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G.D. Gamble
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OA 06 - Global Tobacco Control and Epidemiology I (ID 662)
- Event: WCLC 2017
- Type: Oral
- Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
- Presentations: 2
- Moderators:G. Kovács, Yun Fan
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 511 + 512
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OA 06.03 - Comorbidity and Competing Causes of Death attenuate outcomes in the NLST. (ID 8606)
16:05 - 16:15 | Author(s): G.D. Gamble
- Abstract
- Presentation
Background:
In the National Lung Screening Trial (NLST), annual CT screening reduced lung cancer-specific mortality by 20% and all-cause mortality by 7% relative to chest x-ray (CXR) screening. However, in contrast to other screening approaches, recommendations for CT screening for lung cancer is limited to older heavy smokers, where the risk of death from all smoking-related complications is high, relative to the unscreened population. In the NLST, airflow limitation affects 35% of screening participants and is associated with a 2-4 fold increase risk of lung cancer. We have recently shown that for screening participants with COPD, the reduction in lung cancer-specific mortality with CT screening is only half that seen in those with no COPD (15% vs 28%). We hypothesise that this reduction is due in part to a “competing cause of death” effect.
Method:
Using 10,054 subjects from the ACRIN-NLST sub-study, the current study aimed to compare disease-specific mortality according to the severity of airflow limitation at baseline to better understand it’s relationship with dying of lung cancer and dying of other smoking-related diseases. We also examined this relationship according to baseline risk of lung cancer, using the Brock (Lung cancer risk) Model, and outcomes from screening.
Result:
After 6.4 years of follow-up, there were 699 deaths; 189 (27%) attributed to lung cancer, 166 (24%) to cardiovascular disease, 61 (9%) to respiratory disease and 150 (21%) to other cancers. After stratifying the 10,054 subjects according to severity of airflow limitation (baseline FEV1%predicted and GOLD grade), we found that the risk of dying of lung cancer and risk of dying of other diseases diverged favouring a stronger relationship with non-lung cancer causes. After stratifying the 10,054 subjects according to their risk of lung cancer (tertiles), we found that CT screening in those at highest risk (highest tertile) had only a 12% reduction in lung cancer-specific deaths compared to 23-24% in other lower risk tertiles. This was associated with higher deaths from cardiovascular disease, respiratory disease and other cancers.
Conclusion:
In a CT screening study, where smokers were followed for a mean of 6.4 years, we found worsening lung function and higher underlying risk for lung cancer was associated with a greater tendency to die of causes other than lung cancer. We suggest smokers at the greatest risk for lung cancer, and those with worse lung function, benefit less from CT screening due to a “competing cause of death” effect.
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OA 06.06 - Chr15q25 Locus Confers Risk of Lung Cancer, COPD and Smoking: Triple Whammy Effect in the ACRIN NLST Sub-Study (N=9,270) (ID 8611)
16:40 - 16:50 | Author(s): G.D. Gamble
- Abstract
- Presentation
Background:
Several large genetic studies have consistently linked the cholinergic nicotinic receptor polymorphism (CHRNA3/5, rs 16969968) to lung cancer and smoking addiction. However, we have shown that this genetic variant was also independently associated with susceptibility to chronic obstructive pulmonary disease (COPD). To date this observation, independently linking CHRNA3/5 polymorphism to both COPD and lung cancer, has not been tested prospectively in a cohort study. Using 10,054 subjects from the ACRIN-NLST cohort, a sub-study of the NLST that recruited high risk smokers and followed them for an average of 6.4 years, we examined the association between the CHRNA3/5 variant in the development of lung cancer relative to its role in COPD and lifelong smoking exposure.
Method:
We compared the frequency of the high risk AA genotype in our cohort of 10,054 high risk smokers according to their smoking status, lung function and COPD status. We also compared the lung cancer incidence rate according to the CHRNA3/5 genotype. Lastly we used stepwise logistic regression and mediation analysis to examine the role of the AA genotype of the CHRNA3/5 variant in smoking exposure, COPD and lung cancer.
Result:
Relative to healthy smoking controls, the AA genotype was associated with the presence of COPD (OR=1.3, P<0.001) and the development of lung cancer overall (OR=1.5, P<0.01), lung cancer with pre-existing COPD (OR=1.5, P=0.04), lung cancer with no COPD (OR=1.5, P=0.04). Compared to the GG and AG genotypes, the AA genotype was associated with (a) lower FEV1%pred, lower FEV1/FVC and a 19% increase in risk of COPD; and (b) greater cigs/day, pack years exposure and a 47% increased risk of lung cancer. No differences were found for age, gender, smoking duration, years since quitting and current smoking status. In stepwise logistic regression, we found that age, BMI, AA genotype, smoking exposure and lung function were independently associated with getting lung cancer. In the mediation analyses we found that the AA genotype was independently associated with smoking (OR=1.42,P<0.05), COPD (OR=1.25,P<0.05) and getting lung cancer (OR=1.37, P<0.05).
Conclusion:
This is the first prospective study to confirm that while the CHRNA3/5 variant is associated with lung cancer, more importantly this variant is also independently associated with airflow limitation (COPD). It is also the first cohort study to show that while this genetic variant is also associated with smoking exposure (triple whammy effect), this is independent of its effects on predisposition to both COPD and lung cancer.
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OA 15 - Diagnostic Radiology, Staging and Screening for Lung Cancer II (ID 684)
- Event: WCLC 2017
- Type: Oral
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:Y. Satoh, Jin Mo Goo
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 303 + 304
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OA 15.03 - Gene-Based Risk Stratification of NLST-ACRIN Screening Participants Identifies The "Sweet Spot" of Screening (N=10,054) (ID 8625)
14:50 - 15:00 | Author(s): G.D. Gamble
- Abstract
- Presentation
Background:
Screening of high risk smokers with computed tomography (CT) aims to identify early stage lung cancers in screening participants amenable to curative surgery. The National Lung Screening Trial (NLST) demonstrated a 20% reduction in lung cancer specific mortality in the CT arm compared to chest x-ray (control) arm. European screening trial results to date have failed to show any evidence of a reduction in lung cancer mortality. Reduction in lung cancer mortality comes from the combined effects of successful surgical removal of life-threatening early stage lung cancers and post-operative survival. In screening participants of the NLST, who are older chronic smokers, there exists a balance between mortality from lung cancer and mortality from non-lung cancer related causes.
Method:
This study aimed to validate a gene-based risk tool for dying of lung cancer and examine the outcomes from screening according to tertiles of risk. It also aimed to establish the utility of adding SNP-based data to risk prediction and efficacy in identifying which screening participants get the best outcomes from screening. Using prospective data from the NLST-ACRIN cohort (N=10,054), we examined the utility of combining risk genotypes with clinical risk variables in our risk model for dying of lung cancer. We then stratified screening participants into risk tertiles according to our risk model and compared the outcomes from CT versus CXR screening
Result:
The addition of risk genotypes (combined genetic risk score) to our clinical risk model for dying of lung cancer was significantly improved (AUC increased from 0.61 to 0.66, P=0.014). We show that screening participants in the middle risk tertile achieves a lung cancer specific mortality reduction of 55% and all-cause mortality reduction of 21%. In this group the number of lung cancers averted is maximised (12/1000 person screened) and number needed to screen to avert one lung cancer reduced to 84. We show that this is achieved through minimising pre-existing co-morbid disease and by maximising screen detected lung cancers amenable to CT detection and successful surgical intervention. We believe genetic data provides useful information on lung cancer biology.
Conclusion:
The “Sweet spot” of CT screening comes from identifying high risk smokers optimised according to co-existing premorbid disease (especially COPD), early stage lung cancers amenable to surgical cure and least likely to die of other complications of smoking. Gene-based risk testing appears superior to just clinical risk models alone in prioritising high risk smokers for screening.
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