Schabath, Matthew B.

1512 Background: Tobacco smoking profoundly impacts LC risk; however, data are limited as to what extent SC prior to diagnosis impacts LC overall survival (OS) and lung cancer specific survival (LCSS). LC screening offers a possible teachable moment, but there is uncertainty of SC benefits after a lifetime of smoking. We use the ILCCO database to answer if SC prior to LC dx is associated with better OS and LCSS, considering time since smoking cessation (TSSC). Methods: Using individual data, analysis was performed on 17 ILCCO studies with available TSSC to estimate survival using univariable analysis and models of stage-adjusted and cumulative smoking-adjusted multivariable analysis. Adjusted Hazard Ratios (aHR) from Cox models, cubic spline smooth curves and Kaplan-Meier curves were created. Sensitivity analysis was performed for TSSC and LCSS on 13 studies. Results: Of 34649 patients, 14322 (41%) were current smokers 14273 (41%) ex-smokers and 6054 (18%) never smokers at diagnosis. We confirmed that ex-smokers (aHR 0.88 CI 0.86-0.91) and never smokers (aHR 0.76 CI 0.73-0.8) improved OS compared to current smokers. Amongst ex-smokers, < 2y TSSC (aHR 0.88 CI 0.82-0.94), 2-5y TSSC (aHR 0.83 CI 0.77-0.90) and > 5y TSSC (aHR 0.8 CI 0.76-0.84) had improved OS compared to CS. Sensitivity analysis showed a trend towards improved LCSS survival for < 2y TSSC (aHR 0.95 CI 0.86-1.05) and 2-5y TSSC (aHR 0.93 CI 0.83-1.04), whereas > 5y TSSC significantly improved LCSS by 15% (aHR 0.85 CI 0.78-0.92). To mimic the LC screening participants, in analysis of > 30 pack-years individuals, associations were strikingly strong: < 2y TSSC had improved OS by 14% (aHR 0.86 CI 0.80-0.93); 2-5y TSSC by 17% (aHR 0.83 CI 0.76-0.90); and > 5 TSSC by 22% (aHR 0.78 CI 0.74-0.83), compared to current smokers; for < 30 packs-years, a trend towards better OS was observed for < 2y TSSC (aHR 0.95 CI 0.92-1.02) and 2-5y TSSC (aHR 0.86 CI 0.74-1.01), whereas > 5y TSSC improved OS by 23% (aHR 0.77 CI 0.72-0.82). Conclusions: Among ex-smokers, the risk of overall death was reduced by 12% on < 2y TSSC, 17% on 2-5y TSSC and 20% > 5y TSSC, whereas for LCSS, the benefit was significant only for > 5y TSCC, compared to current smokers at time of diagnosis. Here we demonstrate that convincing screening participants to quit smoking at any point of their trajectory, even just prior to dx such as < 2y TSSC, improved OS, and LCSS benefit was present beyond 5y of quitting. These relationships are independent of pack-years, age, across all stages and other prognostic variables.

1562 Background: In Caucasian-predominant populations, overweight or obese NSCLC pts (BMI≥25-kg/m2) have better prognosis while underweight (BMI≤18.5-kg/m2) pts have a worse prognosis. A large pooled sample allowed us to evaluate the role of ethnicity in this BMI-NSCLC OS relationship. Methods: Using individual data, survival analysis was performed on 15 ILCCO studies, assessing the interactions between ethnicity and BMI on overall survival (OS). Adjusted Hazard Ratios (aHR) from Cox models and adjusted penalized smoothing spline plots were generated. Results: Among 13416 (77%) Caucasian, 2975 (17%) Asian, and 935 (5%) Black NSCLC pts analyzed, we confirmed that for all pts, being underweight at NSCLC diagnosis was associated with worse OS (aHR=1.68, CI 1.5-1.8, p<0.001), while overweight/obese pts had improved survival (aHR 0.89, CI 0.8-0.9, p<0.001), when compared to pts with normal BMI. In general, Black pts had poorer OS than Caucasian pts (aHR 1.26 CI 1.1-1.4, p<0.001). However, the BMI-OS relationship differed according to ethnicity (BMI-ethnicity interaction, p=0.009): Caucasian underweight pts had poorer OS (aHR 1.67, CI 1.5-1.8, P<0.001) while overweight/obese pts had improved OS (aHR 0.89, CI 0.8-0.9, P<0.001). In Asian pts, these two associations were aHR 1.15, CI 0.8-1.5, P=0.33, and aHR 0.91, CI 0.7-1.1, P=0.32, respectively. In Black pts, these two associations were aHR 1.06, CI 0.7-1.5, p=0.73 and 0.75, CI 0.6-0.8 p<0.001, respectively. For overweight/obese patients, as BMI rises from 25-kg/m2 through 45-kg/m2, the prognosis worsens for Caucasian pts, remains stable for Asian pts, but improves for Black pts. Conclusions: InCaucasian pts, being underweight had a greater negative impact on OS than for Asian or Black pts, while being obese had a greater beneficial impact in Blacks than in other ethnic groups. These ethnic differences likely reflect genetically-informed muscle/adipose tissue distributions, where Black pts may have less sarcopenic obesity than other ethnicities. In future prognostic studies, BMI relationships must account for ethnic differences.

Abstract Purpose: DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients. Experimental Design: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan–Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months postdiagnosis, adjusting for age, sex, race, and tumor stage. Results: Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared with those carrying AA alleles, with a HR of 1.36 [95% confidence interval (CI): 1.08–1.72, P = 0.01), but no association with survival was observed for patients carrying the AG genotype (HR = 1.04, 95% CI, 0.84–1.29, P = 0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR = 0.79; 95% CI, 0.61–1.02, P = 0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190. Conclusions: We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors. Clin Cancer Res; 23(24); 7550–7. ©2017 AACR.

Abstract Introduction: DNA topoisomerase inhibitors (e.g. etoposide, irinotecan, teniposide, topotecan) are commonly used for treating small cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) plays a role in repairing DNA damage caused by DNA topoisomerase inhibitors and it is believed to be responsible for resistance to this class of drugs. The purpose of this study was to determine whether common TDP1 polymorphisms are associated with overall survival among SCLC patients. Method: Two common TDP1 SNPs (rs942190 and rs2401863, r2(European)=0.63 and r2(East Asian)=0.26) were analyzed in 898 patients from 10 studies in the International Lung Cancer Consortium, conducted in the U.S., Canada, Japan, Italy, Spain and the United Kingdom. Genotype data were obtained from either the OncoArray Consortium or other existing genome-wide association studies. Cox proportional hazard regression models with robust standard error were used to evaluate genotype associations for overall survival at 36 months post-diagnosis, adjusting for age, sex, race and tumor stage. Results: Patients homozygous for the minor allele (GG) of TDP1 SNP rs942190 were associated with poorer survival compared to those carrying both major alleles (AA), with a hazard ratio (HR) of 1.36 (95% confidence interval (CI): 1.07-1.72, p-value=0.01), but there was no association with survival for patients with the heterozygous genotype (HR=1.02, 95% CI: 0.83-1.27, p-value=0.83). For rs2401863, patients carrying both minor alleles (CC) tended to have better survival than patients carrying AA alleles, but this was within the limits of chance given no significant association (HR=0.79, 95% CI: 0.61-1.02, p-value=0.07). In addition, multi-tissue expression quantitative trait loci (eQTL) analyses from the Genotype-Tissue Expression Project indicated a potential effect of rs942190 on lung tissue, with higher TDP1 gene expression for the GG than AG or AA genotypes. Conclusion: We found that among SCLC patients the TDP1 rs942190 GG genotype was associated with poor overall survival. Further study could determine if this genotype can serve as a predictive marker for the treatment efficacy of DNA topoisomerase inhibitors in SCLC. Citation Format: Pawadee Lohavanichbutr, Lori C. Sakoda, Christopher I. Amos, Susanne M. Arnold, David C. Christiani, Michael P. Davies, John K. Field, Eric B. Haura, Rayjean J. Hung, Takashi Kohno, Maria Teresa Landi, Geoffrey Liu, Yi Liu, Michael W. Marcus, Grainne M. O'Kane, Matthew B. Schabath, Kouya Shiraishi, Stacey A. Slone, Adonina Tardón, Ping Yang, Kazushi Yoshida, Ruyang Zhang, Xuchen Zong, Noel S. Weiss, Chu Chen. Common TDP1 polymorphisms in relation to survival among small cell lung cancer patients in a multicenter study from the International Lung Cancer Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2248. doi:10.1158/1538-7445.AM2017-2248