Incidence Rates of Lung and Bladder Cancer According to Smoking Status and Tumor Subtype: An Analysis of Absolute Risk in Never Smokers

Principal Investigator

Name
Sarina Murray

Degrees
PhD

Institution
National Cancer Institute

Position Title
Cancer Prevention Fellow

Email
sarina.murray@nih.gov

About this CDAS Project

Study
PLCO (Learn more about this study)

Project ID
PLCO-2017

Initial CDAS Request Approval
Jan 16, 2026

Title
Incidence Rates of Lung and Bladder Cancer According to Smoking Status and Tumor Subtype: An Analysis of Absolute Risk in Never Smokers

Summary
Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide and the most common cause of cancer death in the United States. Cigarette smoking is the primary risk factor, and incidence trends closely mirror historical tobacco use, with recent declines reflecting reduced smoking prevalence, though disparities persist by sex, race and ethnicity, and socioeconomic status. However, approximately 10–20% of lung cancer cases occur among never smokers. In this group, incidence is higher in women and East Asian populations and reflects a distinct etiology with greater contributions from genetic susceptibility and non-tobacco exposures, including secondhand smoke, radon, air pollution, occupational carcinogens, and prior lung disease. Although absolute risk is lower than among smokers, lung cancer in never smokers would rank among the leading causes of cancer mortality if considered a distinct disease entity.
Tobacco smoking is the leading risk factor not only for lung cancer but also for bladder cancer, accounting for approximately half of all bladder cancer cases. Bladder cancer is the tenth most diagnosed cancer worldwide, with higher incidence observed among men, older adults, and White populations. Clinically, bladder cancer is classified into non–muscle-invasive and muscle-invasive disease, as well as low- and high-grade tumors, which differ substantially in prognosis, progression, and treatment response. Despite tobacco smoking being the predominant risk factor, a significant proportion of bladder cancer cases occur in never-smokers, implicating alternative etiologic pathways. These may include exposure to occupational carcinogens, environmental pollutants, contaminants in drinking water, and individual genetic susceptibility.
Investigating bladder cancer in never-smokers is critical for identifying subtype-specific risk factors and improving etiologic understanding to support more precise prevention and treatment strategies. Emphasizing accurate estimation of incidence and absolute risk in never-smoker lung and bladder cancer populations can improve risk stratification, inform screening policies, and advance prevention beyond tobacco exposure alone. Using data from the PLCO cancer screening trial is preferable to cancer registries because most registries do not systematically collect smoking data, cannot reliably estimate incidence or exposure–outcome relationships, and often lack comprehensive, standardized variables, limiting the assessment of tobacco smoking’s role as a risk factor.

Aims

Aim 1: Quantify the absolute risk of lung cancer among never-smokers.
Using data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we will estimate the absolute risk of lung cancer among never-smokers. This aim will provide robust incidence estimates in the absence of tobacco exposure and improve understanding of baseline lung cancer risk in this population.

Aim 2: Quantify the absolute risk of bladder cancer among never-smokers and by tumor subtype.
We will estimate the absolute risk of bladder cancer among never-smokers, including analyses stratified by tumor subtype, to characterize risk variation across histologic and molecular categories and clarify bladder cancer burden independent of smoking exposure.

Collaborators

Neal Freedman National Cancer Institute
Sarina Murray National Cancer Institute
Stella Koutros National Cancer Institute