Lung cancer is the leading cause of cancer death worldwide, causing about 1.8 million deaths per year.1 In Ireland, approximately 2,700 people are diagnosed with lung cancer every year.2 Exposure to tobacco smoke is the main aetiologic factor responsible for lung cancer, accounting for approximately two-thirds of cases worldwide and its importance is demonstrated by the decline in lung cancer incidence and mortality that has accompanied the decline in smoking.3-5Despite the preponderance of tobacco smoking as its predominant aetiology, lung cancer is also a health problem in those with no history of smoking, accounting for between 10-20% of cases5,6 and despite the general reduction in lung cancer rates, the rate of lung cancer in non-smokers has been noted to be increasing.5
The term “never smoker” refers to individuals who have smoked less than 100 cigarettes in their lifetime. The majority of lung cancers in non-smokers occur in Non-Small Cell Lung Cancers (NSCLC) and particularly in lung adenocarcinoma.6 A much smaller subset of lung tumours (2%) called carcinoid tumours also show no major relationship to previous smoking history.6 With advances in the understanding of the molecular biology of cancer, substantial differences have been found in the genetic and molecular characteristics of lung cancer in smokers versus non-smokers including clinically significant treatment differences and prognostic outcomes. Several studies have suggested that lung cancer in non-smokers is different enough from a biologic and epidemiologic perspective to be looked at as almost a completely different entity.7-10
Worldwide, 10–20% of patients with lung cancer are non-smokers.11 There are major geographic and gender differences, particularly in Asia, where 60-80% of women with the disease are never smokers.12 Despite non-smoking women more frequently being diagnosed with lung cancer than nonsmoking men, they do have an overall decreased mortality when compared to men. In two American Cancer Society cancer prevention study cohorts, it showed agestandardised lung cancer mortality rates of 12 per 100,000 for never smoking men and 9.5 per 100,000 for never smoking women of European ancestry. In Asian populations, the rates were 26 and 16.1 per 100,000 for men and women, respectively.13
Lung cancer in non-smokers had classically been considered to occur at a younger age most likely due to the development of specific somatic mutations that drive malignancy. However, several studies have shown that increasing age is also a common predisposing factor. The increased risk with age is felt to be due to the longer duration of exposure to potential carcinogenic agents.14
The causative factors for lung cancer in never smokers are generally not well understood but several separate genetic and environmental factors are believed to contribute to lung cancer carcinogenesis which we discuss in the following sections
Second-hand smoke is an important risk factor for lung cancer amongst never smokers. Several studies suggest that approximately 15-35% of lung cancer among never smokers is due to second-hand smoke and that risk may be increased in those with exposure prior to age 25.15,16 Analysis from a case-control study in Europe of 520,000 people estimated that the proportion of lung cancer related to secondhand smoke was 16 to 24 percent in non-smokers. In the European Prospective Investigation into Cancer and Nutrition study evaluating the risk of cancer in nearly 500,000 people, the risk of lung cancer in never smokers was significantly elevated in those with second-hand smoke exposure.17 A meta- analysis from 55 international studies showed specifically that spousal smoking increased the risk of lung cancer in a never smoking spouse.18
Radon is a gaseous decay product of uranium-238 and radium-226 and is capable of damaging respiratory epithelium through the emission of alpha particles. Radon is present in soil, rock, and groundwater, and it can accumulate in homes.
Radon is classified as a Group 1 carcinogen and exposure to radon gas is thought to be the second most important cause of lung cancer worldwide after smoking.19 Internationally, the proportion of lung cancer cases estimated to be attributable to radon ranges from 3-14% depending on the average radon concentration in the country.20
This is of particular importance in Ireland, as Ireland has previously been estimated to have the eighth highest level of indoor radon concentrations amongst OECD countries and radon is estimated to cause approximately 350 cases of lung cancer in Ireland each year.21
A 2018 paper published in the Journal of Environmental Radioactivity showed that, in Ireland, those living in areas where 10%-20% of households are above the national reference level for radon exposure are about three times more likely to report a lung cancer diagnosis than those who live in areas with fewer than 1% of households above the national reference level. The most notable examination of radoninduced lung cancer within an Irish context resulted from two cases of lung cancer in non-smokers which prompted the discovery of a household with levels of indoor radon 250 times higher than the national reference level.22
Outdoor air pollution is also associated with lung cancer risk. Using mean long-term ambient fine particulate matter (PM2.5) as a measure of air pollution, in the Cancer Prevention Study-II, there was a 15-27% increase in lung cancer mortality in never smokers for each 10 mcg/m3 increase in PM2.5 concentrations. In 2019, approximately 300,000 lung cancer deaths worldwide were attributed to PM2.5 exposure.23
Data from a breakthrough study in understanding how air pollution can lead to lung cancer, presented at the European Society of Medical Oncology congress in September 2022 conducted by researchers at the Francis Crick Institute and University College London showed a positive correlation with higher rates of EGFR-mutant lung cancer and other types of cancer found in areas with higher concentrations of PM2.5. The researchers hypothesised that, when inhaled, PM2.5 particles trigger an alarm response in the lungs, causing the inflammation and activation of dormant cells carrying cancer-causing mutations. Mice with EGFR-mutant cells were exposed to air pollution concentrations normally found in cities, and found that the exposed animals were more likely to develop lung cancer than nonexposed mice. The discovery is of global impact because 99% of the world’s population currently live in areas that exceed WHOs annual limit for PM2.5.24
Other environmental factors
Other occupational exposures are known to increase lung cancer risk.
Commonly associated toxins include asbestos, chromium, and arsenic. In a French study of 1493 cases, some occupational exposure was identified in 9.4 percent of women and 48.6 percent of men who developed lung cancer as never smokers 25Arsenic has connected with an increased risk of lung cancer where it contaminates drinking water, such as in some areas of Taiwan and Chile.26 Asbestos exposure alone leads to a six-fold increase in relative risk of developing lung cancer, while asbestos exposure and smoking leads to a 59-fold increase.27Various dietary factors have been studied as possible causes of lung cancer. Higher intake of fruits and vegetables may be protective against lung cancer. One study from Italy showed a link between higher consumption of red meat and an increased risk for the development of lung cancer in never smokers28, and another report indicated that higher consumption of fish may protect against lung cancer in never smokers.29Indoor air pollutants such as fumes from cooking oil and the smoke from burning coal have been linked to lung cancer, particularly in Asia.30,31
The role of oestrogens and other female hormones in lung cancer risk in women is uncertain, regardless of smoking status.33 Multiple studies have shown that the majority of NSCLCs express the oestrogen receptor beta and that the expression of this receptor is more common in never smokers compared with smokers. Other studies have looked at the relationship of lung cancer incidence to early menopause use of hormone therapy, age at first birth, number of children, and use of tamoxifen. However, the results have been inconsistent in establishing a relationship. Data from the randomized WHI trial indicated that women assigned to postmenopausal oestrogen and progesterone had a higher risk of death from lung cancer without a higher incidence of the disease compared with women assigned to placebo . However, women randomised to oestrogen alone had no such increase in lung cancer mortality, nor in lung cancer incidence, compared with those on placebo.34 Further studies are required to establish the role, if any that oestrogen may play in lung cancer development and the effect that anti oestrogen therapies may have on treatment.
The risk of lung cancer among never smokers is increased in those with prior damage to the lungs from underlying pulmonary disease or exposure to radiation or chemotherapy. The extent of this risk is unclear because the vast majority of pulmonary disease is related to smoking. In idiopathic pulmonary fibrosis, an association does seem to be supported by the majority of studies, one study from Li et al in 2014 showed the prevalence rates of lung cancer in patients with IPF (4.8% to 48%) are much higher than patients without IPF (2.0% to 6.4%).35
A 2008 paper by Yang et al. showed that alpha-1-antitrypsin carriers are at a 70–100% increased risk of lung cancer, particularly adenocarcinoma and squamous cell subtypes, depending on smoking intensity, smokers were noted to have a 2–9-fold higher risk of lung cancer than never smokers.36With regards to non-cystic fibrosis bronchiectasis a population based cohort study published in September 2022 showed that the incidence of lung cancer in participants with bronchiectasis was significantly higher regardless of smoking status.37
Adenocarcinoma is more common in never smokers as well as in light smokers and former smokers while squamous cell carcinoma and small cell lung cancer are seen with a higher frequency in heavy smokers.9,12 In a review of published reports on the histology of lung cancer that included smoking data, adenocarcinoma was more common than squamous cell carcinoma among nonsmokers (62% versus 18%, based upon 5144 cases). By contrast, adenocarcinoma was less frequent among smokers (19% versus 53% in 21,853 cases).11,38,39
Genetic factors and Molecular biology
Multiple studies have shown an association between lung cancer in never smokers and a family history of lung cancer, suggesting a significant role for genetic factors.
In a case-control study of 257 cases of lung cancer among never smokers and an equivalent number of control never smokers, lung cancer was significantly more common among those with a positive family history.40
In another case-control study that included over 2400 relatives of 316 never smoker lung cancer cases, there was a 25 percent excess risk of any type of cancer among first-degree relatives of cases, this study also showed an increased risk of early-onset lung cancer (<50 years) among those relatives who smoked. While this study does not directly link a history of lung cancer in non-smokers to future generations developing lung cancer, it does show the importance of genetic factors leading to the development of cancer as well as the risk involved when genetically susceptible individuals partake in smoking.41
Contemporary advances in the understanding of the molecular biology of lung cancer have led to the identification of substantial genetic differences between lung cancer in smokers versus never smokers. These factors are arguably more important than any clinical differences. These genetic changes generally occur in genes that when mutated, fundamentally alter the activity of the cell to promote uncontrolled growth and division and are referred to as driver mutations. While these mutations also occur in smokers, the rate at which they occur in non-smokers is proportionally much higher and particularly in adenocarcinoma where prevalence of clinically actionable driver alterations in never smokers can be as high as 92% in certain populations.42,43
Epidermal Growth Factor receptor (EGFR) mutations
EGFR is a cell surface tyrosine kinase that regulates intracellular signalling pathways to control cellular proliferation. Specific mutations in genes encoding for EGFR (Del19/Exon 21 L858R) results in constitutive or sustained activation of these signalling pathways resulting in aggressive tumour phenotypes. EGFR mutations occur in about 15% of the general population with advanced lung Adenocarcinoma. However in non-smoking patients this rate increases to 30% or more. Furthermore the rates of EGFR positivity increase further in women and in patients from Asian populations where mutations can occur in 60% or more of cases in non-smokers.3,44 Importantly, significantly improved treatment response rates are seen in patients with EGFR mutations who are treated with tyrosine kinase inhibitors (TKIs). Higher response rates and better survival have been reported in never smokers with these drugs compared with current or former smokers.43
Anaplastic Lymphoma Kinase (ALK) gene mutations
The ALK gene also encodes a transmembrane tyrosine kinase that plays an important role in normal cell regulation activities in its normal state. In ALK-activated NSCLC, a rearrangement occurs with another gene ( EML4) to create an activated driver mutation that fuels unrestricted cell growth and division. ALK-rearranged NSCLC comprises 2% to 5% of all NSCLC cases but similarly to EGFR occurs in significantly higher numbers in light and never smokers which account for 70-80% of cases.45 Specific TKI inhibition in ALK positive patients also results in demonstrably better response rates compared to traditional platinum based therapies.45
V-Raf murine sarcoma viral oncogene homolog (BRAF) Mutation/Human epidermal growth factor receptor 2 (HER2)/c-ros oncogene (ROS 1)
There are a number of other cell surface Tyrosine Kinase mutations that can drive malignancy in NSCLC and specifically in nonsmokers. BRAF, HER 2 and ROS 1 are all surface tyrosine kinases that act as driver mutations in 1-2% of lung adenocarcinoma cases and all occur significantly more often in patients who are nonsmokers.46-48 As such, testing for these specific mutations through immunohistochemistry analysis or Next Generation Sequencing (NGS) is increasingly mandated in advanced lung Adenocarcinoma in non-smokers.41-43 Furthermore, even broader testing for a wider spectrum of mutations should be considered through NGS in non-smoking patients if initial molecular profiling is negative as the proportion who will have a potentially targetable mutation is much higher than in smoking populations with advanced NSCLC and show good response rates.43
Non-smokers are defined as those who have smoked less than 100-lifetime cigarettes. Lung cancer in non-smokers almost exclusively occurs NSCLC or Carcinoid tumours and is more likely to occur in women with adenocarcinoma being the most common type. Although the aetiology for lung cancer among never smokers is not always clear, risk factors include secondhand tobacco smoke, radon gas exposure, other environmental exposures and genetic factors. There are important differences at the molecular level between lung cancers arising in never smokers and those in smokers. The best understood of these are the abnormalities in Tyrosine Kinase pathways that occur much more frequently in patients who have never smoked. These include mutations in EGFR, ALK fusion oncogene, HER-2, BRAF, ROS-1 and other mutations for which targeted therapies offer potentially improved treatment response and survival rates. From a public health perspective It is important that patients are aware that lung cancer is a disease that does not exclusively affect current or former smokers and that any patient with persistent troubling chest symptoms should seek medical advice and further testing if required.
Dr Dan Ryan
Dr Sile Toland
References available on request
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