariate cox regression analysis showed neither ASCL1 nor DLL3 expression was independent prognostic factors. ASCL1 and DLL3 were highly expressed in pure SCLC tumor cells, and their expression level was positively correlated. The patients with ASCL1 and DLL3 high expression may represent a distinct subgroup of SCLC benefit from targeted therapy. Therefore, ASCL1 and DLL3 could be potential biomarkers served for selection of related patients.