Abstract 4461: Poor predictive power of BIM deletion polymorphism for EGFR tyrosine kinase inhibitor outcome in non-small cell lung cancer patients harboring EGFR mutation.
Authors: Lee June Koo , Shin Jong-Yeon , Kim Soyeon , Lee Sunhwa , Park Changho , Kim Ji-Yeon , Koh Youngil , Keam Bhumsuk , Min Hye Sook , Kim Tae Min , Jeon Yoon-Kyung , Kim Dong-Wan , Chung Doo Hyun , Heo Dae Seog , Lee Se-Hoon , Kim Jong-il 
Published: August 2014

Abstract
Background. Recently, a germline deletion polymorphism of BIM was reported to predict tyrosine kinase inhibitor (TKI) outcome in patients with chronic myelogenous leukemia or advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation. In this study, we examined the predictive role of BIM deletion in a Korean NSCLC cohort. Also, we explored genetic alteration profile of patients exhibiting primary resistance to EGFR TKI treatment despite EGFR mutation. Methods. Data from 197 consecutive patients who had stage IIIB/IV NSCLC with TKI-sensitive EGFR mutation were collected from the NSCLC database of Seoul National University Hospital between 2006 and 2011. BIM deletion polymorphism was genotyped with polymerase-chain reaction (PCR) and visualized with 2% agarose gel electrophoresis. Additionally, we also examined putative clinical predictors of EGFR TKI outcome, including line of treatment, EGFR genotype, and smoking status. For patients who exhibited primary resistance to EGFR TKI treatment, we performed additional molecular analysis including fluorescence in situ hybridization for MET amplification and ALK fusion, and targeted deep sequencing of 46 cancer-related genes to explore the mechanism of primary resistance. Results. In this cohort, the median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the objective response rate was 78.8%. Patients with wild-type BIM (n = 172; 89.1%) and BIM deletion (n = 21; 10.9%) exhibited no difference in median PFS after EGFR TKI treatment (11.3 months for wild-type BIM, 11.9 months for BIM deletion; P = 0.791). Also, the line of treatment, the genotype of the EGFR-activating mutation, and smoking were not predictive of PFS for EGFR TKIs. However, patients with recurrent disease after curative surgical resection had a longer PFS than patients with initial stage IV disease (16.0 months for recurrent disease, 10.0 months for stage IV disease at initial presentation; P = 0.007). From the examination of pretreatment tissue of 11 patients exhibiting primary resistance, de novo EGFR T790M mutation was identified in one patient. We also found a patient with de novo MET amplification and another patient with ALK fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Conclusion. BIM deletion polymorphism showed poor predictive role in EGFR-mutant NSCLC patient cohort, although their initial report indicated remarkable predictive power. In a small portion of cases with primary resistance, we identified coexistent genetic alterations of cancer-related genes that could explain primary resistance. Our result suggests that the mechanism of primary resistance might be heterogeneous.
Citation Format: June Koo Lee, Jong-Yeon Shin, Soyeon Kim, Sunhwa Lee, Changho Park, Ji-Yeon Kim, Youngil Koh, Bhumsuk Keam, Hye Sook Min, Tae Min Kim, Yoon-Kyung Jeon, Dong-Wan Kim, Doo Hyun Chung, Dae Seog Heo, Se-Hoon Lee, Jong-il Kim. Poor predictive power of BIM deletion polymorphism for EGFR tyrosine kinase inhibitor outcome in non-small cell lung cancer patients harboring EGFR mutation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4461. doi:10.1158/1538-7445.AM2013-4461