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S. Cuffe



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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
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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)

      16:15 - 17:45  |  Author(s): S. Cuffe

      • Abstract
      • Presentation
      • Slides

      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.

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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): S. Cuffe

      • Abstract
      • Presentation
      • Slides

      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.

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    O24 - Cancer Control and Epidemiology III (ID 134)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O24.05 - The impact of body mass index on survival in stage 3 and 4 lung cancer (ID 663)

      16:15 - 17:45  |  Author(s): S. Cuffe

      • Abstract
      • Presentation
      • Slides

      Background
      Obesity has been shown to be an adverse prognostic factor in several cancers, including breast, colorectal, endometrial, ovarian, pancreatic and prostate. However, studies of body mass index (BMI) and outcomes in lung cancer are lacking. Understanding the clinical impact of body weight on cancer outcomes is important given the high prevalence of obesity globally. We retrospectively evaluated the distribution of BMI at diagnosis and its effects on survival in stage 3 and 4 lung cancer patients.

      Methods
      1,121 patients with stage 3 or 4 lung cancer from a single institution were analyzed. Clinicopathologic data were collected retrospectively. Adjusted hazard ratios (aHR) for overall survival (OS) and progression-free survival (PFS) were generated by Cox regression for each BMI (kg/m[2]) category (underweight: <18.5, normal: 18.5-24.9, overweight: 25.0-29.9, obese: ≥30), after adjusting for age, gender, Charlson Comorbidity Index, performance status (PS), clinical stage and treatment regimen.

      Results
      In this cohort (n=1,121), the frequencies of stage 3A, 3B and 4 lung cancers were 35%, 32% and 33%, respectively. There were 633 (57%) adenocarcinomas, 238 (21%) squamous cell carcinomas, 38 (3%) small cell lung cancers, and 210 (19%) other histologies. Patients had variable BMI: 82 (7%) underweight, 550 (49%) normal weight, 333 (30%) overweight, 156 (14%) obese. Being overweight/obese was associated with older age (p=0.002) and stage 3A disease (p=0.001); underweight patients were more likely current smokers (p<0.001). OS was significantly decreased with age ≥65, males, PS 2-3, stage 4, and lack of systemic treatment (p<0.001). Median OS in underweight, normal weight, overweight and obese patients were 14, 23, 24 and 26 months, respectively. Compared with BMI ≥18.5, being underweight was associated with significantly poorer OS (aHR 1.33, 95% CI 1.01-1.77, p=0.045), but not PFS (aHR 1.12, 95% CI 0.86-1.46, p=0.414). The magnitude of this association was greatest among those aged less than 65 years (aHR 1.57, 95% CI 1.11-2.22, p=0.011).

      Conclusion
      In stage 3 and 4 lung cancer, being underweight at diagnosis is associated with significantly poorer OS, especially in patients younger than 65 years of age. Lower BMI is mostly observed in current smokers, while above normal BMI is seen in older patients and stage 3A disease. Unlike other malignancies, obesity does not increase mortality in this population. The BMI-survival relationship in lung cancer requires further study.

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    P1.22 - Poster Session 1 - Epidemiology, Etiology (ID 166)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P1.22-011 - Assessment of the accuracy and reliability of health related behavioural data obtained from patient-reported surveys (PRS) compared with electronic patient records (EPR) in lung cancer patient population (ID 2948)

      09:30 - 16:30  |  Author(s): S. Cuffe

      • Abstract

      Background
      Cigarette smoking, alcohol consumption and presence of co morbidities are important factors that affect health status and mortality in patients diagnosed with lung cancer. While the gold standard for presence or absence of co-morbidities is EPR, the gold standard for obtaining accurate data pertaining to health-related behaviours is by PRS. The purpose of this study is to ascertain, whether in the absence of patient self-reported data, health related behavioural data pertaining to cigarette smoking and alcohol consumption abstracted from EPR provides an accurate and reliable surrogate.

      Methods
      731 lung cancer patients completed a PRS pertaining to information on their lifetime tobacco use, alcohol consumption and whether or not they had been diagnosed with certain co-morbid conditions. Relevant smoking, alcohol consumption and co-morbidity data was collected independently from EPR. Kappa coefficient analysis was used to assess the agreement.

      Results
      Results can be seen in Table 1. Ever/never status for smoking showed almost perfect agreement (k=0.95) between PRS and EPR and surpassed all other health behavioural measures and all co-morbidity agreement values. The calculation of pack-years from EPR and PRS showed substantial agreement (k=0.77); However, categorizing the smoking status into current/ former / never, resulted in only moderate agreement (k=0.47). Alcohol ever/ never status agreement was moderate (0.44) with high sensitivity (0.90) but low specificity (0.50). The lung related co-morbidities like emphysema (k=0.41) and chronic bronchitis (k=0.28) showed fair agreement but with substantial missing data through EPR.

      Table 1
      Health Behaviour N Missing Data in EPR Agreement (k) 95% CI (P value) Se Sp
      Smoking (E/N) 709 0 0.95 (0.79, 0.89) 0.995 0.94
      Smoking (Pkyrs)* 606 81(11%) 0.77 P<0.0001
      Smoking (C/F/N)** 705 4(0.5%) 0.47 (0.41, 0.51)
      Alcohol (E/N) 575 150(20.5%) 0.44 (0.36, 0.52) 0.9 0.5
      Comorbidity
      Emphysema 589 126(17.2%) 0.41 (0.33, 0.49) 0.41 0.95
      Chronic Bronchitis 601 94(12.8%) 0.28 (0.19, 0.37) 0.39 0.88
      *Spearman correlation coefficient
      **Weighted kappa

      Conclusion
      In the absence of PRS data, EPR provides a reliable surrogate for ever/ never smoking status and moderately reliable for lifetime smoking exposure in this lung cancer population. However current/ former/ never smoking status and ever/ never alcohol status cannot be reliably ascertained from medical records. Missing EPR data related to smoking pack years, alcohol consumption and lung co-morbidities is concerning and suggests more systematic or synoptic reporting by physicians would improve opportunities for research