Introduction: Lung cancer survivors are at high risk of developing a second primary lung cancer (SPLC). However, SPLC risk factors have not been established and the impact of tobacco smoking remains controversial. We examined the risk factors for SPLC across multiple epidemiologic cohorts and evaluated the impact of smoking cessation on reducing SPLC risk.Methods: We analyzed data from 7059 participants in the Multiethnic Cohort (MEC) diagnosed with an initial primary lung cancer (IPLC) between 1993 and 2017. Cause-specific proportional hazards models estimated SPLC risk. We conducted validation studies using the Prostate, Lung, *Corresponding author. Disclosure: Dr. Kurian reports receiving research funding to the institution from Myriad Genetics outside of the submitted work. Dr. Wakelee reports receiving personal consulting fees from Janssen, Daiichi Sankyo, Helsinn, Mirati, AstraZeneca, and Blueprint and grants to institution for clinical trial conduct from ACEA Biosciences, Arrys

Background Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC), but little is known about the survival impact of SPLC diagnosis. Methods We analyzed data from 138,969 patients in the Surveillance, Epidemiology, and End Results (SEER), who were surgically treated for initial primary lung cancer (IPLC) in 1988–2013. Each patient was followed from the date of IPLC diagnosis to SPLC diagnosis (for those with SPLC) and last vital status through 2016. We performed multivariable Cox regression to evaluate the association between overall survival and SPLC diagnosis as a time-varying predictor. To investigate potential effect modification, we tested interaction between SPLC and IPLC stage. Using data from the Multiethnic Cohort Study (MEC) (N = 1,540 IPLC patients with surgery), we evaluated the survival impact of SPLC by smoking status. All statistical tests were 2-sided. Results A total of 12,115 (8.7%) patients developed SPLC in SEER over 700,421 person-years of follow up. Compared to patients with single primary lung cancer, those with SPLC had statistically significantly reduced overall survival (hazard ratio [HR]=2.12, 95% confidence interval [CI] = 2.06–2.17; P < .001). The effect of SPLC on reduced survival was more pronounced among patients with early-stage IPLC vs. advanced-stage IPLC (HR = 2.14 [95% CI = 2.08–2.20] vs. 1.43 [95% CI = 1.21–1.70], respectively; Pinteraction <0.001). Analysis using MEC data showed that the effect of SPLC on reduced survival was statistically significantly larger among persons who actively smoked at initial diagnosis vs. those who formerly or never smoked (HR = 2.31 [95% CI = 1.48–3.61] vs. 1.41 [95% CI = 0.98–2.03], respectively; Pinteraction=0.04). Conclusions SPLC diagnosis is statistically significantly associated with decreased survival in SEER and MEC. Intensive surveillance targeting patients with early-stage IPLC and active smoking at IPLC diagnosis may lead to a larger survival benefit.

Background In 2021, the U.S. Preventive Services Task Force (USPSTF) revised its lung cancer screening guidelines to expand screening eligibility. We evaluated screening sensitivities and racial and ethnic disparities under the 2021 USPSTF criteria versus alternative risk-based criteria in a racially and ethnically diverse population. Methods In the Multiethnic Cohort (MEC), we evaluated the proportion of ever-smoking lung cancer cases eligible for screening (ie, screening sensitivity) under the 2021 USPSTF criteria and under risk-based criteria through the PLCOm2012 model (6-year risk ≥ 1.51%). We also calculated the screening disparity (ie, absolute sensitivity difference) for each of four racial or ethnic groups (African American, Japanese American, Latino, Native Hawaiian) versus White cases. Results Among 5,900 lung cancer cases, 43.3% were screen-eligible under the 2021 USPSTF criteria. Screening sensitivities varied by race and ethnicity, with Native Hawaiian (56.7%) and White (49.6%) cases attaining the highest sensitivities, and Latino (37.3%), African American (38.4%), and Japanese American (40.0%) cases attaining the lowest. Latino cases had the greatest screening disparity versus White cases at 12.4%, followed by African American (11.2%) and Japanese American (9.6%) cases. Under risk-based screening, the overall screening sensitivity increased to 75.7%, and all racial and ethnic groups had increased sensitivities (54.5–91.9%). While the screening disparity decreased to 5.1% for African American cases, it increased to 28.6% for Latino and 12.8% for Japanese American cases. Conclusions In MEC, racial and ethnic disparities decreased but persisted under the 2021 USPSTF lung cancer screening guidelines. Risk-based screening through PLCOm2012 may increase screening sensitivities and help to reduce disparities in some, but not all, racial and ethnic groups. Further optimization of risk-based screening strategies across diverse populations is needed.

Background: Lung cancer (LC) survivors in the U.S. are increasing in number, with 5-year survival rates improving by 26% over the past decade. Although LC survivors are at high risk of developing a second primary lung cancer (SPLC), risk factors for SPLC have not been established and the impact of tobacco smoking remains controversial. In this study, we examined risk factors for SPLC among participants in the Multiethnic Cohort (MEC) study, validated our findings with two epidemiologic cohorts–the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and the European Prospective Investigation into Cancer and Nutrition (EPIC)–and evaluated the impact of smoking cessation on SPLC risk. Methods: We analyzed data from 7,299 initial primary lung cancer (IPLC) cases in MEC who were diagnosed from 1993-2017. Incident IPLC and SPLC were identified via linkage to SEER registries, with SPLC defined by Martini and Melamed criteria. Baseline smoking data were obtained at the time of enrollment (1993-1996) and updated with 10-year follow-up data close to IPLC diagnosis, if available. Fine-Gray regression was used to take into account competing risks and to evaluate the associations between risk factors and SPLC, adjusting for age at IPLC diagnosis and IPLC histology and stage. We conducted validation studies with PLCO (N=3,423 LC patients) and EPIC (N=4,605 LC patients) and evaluated the combined effects of risk factors from all three cohorts using meta-analysis. Results: Among 7,299 MEC participants with IPLC, 167 (2.3%) developed a SPLC. Fine-Gray regression analyses identified several factors that were significantly associated with SPLC risk (P<0.05), which included smoking pack-years (HR 1.12 per 10 pack-years (PY); P=0.004) and smoking intensity (HR 1.21 per 10 cigarettes per day (CPD); P=0.017). Individuals who met the U.S. Preventative Services Task Force's (USPSTF) screening criteria (i.e., aged 55-80, smoked ≥30 PY, and ≤15 years since smoking cessation) at the time of IPLC had a 68% increase in SPLC risk (HR 1.68; P=0.001). Validation studies with PLCO and EPIC showed consistent results; the combined effects based on meta-analysis showed a HR 1.15 per 10 PY (Pmeta=0.022) for smoking pack-years, HR 1.18 per 10 CPD (Pmeta=6.0x10-4) for smoking intensity, and HR 1.70 (Pmeta = 1.9x10-5) for meeting the USPSTF criteria. Subset analysis of MEC participants (N=156) who were current smokers at baseline, had 10-year follow-up smoking data, and were diagnosed with IPLC between baseline and 10-year follow-up showed that smoking cessation was associated with a reduced risk of SPLC (HR=0.25; P=0.005). Conclusions: Smoking is a risk factor for SPLC among LC patients and the USPSTF criteria can potentially aid in identifying those at high risk of SPLC. Smoking cessation may reduce SPLC risk after IPLC diagnosis. Further analysis is required to stratify SPLC risk based on comprehensive risk factors and identify LC survivors at high risk of SPLC for CT screening. Citation Format: Jacqueline V. Aredo, Sophia J. Luo, Rebecca Gardner, Thomas P. Hickey, Thomas L. Riley, Lynne R. Wilkens, Loic Le Marchand, Christopher I. Amos, Rayjean J. Hung, Mattias Johansson, Iona Cheng, Heather A. Wakelee, Summer S. Han. Is smoking a risk factor for second primary lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2298.

Background Smoking cessation reduces lung cancer mortality. However, little is known about whether diagnosis of lung cancer impacts changes in smoking behaviors. Furthermore, the effects of smoking cessation on the risk of second primary lung cancer (SPLC) have not been established yet. This study aims to examine smoking behavior changes after initial primary lung cancer (IPLC) diagnosis and estimate the effect of smoking cessation on SPLC risk following IPLC diagnosis. Methods The study cohort consisted of 986 participants in the Multiethnic Cohort Study who were free of lung cancer and active smokers at baseline (1993-1996), provided 10-year follow-up smoking data (2003-2008), and were diagnosed with IPLC in 1993-2017. The primary outcome was a change in smoking status from “current” at baseline to “former” at 10-year follow-up (i.e., smoking cessation), analyzed using logistic regression. The second outcome was SPLC incidence after smoking cessation, estimated using cause-specific Cox regression. All statistical tests were 2-sided. Results Among 986 current smokers at baseline, 51.1% reported smoking cessation at 10-year follow-up. The smoking cessation rate was statistically significantly higher (80.6%) for those diagnosed with IPLC between baseline and 10-year follow-up versus those without IPLC diagnosis (45.4%) during the 10-year period (adjusted odds ratio = 5.12, 95% confidence interval = 3.38 to 7.98, P<0.001). Incidence of SPLC was statistically significantly lower among the 504 participants who reported smoking cessation at follow-up, compared to those without smoking cessation (adjusted hazard ratio = 0.31, 95% confidence interval = 0.14 to 0.67, P=0.003). Conclusion Lung cancer diagnosis has a statistically significant impact on smoking cessation. Quitting smoking after IPLC diagnosis may reduce the risk of developing a subsequent malignancy in the lungs.