Editorial: Increasing Awareness of Lung Cancer in Non-Smokers and Never-Smokers Challenges Current Approaches to Prevention and Screening

Abstract

Lung cancer in never-smokers and in non-smokers accounts for between 15% and 25% of all lung cancers. Assumptions that lung cancer is almost always associated with cigarette smoking may delay diagnosis, treatment, and outcomes in non-smokers. The incidence of lung cancer in non-smokers is rising, especially in younger populations, presenting as adenocarcinoma with specific genetic mutations, and is associated with factors including air pollution and inhalation of second-hand tobacco smoke. In 2021, the United States Preventive Services Task Force (USPSTF) updated its 2013 lung cancer screening guidelines for low-dose computed tomography (LDCT) screening. However, the USPSTF still does not currently recommend lung cancer screening for non-smoking individuals. Therefore, age-based screening could improve cost-effectiveness and detection of lung cancer without missing diagnoses in women and never-smokers. Currently, only Taiwan has a national lung cancer screening program for early detection using LDCT in high-risk individuals. This editorial aims to highlight that non-smokers have risk factors for lung cancer that may challenge current criteria for inclusion in screening programs.

Since the 1950s, tobacco smoking has been recognized as the most significant risk factor for lung cancer [1]. However, lung cancer can be caused by exposure to second-hand tobacco smoke, radon, air pollution, asbestos, and genetic factors [2]. In the US, between 10% and 20% of cases of lung cancer each year (or 20,000 to 40,000 cases) are diagnosed in people who never smoked or who smoked <100 cigarettes in their lifetime [2]. In 2025, lung cancer remains the most common cancer worldwide, with some decline in the incidence in men but rising rates in younger women, possibly due to changes in patterns of cigarette smoking, domestic pollution, and air pollution [3]. Recent projections for lung cancer in the US are estimated to be 226,650 new cases and 124,730 deaths from lung cancer [2,4]. A non-smoker, or never-smoker, has smoked <100 cigarettes in their lifetime, while a never-smoker has smoked ≥100 cigarettes in their lifetime, regardless of status [2]. Lung cancer in never-smokers and in non-smokers (who have smoked <100 cigarettes in their lifetime) accounts for between 15% and 25% of all lung cancers [5].

In a recent review of the literature, Murphy and colleagues have highlighted that assumptions that lung cancer is almost always associated with cigarette smoking may delay diagnosis, treatment, and outcomes in non-smokers [6]. The literature indicates that most lung cancers in nonsmoking individuals are non-small cell lung cancers (NSCLC), including adenocarcinomas (60–80%) and squamous cell carcinomas (10–20%), and that small cell lung cancers are rare (<10%) (Table 1) [6]. In the US, lung cancer in non-smokers currently accounts for between 15–20% of cases and is estimated to have an annual incidence of 14–21 per 100,000 for women and 5–14 per 100,000 for men [6]. Second-hand tobacco smoke, or environmental tobacco smoke, or passive smoke, is the combination of smoke from burning tobacco and exhaled smoke [7]. Second-hand smoke contains more than 60 chemical carcinogens, including benzene, arsenic, chromium, beryllium, and formaldehyde [7]. Epidemiology and disease database studies have shown that, as second-hand smoke exposure has declined with reduced cigarette smoking in some parts of the world, this is still a significant risk factor for lung cancer in non-smokers [8]. It has recently been estimated that in 2021, second-hand smoke accounted for approximately 0.10 million lung cancer deaths worldwide, but with persistent disparities across gender, age groups, and regions [8].

Table 1.

Comparison of lung cancer in smoking and non-smoking individuals [6].

	History of smoking*	Non-smoking**
Incidence of lung cancer	2.99 per 1,000 person-years	0.16 per 1,000 person-years
Global proportion of cases diagnosed	80–85%	15–20%
Gender distribution	91% of men with lung cancer 81% of men with lung cancer	9% of men with lung cancer 19% of men with lung cancer
Median age at diagnosis	70 years	67 years
Histopathology	Adenocarcinoma: 24% Squamous cell carcinoma: 41% Small cell carcinoma: 17%	Adenocarcinoma: 60–80% Squamous cell carcinoma: 17% Small cell carcinoma: 8%
Risk factors	Smoking Occupational exposures Second-hand smoke Radon Air pollution Gamma radiation Previous radiotherapy	Second-hand smoke Occupation al exposures Air pollution Household pollution Family history Previous radiotherapy Germline variants Asian ancestry
Frequency of oncogenic drivers of adenocarcinoma	Approx. 50%	Between 70% and 92%
Current screening recommendations	US: Annual lung LDCT for 50–80 yrs with >20 pack-year history who smoked within the last 15 years [11]	No national screening programs, other than in Taiwan [20]

^*Current or former smokers;

^**Smoked ≤100 cigarettes in a lifetime;

LDCT – low-dose computed tomography. Adapted from Murphy et al, 2025 [6].

The incidence of lung cancer in non-smokers is rising, especially in younger populations, often presenting as adenocarcinoma with specific genetic mutations, and is associated with factors including air pollution, radon exposure, and inhalation of second-hand tobacco smoke [6,9]. Risk factors for lung cancer in nonsmoking individuals include exposure to passive smoking, air pollution, asbestos and radon exposure, and a family history of lung cancer (Table 1) [6]. The primary genomic targets for therapy include EGFR and ALK gene rearrangements, but tumor mutation burden is lower in lung cancers from nonsmoking individuals [6]. Therefore, molecular diagnostics with next-generation sequencing (NGS) should be performed on lung cancer tumor tissue from nonsmoking individuals so that targeted therapy, for example, with tyrosine kinase inhibitors, can commence [6].

In 2022, Zhang and colleagues investigated the risk factors associated with lung cancer in people with different genetic risks and smoking habits, based on a cohort study of participants from the UK Biobank [10]. The study included 345,794 participants, 26.2% former smokers and 9.8% current smokers of European ancestry who were followed up for an average of 7.2 years (range, 6.5–7.8 years) [10]. In the follow-up period, 1,687 study participants (0.49%) developed lung cancer, and high genetic risk and smoking were independently associated with an increased risk of lung cancer, but the increased risk of smoking was much more significant than heredity [10]. The authors identified that smoking cessation might prevent 76.4% of new diagnoses [10].

On March 9, 2021, the United States Preventive Services Task Force (USPSTF) updated its 2013 lung cancer screening guidelines for low-dose computed tomography (LDCT) screening [11,12]. The 2021 USPSTF lung cancer screening guidelines recommended reducing the minimum smoking history from 30 to 20 pack-years for those who currently smoke or quit within the last 15 years, and the lower limit of the screening age from 55 to 50 years [11,12]. These guidelines aimed to support screening for lung cancer in more high-risk women and racial minorities, as was estimated to save an additional 10,000 to 20,000 lives each year in the US [12,13]. However, the USPSTF still does not currently recommend lung cancer screening for non-smoking individuals [12,13].

In January 2024, the American Cancer Society (ACS) published its 2023 update of the ACS 2013 lung cancer screening guidelines for screening adults at high risk of lung cancer [14]. The ACS Guideline Development Group evaluated the evidence from the literature and from recent screening guidelines and supported recommendations for annual lung cancer screening with LDCT lung imaging for individuals aged 50–80 years who currently smoke or have a ≥20 pack-year smoking history [14]. The International Association for the Study of Lung Cancer (IASLC) published nine recommendations in 2024 for a five-year roadmap (2023 to 2027) for global lung cancer screening [13,15].

In 2019 and 2020, results from clinical trials, including the US National Lung Screening Trial (NSLT) and the Dutch-Belgian Randomized Lung Cancer Screening Trial, supported screening for lung cancer with LDCT imaging [16,17]. In early 2025, Anderer identified that, in the US, recent cancer screening programs have significantly reduced mortality rates from five main types of cancer, compared with recent advances in treatment over the past 45 years, between 1975 and 2020 [18]. Recently, Bandi and colleagues estimated the number of deaths prevented and life-years gained from lung cancer screening at current and 100% uptake levels [19]. However, for lung cancer, there have been several challenges for the implementation of cancer screening, including the choice of screening populations [5,18,19].

In Taiwan, lung cancer has been most common in never-smokers who have previously presented at a late stage [20]. In 2024, the TALENT trial results reported the outcomes from LDCT screening of 12,011 asymptomatic Taiwanese non-smoking individuals aged between 55–75 years between 2015 and 2019, who had risk factors for lung cancer, including a first-degree relative with lung cancer, exposure to second-hand smoke, or outdoor and indoor pollution (NCT02611570) [20]. Screening in this study identified 318 early-stage lung cancers (2·6%), including 2.7% of the 318 cases with a family history of lung cancer and 1.6% without a family history [20]. A positive LDCT scan showed 92·1% sensitivity and 84·6% specificity, with the majority of cancers detected being adenocarcinomas and 77·4% being stage I disease [20]. Family history of lung cancer in a first-degree relative significantly increased the risk of lung cancer and rates of invasive lung cancer with increasing age [20]. Based on the findings from this study, since 2022, in Taiwan, non-smoking women aged between 45–74 years and men aged 50–74 years with a family history of lung cancer are offered biennial LDCT scans [20]. Following the findings of this trial, only Taiwan currently has a national lung cancer screening program for early detection using LDCT in high-risk individuals [20].

The global incidence and trends for lung cancer in non-smokers and never-smokers are difficult to determine because of inaccuracies in recording smoking history. However, Ge and colleagues recently published the findings from a retrospective population-based study using data from regional electronic health records (EHRs) in Eastern China between 2009 and 2020 [21]. These authors identified that from a total of 1,080,317 adults who had never smoked, there were 4,061 diagnoses of lung cancer [21]. In this population of never-smokers, between 2009 and 2020, the incidence of lung cancer in men showed an increasing annual trend (average annual percentage change) of 10.51% from 9.51 to 43.4 per 100,000 [21]. However, the incidence of lung cancer in women increased even more with an increasing annual trend (average annual percentage change) of 22.39% from 3.57 to 51.68 per 100,000 [21]. With improved diagnosis and treatments, the survival of never-smokers diagnosed with lung cancer improved for men from 39% in 2010 to 64% in 2018, and for women from 57% in 2009 to 86% in 2020 [21]. Mortality from lung cancer in never-smokers in Eastern China remained stable between 2014 and 2020 [21]. The increasing trend in lung cancer incidence was found across most age groups, except the elderly population of both genders (≥85 years) and in men aged 45–54 years [21]. This study also revealed that the increase was most evident in younger individuals aged <45 years, with younger men having an increasing annual trend (average annual percentage change) of 21.10% (from 3.57% to 41.60%), and younger women having an increasing annual trend (average annual percentage change) of 32.05% (from 23.73% to 40.92%) [21]. The standardized average age of onset/diagnosis of lung cancer in never-smokers decreased significantly over time in women but not men, and in men and women, the incidence of lung adenocarcinoma increased [21]. These significant recent trends within a population highlight the need for the identification of causative factors for the increasing incidence of lung cancer in never-smokers in the younger age group and in women, so that public health and preventive measures can be implemented but also support the need for lung cancer screening in never-smokers, younger age groups, and women.

In 2023, a national survey by the UK National Cancer Research Institute Lung Study Group (NCRI-LSG) found that lung cancer in never-smokers accounted for 15% of lung cancers diagnosed in the UK [22]. These findings identified lung cancer in never-smokers as the eighth most common cancer in the UK [22]. The NCRI-LSG in the UK identified knowledge gaps in awareness of this leading cancer type and four key themes for research and public health strategies, including raising awareness of lung cancer in never-smokers, risk assessment and early diagnosis, increased research on the biology of this type of lung cancer, and improving patient outcomes [22].

Recently, Yang and colleagues investigated 997 patients in the US diagnosed with lung cancer from 2018 to 2023 and identified that only 35.1% met the USPSTF screening criteria (age, 50–80 years; ≥20 pack-years; current smoker or quit smoking for <15 years) [23]. They found that the current USPSTF guideline criteria excluded two-thirds of patients, with a disproportionate number of women and never-smokers [23]. These investigators identified that expanding the criteria to universal age-based screening (40–85 years) could detect 93.9% of lung cancers [23]. Yang and colleagues also suggested that current screening guidelines do not identify most patients with lung cancer, and that age-based screening could improve cost-effectiveness and detection of lung cancer without missing diagnoses in women and never-smokers [23].

Conclusions

The recent increase in awareness of lung cancer in non-smokers and never-smokers is now challenging existing prevention and screening programs by highlighting gaps in identifying cancer risk, adapting current smoking-focused guidelines to include a broader patient population, and necessitating the development of new risk models for lung cancer. Although screening with LDCT lung imaging of high-risk individuals with a smoking history reduces lung cancer mortality, current screening guidelines and the screening eligibility criteria may miss at least 50% of lung cancers [24]. Although studies and clinical trials have shown the benefits of lung cancer screening for smokers, these studies and trials have excluded non-smokers and never-smokers [16,17,22]. Because some known risk factors may predict lung cancer risk in non-smokers, it is still unclear how this population may be stratified according to risk and whether screening with LDCT imaging could be more widely available. Similar considerations could also be given to current and ex-smokers who do not fulfil the current screening inclusion criteria but are at increased risk for lung cancer.