Abstract
BackgroundGermline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in diverse tumors. To determine the clinical utility of detecting BIM deletion polymorphisms (par4226 bp/ par363 bp) in EGFR positive non-small-cell lung cancer (NSCLC) we examined the outcomes of patients with and without BIM alterations.ResultsBIM deletion was present in 14 patients (15.7%). There were no significant differences between patients with and without BIM-del in clinical characteristics or EGFR mutation type; however, those with BIM-del had a worse overall response rate (ORR) to erlotinib (42.9% vs. 73.3% in patients without BIM-del; p=0.024) as well as a significantly shorter progression-free survival (PFS) (10.8 BIM-del+ vs. 21.7 months for patients without BIM-del; p=0.029) and overall survival (OS) (15.5 BIM-del+ vs. 34.0 months for patients without BIM-del; p=0.035). Multivariate Cox regression analysis showed that BIM-del+ was an independent indicator of shorter PFS (HR 3.0; 95%CI 1.2-7.6; p=0.01) and OS (HR 3.4; 95%CI 1.4-8.3; p=0.006).MethodsWe studied 89 NSCLC Hispanic patients with EGFR mutation who were treated with erlotinib between January 2009 and November 2014. BIM deletion polymorphisms (BIM-del) was analyzed by PCR in formalin-fixed paraffin-embedded (FFPE) tissues of tumor biopsies. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM-del.ConclusionsThe incidence of BIM-del found in Hispanic patients is similar to that previously described in Asia. This alteration is associated with a poor clinical response to erlotinib and represents an independent prognostic factor for patients who had NSCLC with an EGFR mutation.
Highlights
Lung cancer is the leading cause of cancer related death in the developed countries and in Latin America, and non–small-cell lung cancer (NSCLC) accounts for most cases [1, 2]
This alteration is associated with a poor clinical response to erlotinib and represents an independent prognostic factor for patients who had non-smallcell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation
There were no significant differences between patients with and without BIM deletion polymorphisms (BIM-del) regarding clinical characteristics or type of EGFR mutation, but a difference was obtained with previous tobacco exposure (p = 0.04) (Table 2)
Summary
Lung cancer is the leading cause of cancer related death in the developed countries and in Latin America, and non–small-cell lung cancer (NSCLC) accounts for most cases [1, 2]. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and afatinib, are widely used to treat advanced NSCLC harboring an EGFR mutation. Such drugs have improved the progression free survival (PFS), overall survival (OS) and quality of life compared with first line platinum-based doublet chemotherapy [7,8,9,10]. Several mechanisms of secondary resistance have been revealed, including: EGFR T790M mutation (the most frequent), mesenchymalepithelial transition, MET amplification, phosphatidylinositol4-5-bisphosphate 3-kinase mutations (PI3K) and small-cell lung cancer transformation [12,13,14,15]. An interesting mechanism related with germline polymorphisms is proapoptotic protein Bcl-2-like 11 (BIM) which has been described and could potentially explain primary resistance to EGFR TKIs [20]. To determine the clinical utility of detecting BIM deletion polymorphisms (par4226 bp/ par363 bp) in EGFR positive non-smallcell lung cancer (NSCLC) we examined the outcomes of patients with and without BIM alterations
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