• Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Université Paris-Est-Créteil, Inserm, IMRB, Créteil, France. Electronic address: sebastien.gendarme@u-pec.fr.
• Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Department of Integrative Oncology, BC Cancer Research Institute, BC, Canada; School of Population and Public Health, University of British Columbia, BC, Canada.
• Université Paris-Est-Créteil, Inserm, IMRB, Créteil, France; APHP, Mondor Teaching Hospital, Department of Public Health, Creteil, France.
• Department of General Internal Medicine and Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

HYPOTHESIS: To evaluate how comorbidities affect mortality benefits of lung cancer screening (LCS) with low-dose computed-tomography (LDCT).

METHODS: We developed a comorbidity index (PLCO-ci) using LCS-eligible participants' data from the Prostate Lung Colorectal and Ovarian (PLCO) trial (training set) and the National Lung Screening Trial (NLST) (validation set). PLCO-ci predicts 5-year non-lung cancer (LC) mortality using a regularized Cox model; with performance evaluated by the area under the ROC curve (ROC_AUC). In NLST, LC mortality (per original publication) was compared between LDCT and chest X-ray arms across PLCO-ci quintile (Q1-5) using cause-specific hazard ratio (csHR) with 95% confidence intervals [95%CI].

RESULTS: Analyses included 34,690 PLCO and 53,452 NLST participants (mean age: 62 (±5) and 61 (±5) years old, 58% and 59% males, 39% and 41% active smokers, respectively). PLCO-ci predicted 5-year non-LC mortality with ROC_AUC [95%CI] of 0.72 [0.71-0.74] in PLCO and 0.69 [0.67-0.70] in NLST. In NLST, at median follow-up of 6.5 years, LC mortality was significantly reduced for participants with intermediate comorbidity (Q2-Q3-Q4): csHR [95% CI] 0.62 [0.41-0.95], 0.68 [0.48-0.96] and 0.72 [0.54-0.96] respectively, with a non-statistically significant reduction for Q1 (csHR=0.72 [0.45-1.17]) and no reduction for Q5 participants (csHR=0.99 [0.79-1.23]). Participants in Q2-Q3-Q4 (60%) accounted for 89% of LC deaths averted among all NLST participants. Q1 participants had low LC incidence, while Q5 had higher localized LC lethality, more squamous cell carcinomas, and untreated LC.

CONCLUSION: The PLCO-ci developed in this work shows that individuals with intermediate comorbidity benefited the most from LCS, highlighting the need of addressing comorbidities to achieve LC mortality benefits.