Clinical Significance of BIM Deletion Polymorphism in Non–Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation

Abstract

Background:Germline alterations in the proapoptotic protein Bcl-2–like 11 (BIM) can have a crucial role in tumor response to treatment. To determine the clinical utility of detecting BIM deletion polymorphism in non–small-cell lung cancer positive for epidermal growth factor receptor (EGFR) mutation, we examined outcomes of patients with and without BIM alterations.Methods:We studied 70 patients with EGFR mutation-positive non–small-cell lung cancer who were treated with an EGFR tyrosine kinase inhibitor between January 2008 and January 2013. BIM deletion was analyzed by polymerase chain reaction in 58 samples of peripheral blood and 24 formalin-fixed paraffin-embedded slides of surgical specimens (20 of lung tissue and four of brain tissue); both blood and tissue specimens were available for 12 patients. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM deletion.Results:BIM deletion was present in 13 of 70 patients (18.6%). There were no significant differences between patients with and without BIM deletion in clinical characteristics, rate of response to EGFR tyrosine kinase inhibitor, or incidence of adverse events. Patients with BIM deletion had significantly shorter progression-free survival (PFS) than those without BIM deletion (median, 227 versus 533 days; p < 0.001). Multivariate Cox regression analysis showed that BIM deletion was an independent indicator of shorter PFS (hazard ratio, 3.99; 95% confidence interval, 1.864–8.547; p < 0.001).Conclusions:Polymerase chain reaction successfully detected BIM deletion in samples of peripheral blood and formalin-fixed paraffin-embedded slides of surgical specimens. BIM deletion was the most important independent prognostic factor in shorter PFS.

Multiple resistant factors in lung cancer with primary resistance to EGFR-TK inhibitors confer poor survival

“…Lee et al also found that 3 of 11 patients showing primary resistance to EGFR-TKIs possessed this polymorphism, whereas BIM deletion polymorphism was not predictive of PFS for EGFR-TKIs [24]. Several studies reported contrary results associated BIM deletion with PFS [50][51][52]. Therefore, although we also detected this polymorphism in 4 of 21 patients, the exact role of BIM polymorphism in the response to EGFR-TKIs requires further investigation.…”

Common EGFR -Mutated Subgroups (Del19/L858R) in Advanced Non-Small-Cell Lung Cancer: Chasing Better Outcomes with Tyrosine Kinase Inhibitors

“…BIM mRNA expression is also implicated as an early adaptive biomarker of resistance in EGFRm NSCLC patients [39]; a subset analysis by EGFR-mutation type was not provided for this study. Similarly, BIM deletion polymorphisms were associated with shorter PFS in EGFRm patients treated with an EGFR-TKI [47,48]. As BIM polymorphisms constitute a germ-line alteration, their pattern of distribution should not differ significantly between EGFRmutation subtypes [49], thereby falling short of a plausible hypothesis to explain the lower efficacy of EGFR-TKIs in L858R-mutated patients.…”

Emerging treatment for advanced lung cancer withEGFRmutation

“…In some retrospective studies, PFS was significantly shorter upon EGFR TKI treatment in EGFR-mutant lung cancer patients with. These data suggest that BIM gene polymorphism could be postulated as a biomarker of EGFR TKI resistance, but larger prospective studies are required to justify that [77][78][79]. Histone deacetylase (HDAC) inhibition can restore BIM function and sensitize the cancer cells to EGFR TKI in patients with EGFR-mutant NSCLC in whom resistance is associated with a common BIM polymorphism [80].…”