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A.K. Azad
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MO05 - Prognostic and Predictive Biomarkers II (ID 95)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:J. Hu, S. O'Toole
- Coordinates: 10/28/2013, 16:15 - 17:45, Parkside Auditorium, Level 1
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MO05.11 - The Effect of Two BRM Promoter Polymorphisms on the Risk of Advanced Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) in Smokers (ID 1987)
17:15 - 17:20 | Author(s): A.K. Azad
- Abstract
- Presentation
Background
BRM, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene in lung cancer. Loss of BRM expression occurs in 15% of lung cancers. Two BRM promoter insertion polymorphisms (BRM-741 and BRM-1321) lead to epigenetic silencing of BRM and highly correlate with loss of BRM expression and function in lung tumors. Pharmacologic reversal of the epigenetic changes of BRM is feasible. We previously demonstrated a strong risk association between these two polymorphisms and susceptibility to early stage NSCLC. Here, we evaluate the association between the two BRM polymorphisms and risk of developing: 1) advanced NSCLC, and 2) SCLC among smokers.Methods
Genotyping for BRM promoter polymorphisms was performed using TaqMan. The cohorts analyzed were: 1) 417 stage III-IV NSCLC cases and 2) 111 SCLC cases treated at the Princess Margaret Cancer Centre (PMCC), Toronto; and 3) 43 SCLC cases from the University of Florida (U of F), all with a smoking history of ≥1 pack-year. Cases were matched to healthy controls by frequency distribution (1:2 for PMCC cases; 1:1 for U of F cases) based on age, gender, pack-year smoking history, and either current smoking status (PMCC) or ethnicity (U of F). Adjusted odds ratios (aORs) with their 95% confidence intervals (CI) of the association between polymorphisms and lung cancer risk were estimated by multiple logistic regression models.Results
Of the 417 NSCLC cases, 59% were male; 41%, current smokers; 63%, adenocarcinoma; 51%, stage IV; median age, 63 years. The frequency of homozygosity was BRM-741, 21%; BRM-1321, 20%; both, 11%. The homozygous variants of BRM-741 and BRM-1321 were associated with an increased risk of advanced NSCLC compared to the wild types, with aOR’s of 1.6 (95% CI: 1.1-2.2; p=0.008) and 1.4 (95% CI: 1.0-2.0; p=0.04), respectively. Being homozygous for both BRM promoter variants carried an even greater risk (aOR 2.4 [95% CI: 1.4-4.0; p=0.0009]), with the strongest effect observed among current smokers (aOR 3.4; p=0.0005), and those with a histological diagnosis other than adenocarcinoma (aOR 3.2; p=0.0005). Among the 111 PMCC SCLC cases, 62% were male; 56%, current smokers; median age 65 years; of the 43 U of F SCLC cases, 35% were male; median age, 63 years. The presence of double homozygous variants of BRM-741 and BRM-1321 had no effect on the risk of developing SCLC in either of the two cohorts analyzed, with aOR’s of 1.1 (95% CI: 0.3-3.5; p=0.94) and 0.3 [95% CI: 0.04-2.41; p=0.27), respectively.Conclusion
The presence of double homozygous variants of the BRM promoter polymorphisms, BRM-741 and BRM-1321, significantly increases the risk of advanced NSCLC among individuals with a smoking history greater than one year, with the strongest effect observed among current smokers. In contrast, the same two polymorphisms had no effect on the risk of developing SCLC in either of the two cohorts analyzed. Thus, this study offers further insight into potential mechanisms underlying the genetic susceptibility to developing advanced NSCLC among smokers. Validation in larger populations is warranted.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O01 - Prognostic and Predictive Biomarkers I (ID 94)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:T. Mitsudomi, V. Gregorc
- Coordinates: 10/28/2013, 10:30 - 12:00, Parkside Auditorium, Level 1
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O01.03 - BRM Promoter Variants and Survival Outcomes of Advanced Non-Small Cell Lung Cancer (NSCLC) Patients: A Validation Study in the NCIC Clinical Trials Group (NCIC-CTG) BR24 Clinical Trial (ID 1999)
10:50 - 11:00 | Author(s): A.K. Azad
- Abstract
- Presentation
Background
BRM, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene in NSCLC. Loss of BRM expression occurs in 15% of NSCLC, and has been linked to adverse outcome. 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 linked to loss of BRM expression and function in lung tumors, and double the risk of lung cancer. Pharmacological reversal of the epigenetic changes of BRM is feasible. In this study we evaluated the association between the BRM promoter variants and survival outcomes of advanced NSCLC patients.Methods
The training cohort consisted of 564 stage III-IV NSCLC patients treated at the Princess Margaret Cancer Centre, Toronto 2006-2010. The validation cohort comprised 219 stage IIIb-IV NSCLC patients from the NCIC-CTG BR24 clinical trial, a phase II/III double-blind randomized trial of cediranib versus placebo in patients receiving carboplatin/paclitaxel for the treatment of advanced or metastatic NSCLC. Genotyping for the BRM promoter variants was performed using Taqman. Associations of BRM promoter variants and overall (OS) and progression free survival (PFS) were assessed using Cox proportional hazard models adjusted for clinically relevant variables, and in the case of the BR24 population, stratified by treatment arm.Results
Among the training cohort, 73% were Caucasian, 52% male, median age 63 yrs, 55% stage IV disease, and 67% adenocarcinoma. Median OS was 1.6yrs; median follow up, 3.6yrs. The frequency of homozygosity was BRM-741, 23%; BRM-1321, 21%; both 12%. Homozygous variants of BRM-741 were strongly associated with worse OS (adjusted HR [aHR] 2.5 [95% CI: 1.9-3.3; p=6x10E-10]) and PFS (aHR 2.0 [95% CI: 1.6-2.6; p=9x10E-8]) compared to the wild types. Similar findings were observed for the BRM-1321 homozygous variants (aHR for OS of 2.0 [95% CI: 1.5-2.6; p=2x10E-6]; aHR for PFS of 1.8 [95% CI: 1.4-2.4; p=3x10E-6]). The presence of double homozygous BRM-741 and BRM-1321 variants was strongly associated with worse OS (aHR 2.8 [95% CI: 1.9-4.0; p=7x10E-8]) and PFS (aHR 2.7 [95% CI: 1.9-3.8; p=1x10E-8]). Genotyping was possible for 219/296 BR24 participants. Of these, 59% were male, median age 59 yrs, 83% stage IV, 46% adenocarcinoma, with 50% receiving cediranib. Individuals carrying the homozygous variants of both BRM-741 and BRM-1321 (13% of cases) had a substantially worse OS (aHR 9.0 [95% CI: 4.3-18.5; p=1x10E-9]) and PFS (aHR 3.8 [95% CI: 1.9-7.3; p=3x10E-5]) compared to the wild types, irrespective of whether they were treated with cediranib (aHR for OS of 6.4; p=1x10E-4; aHR for PFS of 2.1; p=0.02) or placebo (aHR for OS of 16.8; p=2x10E-7; aHR for PFS of 8.3; p=1x10E-4).Conclusion
The same two homozygous BRM promoter variants that are associated with increased risk of NSCLC are also strongly associated with adverse OS and PFS in this study of advanced NSCLC patients. We are completing additional studies focusing on the relationship between the BRM promoter variants and BRM protein expression; results will be presented at the meeting.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
