Advancing Precision Research for Lung Cancer in Never Smokers and Its Risk Factors

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Topic Description

Post Date: October 4, 2026

Expiration Date: October 4, 2028

Purpose:

The purpose of this topic is to accelerate precision cancer research and technology development for lung cancer in never-smokers. This effort spans multiple disciplines, including epidemiology, cancer biology, preclinical translational research, and clinical trials. The goal is to identify risk factors, elucidate etiologies, understand biology, develop strategies for early detection and prevention, and advance interventions for diagnosis and therapy across the cancer continuum.

Background:

Lung cancer remains one of the leading causes of cancer-related mortality globally, with smoking as the primary risk factor. However, an increasing proportion of lung cancer cases are diagnosed in never smokers. Lung cancer in never smokers (LCINS) refers to those individuals who have never smoked or who have smoked fewer than 100 cigarettes in their lifetime. In the United States (USA), LCINS represents a significant yet understudied public health issue, accounting for approximately 10% to 20% of lung cancers annually. Many patients are diagnosed at an advanced metastatic stage. LCINS is characterized by distinct pathobiology and shows differential responses to therapies, including immunotherapy, compared to smoking-associated lung cancer. LCINS is estimated to be the eighth leading cause of cancer-related mortality in the USA (CA Cancer J Clin. 2023 Jan;73(1):17-48.) and the fifth globally (CA Cancer J Clin. 2024 May-Jun;74(3):229-263.). 

The demographics of LCINS differ from smoking-related lung cancer, occurring more frequently in women and disproportionately higher in Asian women with rising incidence in younger age. There is a lack of comprehensive data across diverse populations, including rural and tribal communities. Moreover, there is a gap in understanding the effect of risk factors, such as ancestry genetics, germline variation, epigenetics, sex, age, lung injury from infection, non-tobacco-associated lung diseases of chronic obstructive pulmonary and emphysema, medical comorbidities, lifestyle, radon, second-hand smoke, air pollution, occupational exposure, and other biological and environmental factors on LCINS outcome across the cancer continuum. 

Accelerating precision research for LCINS and its risk factors is critically important to address these scientific gaps and improve outcomes for Americans. 

Central Scientific Contact:
Dani Xi, Ph.D.
[email protected]

Participating ICOs

National Cancer Institute (NCI)

Topics of interest to NCI include, but are not limited to:

  • Investigate the biological and environmental factors, including sex and ancestry, contributing to LCINS initiation, progression, and patient care outcomes across the cancer continuum.  
  • Understand the mechanisms that distinguish the biology of LCINS from tobacco-associated lung cancers, both within tumor cells and between cells of the microenvironment. 
  • Advance early detection and diagnostics strategies to inform early screen criteria, and guide prevention and therapeutics, including biomarker development.
  • Develop mechanism-driven precision interventions to improve prevention and therapeutics, such as addressing therapeutic resistance, targeting rare mutations and non-mutational alterations, and developing cancer vaccine and effective immunotherapies.
  • Develop innovative human relevant research models, databases, computation methods/AI, and other emerging technologies.
ICO Scientific Contact:
Dani Xi, Ph.D.
[email protected]

National Institute of Environmental Health Sciences (NIEHS)

Topics of interest include:

  • New Approach Methodologies to identify chemicals/environmental exposures that are potential lung carcinogens to uncover novel pathways and reveal susceptibilities for development of lung cancer
  • Mechanistic studies that prioritize emerging hallmarks of cancers (e.g. avoiding immune detection) and their enabling factors (e.g. tumor promoting inflammation)
  • For human epidemiology studies: prioritization of studies of chemicals with limited evidence (e.g., benzene, toluene, ethylbenzene, and xylenes or BTEX, non-arsenical insecticides) over those with sufficient evidence (e.g., asbestos, air pollution, radon) including biomarkers of exposure and carcinogenesis and robust approaches to separate the effects from smoking and other established risk factors
  • Research to inform the development of early detection of lung cancer based on unique characteristics of disease in patients with exposure to known lung carcinogens
ICO Scientific Contact:
Brittany Trottier, PhD, MPH
[email protected]

Abee Boyles, PhD
[email protected]

National Institute on Minority Health and Health Disparities (NIMHD)

NIMHD has a specific interest in lung cancer in never-smokers as an increasingly recognized source of cancer morbidity and mortality with documented disparities in incidence, stage at diagnosis, molecular features, treatment receipt, and survival. Higher prevalence has been observed among women, several Asian populations, some Hispanic groups, persons in lower-income or rural areas, and patients with limited access to thoracic oncology care, comprehensive molecular testing, targeted therapy, and clinical trials. Areas of interest include: 

  • Novel observational studies of radon, secondhand smoke, indoor and outdoor air pollution, occupational exposures, chronic lung disease, diet, stress biology, and comorbidity
  • Mechanistic studies of immune and inflammatory pathways
  • Interventions to improve risk prediction, early detection biomarkers, imaging, prevention, treatment selection, and implementation of guideline-concordant care.
IC may give special consideration to support meritorious applications in this topic area.
ICO Scientific Contact:
Priscah Mujuru, DrPH, MPH, RN
[email protected]

Office of Disease Prevention (ODP)

ODP provides co-funding support for innovative prevention research that employs rigorous study design, measurement, and analytical methods. For this topic, ODP is particularly interested in research that tests strategies to address modifiable risk factors for lung cancer in never-smokers, prevent exposure to risks, and promote early detection.

This office does not award grants. Applications must be relevant to the objectives of at least one of the participating Institutes or Centers listed in this topic.
ICO Scientific Contact:
Elizabeth L. Neilson, PhD, MPH, MSN
[email protected]

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