LABORATORIO DE URGENCIAS

Lung Cancer in Nonsmoking Individuals

 A Review

                                              Cian Murphy, PhD; Tej Pandya, MBChB; Charles Swanton, MD,PhD, et al                                                                          Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, United Kingdom
                                                                The Royal Marsden Hospital, London, United Kingdom
                                                                UKRI UCL Centre,Doctoral Training in AI-enabled Healthcare Systems, University College London, United Kingdom
                                                                Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, United Kingdom
                                                                Department of Oncology, University College London Hospitals, London, United Kingdom
                                                                Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
                                                                Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia

                                                                             JAMA (October 2025); Published Online  / doi: 10.1001/jama.2025.17695

Lung cancer in nonsmoking individuals (defined as people who have smoked fewer than 100 cigarettes in their lifetime) accounts for 15% to 20% of all lung cancer cases worldwide. In the US, the annual incidence of lung cancer in nonsmoking individuals is 14.4 to 20.8 per 100 000 person-years in females and 4.8 to 12.7 per 100 000 person-years in males.
Lung cancer is the leading cause of cancer-related mortality worldwide, causing approximately 1.8 million deaths in 2022.¹ 
Although tobacco smoking is the predominant risk factor for lung cancer, present in 80% to 85% of cases, smoking rates are declining in the US and in many other parts of the world. In parallel with a decrease in adult US smoking rates (23.3% in 2000 vs 11.5% in 2021²), lung cancer incidence in the US declined from 68 per 100 000 in 2000 to 47 per 100 000 in 2021.³
Lung cancer among nonsmoking individuals accounts for 15% to 20% of all lung cancer cases^4 ,5 and may be related to factors including age, air pollution, passive smoking, radon exposure, asbestos exposure, and germline genetic risk.^6-8 
The misperception that lung cancer is almost invariably caused by smoking may delay assessment and diagnosis.^9,10 
This review discusses the epidemiology, risk factors, screening, clinical presentation, assessment, diagnosis, treatment, and prognosis of lung cancer in nonsmoking individuals

Methods

A PubMed search for English-language articles describing studies on lung cancer in nonsmoking individuals was conducted from January 1, 2005, to August 1, 2025. In total, 902 studies were retrieved from this search and 92 were included in this review, consisting of 6 meta-analyses or systematic reviews, 16 randomized clinical trials, 8 prospective cohort studies, 7 retrospective cohort studies, 3 cross-sectional studies, 4 observational or case-control studies, 13 genomic or molecular studies, 11 narrative reviews, 10 statistical or surveillance reports, 11 guidelines or recommendation statements, 2 registry or database studies, and 1 preclinical or experimental study.

Epidemiology and Screening

Most lung cancers in nonsmoking individuals are adenocarcinomas (60%-80%), and are diagnosed at a median age of 67 years compared with age 70 years in people with a history of smoking (defined as people who currently or formerly smoked) (Figure).^4-6,11-13 The absolute incidence of lung cancer in nonsmoking individuals in the US and worldwide is increasing. A retrospective study of 10 000 cases from 3 US hospital networks reported that the proportion of lung cancer among nonsmoking individuals increased from 8% to 14.9% from 1990 to 2013.⁴ A pooled analysis of 7 Finnish cohorts reported an absolute increase in lung cancer among nonsmoking individuals from 6.9 per 100 000 person-years in 1972 to 12.9 per 100 000 person-years in 2015.¹⁴ Lung cancer is the third most diagnosed cancer worldwide, and if lung cancer in nonsmoking individuals were classified as a distinct entity, it would be the seventh most common cancer.¹⁵
There are substantial ethnic, racial, and geographic differences in the incidence of lung cancer in nonsmoking individuals.
The age-adjusted incidence rate of lung cancer in nonsmoking individuals who were Asian females in the US between 2000 and 2013 was 17.5 per 100 000 individuals (95% CI, 15.0-20.2) compared with 10.1 per 100 000 (95% CI, 9.0-11.3) for non-Hispanic White females.¹⁶
The incidence of lung cancer in nonsmoking individuals worldwide is higher among women than men; however, this may be confounded by the difference in the population at risk.^17,18 In Taiwan, up to 83% of lung cancer cases among nonsmoking individuals occur in women.^5,19,20 Smoking has historically been higher among males than females and there are concerns about the accuracy of data on smoking status.²⁰ For example, a study of electronic health care records of 16 874 individuals in the US reported 80% had inaccuracies in their smoking history.²¹ In addition, the US Surveillance, Epidemiology, and End Results program, which aggregates survival data from lung cancers registered in the US, does not record smoking status.²²
A pooled analysis of 7 Finnish cohorts demonstrated an age-standardized increase in lung cancer among female nonsmoking individuals (0.4 per 100 000 person-years in 1972 vs 6.2 per 100 000 person-years in 2015) compared with a stable rate of lung cancer among male nonsmoking individuals (6.5 per 100 000 person-years in 1972 vs 6.7 per 100 000 person-years in 2015).¹⁴ 
A study that included 6 population-based cohorts (n = 1 364 658 individuals, n = 5379 incident lung cancer cases) reported that the age-adjusted incident rate ranged from 14.4 to 20.8 per 100 000 person-years in nonsmoking females and 4.8 to 12.7 per 100 000 person-years in nonsmoking males.¹¹

Environmental Risk Factors
Several environmental exposures are associated with an increased risk of lung cancer in nonsmoking individuals. Radon, a colorless gas that arises from the radioactive decay of uranium found in rocks and soil, is classified as a class I carcinogen by the International Agency for Research on Cancer.²³ Up to 21 000 cases of lung cancer–related deaths in the US annually are due to radon, leading the US Centers for Disease Control and Prevention to recommend that all homes be tested for radon, but radon testing is not federally mandated as a requirement for a home sale.²⁴ A meta-analysis containing estimates from 4 pooled studies (incorporating data from 24 individual case-control studies), 1 case-control study, and 1 cohort study reported an adjusted excess relative risk of lung cancer of 0.15 (95% CI, 0.06-0.25) per 100 Bq/m³ increase in radon.²⁵ For homes that have radon levels at or above 4 pCi/L, or 150 Bq/m³, the Environmental Protection Agency recommends reducing radon levels using measures such as active soil depressurization and improved ventilation. Because no level of radon exposure is considered safe, the Environmental Protection Agency also advises homeowners to consider mitigation for levels between 2 and 4 pCi/L (75-150 Bq/m³).²⁶
In 2022, worldwide, approximately 200 000 cases of lung adenocarcinoma, the predominant histologic subtype of lung cancer, were attributed to ambient air pollution, estimated using a population-attributable fraction model.⁸ Specifically, particulate matter with a diameter of less than 2.5 µm (PM_2.5), found in diesel exhaust or smoke from indoor cooking, can penetrate the alveoli and enter the bloodstream after inhalation. PM_2.5, a known cause of lung cancer, promotes tumorigenesis via an influx of macrophages and release of interleukin-1β.²⁷ Approximately 99% of people worldwide live in areas that exceed World Health Organization guidelines on PM_2.5 (<5 µg/m³ annually). A recent multicountry study (6799 lung cancer cases, including 3615 lung cancer cases in nonsmoking individuals and 26 807 controls without lung cancer) reported an association between PM_2.5 levels and EGFR-driven lung cancer incidence, with the relative incidence rates increasing by 0.63 to 1.82 (per 100 000 population), per 1 µg/m³ increase of PM_2.5.²⁸
Other environmental particulates associated with lung cancer in nonsmoking individuals include asbestos and silica, which are considered group 1 carcinogens by the International Agency for Research on Cancer.²⁹ Secondhand smoke exposure is also associated with an increased risk of lung cancer among nonsmoking individuals.
A systematic review of a retrospective observational cohort and 5 case-control studies that included 622 469 individuals reported a hazard ratio (HR) of 1.28 (95% CI, 1.10-1.48) for lung cancer in nonsmoking individuals.³⁰ A secondary analysis of the Global Burden of Disease Study data reported that secondhand smoke was responsible for nearly 100 000 deaths worldwide in 2021.³¹ Prior radiotherapy to the chest is another risk factor for lung cancer; a retrospective observational study that found 1.74% of 613 746 patients (smoking status unavailable) who received radiotherapy during breast cancer treatment subsequently developed lung cancer.³²

Familial and Genetic Risk
Data from a case-control study of 24 380 individuals with lung cancer and 23 399 controls indicated that individuals with a first-degree relative with lung cancer had an odds ratio of 1.51 (95% CI, 1.39-1.63) for developing lung cancer compared with those without this family history.³³
Large-scale genome-wide association studies have identified a pattern of low penetrance germline variants in regions such as 5p15.33 and 3q28 associated with increased risk of lung cancer in nonsmoking individuals. These variants involve multiple genes associated with cell cycle regulation, DNA damage, immune response, and genomic stability.³⁴ Singular, highly penetrant germline variants in genes such as EGFR and YAP1 are rare, but have been reported in familial lung cancers from Western and Asian populations, respectively.^35,36 Clonal hematopoiesis, the age-related expansion of a subpopulation of hematopoietic cells with acquired somatic mutations, has been associated with the incidence of many diseases, including lung cancer. In a clonal hematopoiesis case-control study of 104 cases of incident lung cancers and 343 age-, smoking status–, and sex-matched controls, the odds ratio for risk of incident lung cancer was 1.43 (95% CI, 1.06-1.94). Although limited by the relatively small number of nonsmoking individuals (11 cases and 35 controls) included in the analysis, this effect may be independent of smoking history.³⁷
Compared with people with a history of smoking and lung cancer, nonsmoking individuals with lung cancer have higher rates of somatic variants and gene rearrangements that activate genes that directly contribute to carcinogenesis and represent potential molecular targets.^38 -42 For example, in a study of 17 712 patients with lung cancer, somatic mutations in the EGFR gene were identified in 40% to 60% of lung cancer tumor tissue in nonsmoking individuals compared with approximately 10% of people with a history of smoking and lung cancer.⁴³ 
A study of 121 patients with lung cancer younger than age 40 years (73% nonsmoking individuals) indicated that 84% carried an actionable oncogenic variant⁴⁴. Rearrangements in the ALK and ROS1 genes are found in 5% to 14% and 1% to 2% of tumors, respectively, of patients with lung cancer,⁴⁵ but with higher rates in nonsmoking individuals (odds ratio, 3.57 [95% CI, 2.04-6.25] for RET fusions in nonsmoking individuals compared with people with a history of smoking).⁴⁶ Other actionable genomic alterations found more frequently in lung cancer biopsy specimens from nonsmoking individuals compared with people with a history of smoking include somatic variants in ERBB2 (formerly HER2), and gene fusions or rearrangements in RET, NTRK1/2/3, and NRG1.^46,47 A study of nonsmoking patients with lung adenocarcinomas (n = 160) reported 78% to 92% had clinically actionable driver variations compared with 49.5% in people who had ever smoked (n = 299).³⁸ A study of 188 lung adenocarcinomas that included 20 nonsmoking individuals found that nonsmoking individuals had a 10-fold lower tumor mutational burden, defined as the total number of DNA mutations in cancer cells, than tumors from people with a history of smoking.⁴⁸

Screening
To reduce lung cancer mortality, the US Preventive Services Task Force (USPSTF) guidelines recommend low-dose computed tomographic (CT) scanning for individuals aged 50 to 80 years with a 20 or more pack-year history of smoking who currently smoke or quit within the past 15 years.^49-52 However, the USPSTF does not currently recommend screening for lung cancer in nonsmoking individuals.^53,54 In contrast, Taiwan initiated a national lung cancer early detection program in 2022, offering biennial low-dose CT scans to nonsmoking individuals (aged 45-74 years for females and 50-74 years for males) with a family history of lung cancer.⁵⁵ This screening program was based on results from a study that performed CT screening for 12 011 asymptomatic Taiwanese nonsmoking individuals aged 55 to 75 years with risk factors such as having a first-degree relative with lung cancer, passive smoking exposure, or cooking without ventilation. This study reported that 2.7% with a family history of lung cancer were diagnosed with incident lung cancer, in contrast to 1.6% without a family history (P < .0001), and 77.4% of lung cancers were diagnosed at stage I.⁵⁵

Clinical Presentation
Among individuals diagnosed with lung cancer, nonsmoking individuals have a similar clinical presentation as individuals with a history of tobacco consumption.³⁸ In a registry of 9876 patients diagnosed with lung cancer in Spain, 1177 (11.9%) were nonsmoking individuals.
Among nonsmoking individuals, the most common symptoms at diagnosis were cough (34%), dyspnea (29%), pain (28%), and weight loss (19%). The percentage who were asymptomatic (31.5% of all patients) did not differ when stratified by smoking status.⁵⁶ 
In a retrospective series of 539 patients who underwent surgical resection for primary lung cancer at the University of California,
Los Angeles, 345 (64%) were asymptomatic and had their tumors discovered incidentally on CT imaging and 143 (41%) were people who had never smoked.⁵⁷

Assessment and Diagnosis

Imaging
The recommended imaging study for patients with chest symptoms concerning for lung cancer or with an abnormality detected on chest radiograph is a contrast-enhanced chest CT to evaluate the primary lesion and assess for nodal involvement and metastases.
Brain imaging, preferably magnetic resonance imaging, should be performed in all patients diagnosed with lung cancer, as 10% to 25% have brain metastases at diagnosis.⁵⁸ This rate may be higher in patients with genomic alterations such as EGFR mutations and ALK or RET fusions with 52% of 50 patients presenting with brain metastases having an EGFR variation in 1 study.⁵⁸ Fluorodeoxyglucose positron emission tomography–CT should be performed for patients being considered for potentially curative local therapy (such as radiotherapy or surgery) to determine extent of nodal involvement and to exclude metastatic disease.⁵⁹
Patients with indeterminate pulmonary nodules (a focal distinct radiographic density surrounded by lung tissue) should undergo follow-up imaging based on the Fleischner Society guidelines. More than 95% of indeterminate pulmonary nodules are benign and the probability of malignancy is less than 1% for all nodules smaller than 6 mm⁶⁰

Tissue Diagnosis and Molecular Testing
Biopsy of tumor tissue in the lung and/or lymph nodes performed with percutaneous biopsy or bronchoscopic biopsy, often guided by endobronchial ultrasound, confirms the diagnosis and may be useful for staging. Molecular testing should be performed for all nonsmoking individuals with lung cancer to aid decision-making about use of targeted therapy and immunotherapy.⁶¹ High-throughput next-generation sequencing with DNA and RNA panels is currently recommended to identify genetic variants or rearrangements in genes including EGFR, ALK, ROS1, and RET for consideration of targeted therapies.⁶¹ Characterization of circulating tumor DNA (ctDNA) or liquid biopsy is emerging as a test for detecting actionable genomic variants in plasma and may be particularly useful if limited tissue is available for molecular analyses. A study of 171 individuals with lung cancer reported that compared with patients with ctDNA–high status (n = 38), those with a preoperative ctDNA–negative status (n = 18) had improved 5-year overall survival (100% [95% CI, 100%-100%] vs 48.8% [95% CI, 34.7%-68.7%]; P = .0024).⁶² Among patients who develop resistance to treatment, rebiopsy of lung cancer or liquid biopsy can reveal mechanisms of resistance such as alterations in genes encoding components of the PI3K/AKT/mTOR pathway and alterations in RAS, which can guide subsequent treatment strategies.⁶³

Staging
Most nonsmoking individuals with lung cancer are diagnosed at an advanced stage, typically with unresectable locally advanced disease (stage III) or distant metastases (stage IV). In a retrospective cohort study of 254 nonsmoking patients with lung cancer, 62.9% were diagnosed with stage III or IV disease.⁶⁴ In another retrospective cohort study of 795 nonsmoking patients, 43.4% were diagnosed with stage IIIB to IV cancer.⁶⁴ 
Early detection of lung cancer in nonsmoking individuals may be difficult due to absence of routine screening in this population and the often nonspecific symptoms such as cough and fatigue. However, staging at diagnosis can vary significantly by geography and by use of CT screening. For example, in the targeted low-dose CT screening trial for high-risk people who had never smoked in Taiwan, 246 of 257 (95.7%) were diagnosed with stage IA or IB lung cancer, demonstrating the potential effect of screening in shifting diagnosis toward earlier stages.⁵⁵

Treatment (In the original publication mentioned at the beginning)

Prognosis

Lung cancer survival primarily depends on stage at diagnosis (5-year survival rate of 65% for stage I vs <10% for stage IV), performance status, and presence of actionable genetic alterations for treatment.⁸⁵ A prospective cohort study of 5594 patients with NSCLC (61.8% lung adenocarcinoma) reported a median overall survival of 58.9 months (95% CI, 51.9-67.4) for 795 nonsmoking individuals (55.8% stage 1A-IIIA, 43.4% stage IIIB-IV), a median overall survival of 51.2 months (95% CI, 47.7-54.6) for 3308 people who had previously smoked (68.9% stage 1A-IIIA, 30.1% stage IIIB-IV), and a median overall survival of 34 months (95% CI, 29.1-42.3) for 1491 people who currently smoked (63.6% stage 1A-IIIA, 35.9% stage IIIB-IV).⁶⁴
Significant improvements in PFS and overall survival among patients with lung cancer have occurred with use of targeted therapies directed at oncogenic drivers.^59 ,86,87 A population-based study using the Surveillance, Epidemiology, and End Results data reported that 2-year lung cancer–specific survival improved from 26% for patients diagnosed in 2001 to 35% in 2014, a change largely attributable to the advent of targeted therapies. A French study reported that median overall survival among patients diagnosed with lung adenocarcinoma increased from 8.5 months in 2000 (n = 1684) to 20.7 months in 2020 (n = 5015), although no information on smoking status was provided.⁸⁸ The median overall survival for advanced EGFR mutation–positive lung cancer treated with EGFR inhibitors is currently 38.6 months and the median overall survival for patients with advanced ALK-positive NSCLC treated with ALK inhibitors exceeds 5 years among people with a history of smoking and nonsmoking individuals. ^.75,89

Practical Considerations
Individuals with lung cancer may face stigma due to the disease’s association with smoking, which can lead to feelings of isolation.⁸¹ Patient education and psychosocial support for nonsmoking individuals with lung cancer enhances well-being and may improve outcomes through greater adherence to treatment as found in a systematic review of 18 cohorts.⁸⁰ A trial of 151 patients with metastatic lung cancer randomized to early palliative care (n = 77 with 18 nonsmoking individuals) vs standard of care (n = 74 with 16 nonsmoking individuals) found that early palliative care led to significant improvement in quality of life, reduced depressive symptoms, and improved median survival (11.6 months vs 8. 9 months, P = .02).⁹⁰ Many support and advocacy groups exist, including those focusing on specific molecular subtypes of lung cancer. Proactive follow-up of respiratory symptoms with CT imaging, regardless of a patient’s smoking history, could lead to earlier-stage lung cancer diagnosis, a message echoed by awareness campaigns such as See Through the Symptoms¹⁰ and All You Need Is Lungs.⁹

Limitations

This review has several limitations. First, smoking history is often not included in many databases, cancer registries, and clinical trials, making it difficult to accurately determine the incidence and prevalence of lung cancer in nonsmoking individuals and to evaluate treatment outcomes based on smoking status. Second, accurate quantification of environmental exposures, such as air pollution, is challenging. Third, the quality of the evidence was not formally evaluated. Fourth, some articles may have been missed.

Conclusions

Lung cancer in nonsmoking individuals accounts for 15% to 20% of the lung cancer cases worldwide. Among patients with lung cancer, nonsmoking individuals are more likely to have genomic alterations, such as EGFR mutations or ALK gene rearrangements, and these patients have improved survival when treated with TKIs compared with chemotherapy.

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