Clinical significance of BIM deletion polymorphism in non-small cell lung cancer with epidermal growth factor receptor mutation.

Abstract

11052 Background: Germ line alterations in the proapoptotic protein BCL2-like 11 (BIM) can have a crucial role in how a tumor responds to treatment. To clarify the clinical usefulness of detecting BIM deletion polymorphism in non-small cell lung cancer (NSCLC) with positive epidermal growth factor receptor (EGFR) mutation we examined the prognosis in patients with or without the BIM changes. Methods: Seventy NSCLC patients with positive EGFR mutation treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) between January 2008 and January 2013 were enrolled in this study. BIM deletion polymorphism was analyzed by PCR in 58 peripheral blood samples, 24 formalin-fixed paraffin-embedded (FFPE) slides of surgical specimens (lung tissue in 20, brain tissue in 4), and 12 samples that included both blood and tissue specimens. We performed retrospective analyses on clinical characteristics, response rate and toxicity of EGFR-TKI, and estimated the prognosis in patients with or without BIM deletion polymorphism. Results: BIM deletion polymorphism was present in 13 of 70 patients (18.6%) with homozygous deletion in 1 and heterozygous deletion in 12. There was no discordance between the two types of samples among the 12 patients. There were no significant differences between patients with or without BIM deletion polymorphism on clinical characteristics, response rate to EGFR-TKI and incidence of EGFR-TKI toxicity. Patients with BIM deletion polymorphism showed significantly shorter PFS that in patients without BIM deletion polymorphism (median: 216 days vs. 430 days, p < 0.001). There was no significant difference in OS. In multivariate analyses using the Cox regression model, BIM deletion polymorphism (hazard ratio = 4.2, p< 0.001, 95% CI = 2.026-8.777) was identified as an independent factor for shorter PFS. Conclusions: BIM deletion polymorphism could be detected by PCR on peripheral blood samples and FFPE slides of surgical specimens. BIM deletion polymorphism has emerged as an independent prognostic factor for shorter PFS. Therefore, new treatment strategies should be established for patients with BIM deletion polymorphism.

The BIM Deletion Polymorphism and its Clinical Implication in Patients with EGFR-Mutant Non–Small-Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors

“…[33][34][35] On the basis of these results, studies have highlighted the clinical benefits of BH3-mimetic drugs or histone deacetylase inhibitors in patients with the BIM deletion polymorphism. 19,32 However, the BIM deletion polymorphism was not predictive of EGFR TKIs outcome in this study, which is consistent with previous findings in Korea from Lee et al 31 Data from Lee et al 31 demonstrated no difference in the PFS among patients with and without the BIM deletion polymorphism (11.9 months with BIM deletion vs. 11.3 months without, p = 0.791). Similarly, Isobe et al 32 reported that patients with the BIM deletion polymorphism had similar ORR and DCR but shorter PFS than did patients without the mutation.…”

“…These proportions are relatively consistent with prior reports. 20,[31][32][33] We also found that the distribution of BIM deletion polymorphisms was not associated with any specific clinicopathologic features.…”

“…We analyzed the BIM deletion polymorphisms using genomic DNA from peripheral blood samples only. A report by Isobe et al 32 showed that there is no discordance between the BIM status of peripheral blood and FFPE samples; still, validating the BIM status in the tumor tissue would have been ideal. We did not analyze other coexisting genetic abnormalities beyond that of the BIM deletion polymorphism.…”

Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target

“…The inability of EGFRi to induce apoptosis has been recently delineated as an important mechanism of upfront resistance to EGFRi (9)(10)(11)(12)(48)(49)(50). Although these studies, including ours, have focused on a clearly important role for the proapoptotic BIM, MCL-1 has become an increasingly relevant drug target and accordingly the development of MCL-1-specific inhibitors has excelled (39,43,51).…”

Phase I study of vorinostat with gefitinib in BIM deletion polymorphism/epidermal growth factor receptor mutation double‐positive lung cancer

“…BIM upregulation is essential for the induction of apoptosis in lung cancer cells with EGFR mutations treated with first‐generation EGFR‐TKI, and low BIM protein levels are associated with resistance to EGFR‐TKI . Underlying the importance of BIM in EGFR‐TKI resistance, a functional BIM deletion polymorphism, specifically, a 2903‐bp deletion in intron 2, was discovered in East Asian individuals (13%‐18%) and found to confer inferior responses to EGFR‐TKI . Subsequently, the BIM deletion was also found in South American patients with NSCLC (15.7%) .…”