186P - Association of two BRM promoter variants with survival outcomes of stage IV non small cell lung cancer (NSCLC) patients

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Lung and other Thoracic Tumours
Translational Research
Presenter Sinead Cuffe
Authors S. Cuffe1, A.K. Azad2, Y. Brhane3, D. Cheng2, Z. Chen2, W. Xu3, F.A. Shepherd4, M. Tsao5, D. Reisman6, G. Liu4
  • 1Princess Margaret Hospital, University Health Network, M5G 2M9 - Toronto/CA
  • 2Applied Molecular Oncology, Princess Margaret Hospital, Ontario Cancer institute, Toronto/CA
  • 3Department Of Biostatistics, Princess Margaret Hospital, Ontario Cancer Institute, Toronto/CA
  • 4Department Of Medical Oncology, Princess Margaret Hospital, University Health Network, M5G 2M9 - Toronto/CA
  • 5Pathology Department, Princess Margaret Hospital, University Health Network, Toronto/CA
  • 6Division Of Hematology/oncology, University of Florida, Florida/US

Abstract

Background

BRM, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of lung cancers. Two BRM promoter insertion variants (BRM-741 and BRM-1321) result in epigenetic silencing of BRM through recruitment of histone deacetylases. The presence of double homozygous BRM variants is associated with loss of BRM expression, and double the risk of lung cancer. Recently, pharmacological reversal of the epigenetic changes of BRM has been shown to be a potentially viable therapeutic strategy. We investigated the association between BRM promoter variants and survival outcomes in advanced NSCLC patients.

Methods

313 stage IV NSCLC patients treated in Princess Margaret Hospital from 2006-2010 were genotyped for the BRM promoter variants using TaqMan. Association of BRM variants and overall (OS) and progression free survival (PFS) were assessed using multivariate Cox proportional hazards models.

Results

71% were Caucasian; 71%, adenoca; median age, 63 yrs; Median OS, 1.1 yrs; median follow up, 1.8 yrs. The frequency of homozygosity was: BRM-741 25%; BRM-1321 21%; both 12%. Homozygous variants of BRM-741 were strongly associated with worse OS (adjusted HR [aHR] 3.5 [95% CI: 2.4-5.0; p = 1x10E-11]) and PFS (aHR 2.3 [95% CI: 1.6-3.1; p = 8x10E-7]), compared to the wildtypes. Similar findings were observed for the BRM-1321 homozygous variants (aHR for OS of 2.5 [95% CI: 1.7-3.5; p = 1.1x10E-6]; aHR for PFS of 1.9 [95% CI: 1.3-2.6; p = .0004]). Finally, the presence of double homozygous BRM-741 and BRM-1321 variants was strongly associated with substantially worse OS (aHR 4.4 [95% CI: 2.7-7.1, p = 1x10E-9]) and PFS (aHR 3.6 [95% CI: 2.3-5.6, p = 2x10E-8]).

Conclusion

The same two homozygous BRM promoter variants that are associated with increased risk of lung cancer are also strongly associated with adverse OS and PFS in this cohort of stage IV NSCLC patients. Validation of the results in prospective clinical trials is underway and will better elucidate whether these BRM promoter variants are prognostic or predictive.

Disclosure

All authors have declared no conflicts of interest.