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L. Cheng

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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 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)

      10:30 - 12:00  |  Author(s): L. Cheng

      • Abstract
      • Presentation
      • Slides

      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.

      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.

      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).

      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.

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