research on lung cancer and smoking

What Are the Risk Factors for Lung Cancer?

Research has found several risk factors that may increase your chances of getting lung cancer.

This animated infographic shows the positive changes the body experiences over time after quitting smoking.

Cigarette smoking is the number one risk factor for lung cancer. In the United States, cigarette smoking is linked to about 80% to 90% of lung cancer deaths. Using other tobacco products such as cigars or pipes also increases the risk for lung cancer. Tobacco smoke is a toxic mix of more than 7,000 chemicals. Many are poisons. At least 70 are known to cause cancer in people or animals.

People who smoke cigarettes are 15 to 30 times more likely to get lung cancer or die from lung cancer than people who do not smoke. Even smoking a few cigarettes a day or smoking occasionally increases the risk of lung cancer. The more years a person smokes and the more cigarettes smoked each day, the more risk goes up.

People who quit smoking have a lower risk of lung cancer than if they had continued to smoke, but their risk is higher than the risk for people who never smoked. Quitting smoking at any age can lower the risk of lung cancer.

Cigarette smoking can cause cancer almost anywhere in the body. Cigarette smoking causes cancer of the mouth and throat, esophagus, stomach, colon, rectum, liver, pancreas, voicebox (larynx), lung, trachea, bronchus, kidney and renal pelvis, urinary bladder, and cervix, and causes acute myeloid leukemia.

Secondhand Smoke

Smoke from other people’s cigarettes, pipes, or cigars ( secondhand smoke ) also causes lung cancer. In the United States, one out of four people who don’t smoke, including 14 million children, were exposed to secondhand smoke during 2013 to 2014.

This video explains what radon is, how it can enter your home and cause lung cancer, and how to fix a radon problem if needed.

After smoking, radon is the second leading cause of lung cancer in the United States. Radon is a naturally occurring gas that forms in rocks, soil, and water. It cannot be seen, tasted, or smelled. When radon gets into homes or buildings through cracks or holes, it can get trapped and build up in the air inside. People who live or work in these homes and buildings breathe in high radon levels. Over long periods of time, radon can cause lung cancer.

The U.S. Environmental Protection Agency (EPA) estimates that radon causes about 21,000 lung cancer deaths each year. The risk of lung cancer from radon exposure is higher for people who smoke than for people who don’t smoke. However, the EPA estimates that more than 10% of radon-related lung cancer deaths occur among people who have never smoked cigarettes. Nearly one out of every 15 homes in the United States has high radon levels. Learn how to test your home for radon and reduce the radon level if it is high.

Other Substances

Examples of substances found at some workplaces that increase risk include asbestos, arsenic, diesel exhaust, and some forms of silica and chromium. For many of these substances, the risk of getting lung cancer is even higher for those who smoke. Living in areas with higher levels of air pollution may increase the risk of getting lung cancer.

Personal or Family History of Lung Cancer

If you are a lung cancer survivor, there is a risk that you may develop another lung cancer, especially if you smoke. Your risk of lung cancer may be higher if your parents, brothers or sisters, or children have had lung cancer. This could be true because they also smoke, they live or work in the same place where they are exposed to radon and other substances that can cause lung cancer, or because of an inherited genetic mutation.

Radiation Therapy to the Chest

Cancer survivors who had radiation therapy to the chest are at higher risk of lung cancer.

Scientists are studying many different foods and dietary supplements to see whether they change the risk of getting lung cancer. There is much we still need to know. We do know that people who smoke and take beta-carotene supplements have increased risk of lung cancer. For more information, visit Lung Cancer Prevention.

Also, arsenic and radon in drinking water (primarily from private wells ) can increase the risk of lung cancer.

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Lung cancer begins in the cells of your lungs.

Lung cancer is a type of cancer that begins in the lungs. Your lungs are two spongy organs in your chest that take in oxygen when you inhale and release carbon dioxide when you exhale.

Lung cancer is the leading cause of cancer deaths worldwide.

People who smoke have the greatest risk of lung cancer, though lung cancer can also occur in people who have never smoked. The risk of lung cancer increases with the length of time and number of cigarettes you've smoked. If you quit smoking, even after smoking for many years, you can significantly reduce your chances of developing lung cancer.

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Lung cancer typically doesn't cause signs and symptoms in its earliest stages. Signs and symptoms of lung cancer typically occur when the disease is advanced.

Signs and symptoms of lung cancer may include:

• A new cough that doesn't go away
• Coughing up blood, even a small amount
• Shortness of breath
• Losing weight without trying

When to see a doctor

Make an appointment with your doctor if you have any persistent signs or symptoms that worry you.

If you smoke and have been unable to quit, make an appointment with your doctor. Your doctor can recommend strategies for quitting smoking, such as counseling, medications and nicotine replacement products.

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Smoking causes the majority of lung cancers — both in smokers and in people exposed to secondhand smoke. But lung cancer also occurs in people who never smoked and in those who never had prolonged exposure to secondhand smoke. In these cases, there may be no clear cause of lung cancer.

How smoking causes lung cancer

Doctors believe smoking causes lung cancer by damaging the cells that line the lungs. When you inhale cigarette smoke, which is full of cancer-causing substances (carcinogens), changes in the lung tissue begin almost immediately.

At first your body may be able to repair this damage. But with each repeated exposure, normal cells that line your lungs are increasingly damaged. Over time, the damage causes cells to act abnormally and eventually cancer may develop.

Types of lung cancer

Doctors divide lung cancer into two major types based on the appearance of lung cancer cells under the microscope. Your doctor makes treatment decisions based on which major type of lung cancer you have.

The two general types of lung cancer include:

• Small cell lung cancer. Small cell lung cancer occurs almost exclusively in heavy smokers and is less common than non-small cell lung cancer.
• Non-small cell lung cancer. Non-small cell lung cancer is an umbrella term for several types of lung cancers. Non-small cell lung cancers include squamous cell carcinoma, adenocarcinoma and large cell carcinoma.

Risk factors

A number of factors may increase your risk of lung cancer. Some risk factors can be controlled, for instance, by quitting smoking. And other factors can't be controlled, such as your family history.

Risk factors for lung cancer include:

• Smoking. Your risk of lung cancer increases with the number of cigarettes you smoke each day and the number of years you have smoked. Quitting at any age can significantly lower your risk of developing lung cancer.
• Exposure to secondhand smoke. Even if you don't smoke, your risk of lung cancer increases if you're exposed to secondhand smoke.
• Previous radiation therapy. If you've undergone radiation therapy to the chest for another type of cancer, you may have an increased risk of developing lung cancer.
• Exposure to radon gas. Radon is produced by the natural breakdown of uranium in soil, rock and water that eventually becomes part of the air you breathe. Unsafe levels of radon can accumulate in any building, including homes.
• Exposure to asbestos and other carcinogens. Workplace exposure to asbestos and other substances known to cause cancer — such as arsenic, chromium and nickel — can increase your risk of developing lung cancer, especially if you're a smoker.
• Family history of lung cancer. People with a parent, sibling or child with lung cancer have an increased risk of the disease.

Complications

Lung cancer can cause complications, such as:

• Shortness of breath. People with lung cancer can experience shortness of breath if cancer grows to block the major airways. Lung cancer can also cause fluid to accumulate around the lungs, making it harder for the affected lung to expand fully when you inhale.
• Coughing up blood. Lung cancer can cause bleeding in the airway, which can cause you to cough up blood (hemoptysis). Sometimes bleeding can become severe. Treatments are available to control bleeding.
• Pain. Advanced lung cancer that spreads to the lining of a lung or to another area of the body, such as a bone, can cause pain. Tell your doctor if you experience pain, as many treatments are available to control pain.

Fluid in the chest (pleural effusion). Lung cancer can cause fluid to accumulate in the space that surrounds the affected lung in the chest cavity (pleural space).

Fluid accumulating in the chest can cause shortness of breath. Treatments are available to drain the fluid from your chest and reduce the risk that pleural effusion will occur again.

Cancer that spreads to other parts of the body (metastasis). Lung cancer often spreads (metastasizes) to other parts of the body, such as the brain and the bones.

Cancer that spreads can cause pain, nausea, headaches, or other signs and symptoms depending on what organ is affected. Once lung cancer has spread beyond the lungs, it's generally not curable. Treatments are available to decrease signs and symptoms and to help you live longer.

There's no sure way to prevent lung cancer, but you can reduce your risk if you:

• Don't smoke. If you've never smoked, don't start. Talk to your children about not smoking so that they can understand how to avoid this major risk factor for lung cancer. Begin conversations about the dangers of smoking with your children early so that they know how to react to peer pressure.
• Stop smoking. Stop smoking now. Quitting reduces your risk of lung cancer, even if you've smoked for years. Talk to your doctor about strategies and stop-smoking aids that can help you quit. Options include nicotine replacement products, medications and support groups.
• Avoid secondhand smoke. If you live or work with a smoker, urge him or her to quit. At the very least, ask him or her to smoke outside. Avoid areas where people smoke, such as bars and restaurants, and seek out smoke-free options.
• Test your home for radon. Have the radon levels in your home checked, especially if you live in an area where radon is known to be a problem. High radon levels can be remedied to make your home safer. For information on radon testing, contact your local department of public health or a local chapter of the American Lung Association.
• Avoid carcinogens at work. Take precautions to protect yourself from exposure to toxic chemicals at work. Follow your employer's precautions. For instance, if you're given a face mask for protection, always wear it. Ask your doctor what more you can do to protect yourself at work. Your risk of lung damage from workplace carcinogens increases if you smoke.
• Eat a diet full of fruits and vegetables. Choose a healthy diet with a variety of fruits and vegetables. Food sources of vitamins and nutrients are best. Avoid taking large doses of vitamins in pill form, as they may be harmful. For instance, researchers hoping to reduce the risk of lung cancer in heavy smokers gave them beta carotene supplements. Results showed the supplements actually increased the risk of cancer in smokers.
• Exercise most days of the week. If you don't exercise regularly, start out slowly. Try to exercise most days of the week.

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• Non-small cell lung cancer. National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed Jan. 13, 2020.
• AskMayoExpert. Non-small cell lung cancer (adult). Mayo Clinic; 2019.
• Small cell lung cancer. National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed Jan. 13, 2020.
• Niederhuber JE, et al., eds. Cancer of the lung: Non-small cell lung cancer and small cell lung cancer. In: Abeloff's Clinical Oncology. 6th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Jan. 13, 2020.
• AskMayoExpert. Small cell lung cancer (adult). Mayo Clinic; 2018.
• Lung cancer prevention (PDQ). National Cancer Institute. https://www.cancer.gov/types/lung/patient/lung-prevention-pdq. Accessed March 14, 2020.
• Lung cancer — non-small cell: Screening. American Society of Clinical Oncology. https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/screening. Accessed March 14, 2020.
• Detterbeck FC, et al. Diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013; doi:10.1378/chest.12-2377.
• Amin MB, et al., eds. Lung. In: AJCC Cancer Staging Manual. 8th ed. Springer; 2017.
• Leventakos K, et al. Advances in the treatment of non-small cell lung cancer: Focus on nivolumab, pembrolizumab and atezolizumab. BioDrugs. 2016; doi:10.1007/s40259-016-0187-0.
• Warner KJ. Allscripts EPSi. Mayo Clinic. Jan. 13, 2020.
• Cairns LM. Managing breathlessness in patients with lung cancer. Nursing Standard. 2012; doi:10.7748/ns2012.11.27.13.44.c9450.
• Cancer. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed March 14, 2020.
• Temel JS, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. New England Journal of Medicine. 2010; doi:10.1056/NEJMoa1000678.
• Dong H, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine. 1999;5:1365.
• Searching for cancer centers. American College of Surgeons. https://www.facs.org/search/cancer-programs. Accessed March 14, 2020.
• Dunning J, et al. Microlobectomy: A novel form of endoscopic lobectomy. Innovations. 2017; doi:10.1097/IMI.0000000000000394.
• Aberle DR, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. New England Journal of Medicine. 2011; doi:10.1056/NEJMoa1102873.
• Brown AY. Allscripts EPSi. Mayo Clinic. July 30, 2019.
• Wang S, et al. Current diagnosis and management of small-cell lung cancer. Mayo Clinic Proceedings. 2019; doi:10.1016/j.mayocp.2019.01.034.
• Antonia SJ, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. New England Journal of Medicine. 2017; doi:10.1056/NEJMoa1709937.
• Lorigan P, et al. Lung cancer after treatment for Hodgkin's lymphoma: A systematic review. Lancet Oncology. 2005; doi:10.1016/S1470-2045(05)70387-9.
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• Open access
• Published: 22 February 2022

Association of smoking and polygenic risk with the incidence of lung cancer: a prospective cohort study

• Peidong Zhang 1 , 2   na1 ,
• Pei-Liang Chen 1   na1 ,
• Zhi-Hao Li 1 ,
• Ao Zhang 3 ,
• Xi-Ru Zhang 1 ,
• Yu-Jie Zhang 1 ,
• Dan Liu 1 &
• Chen Mao   ORCID: orcid.org/0000-0002-6537-6215 1 , 4  

British Journal of Cancer volume  126 ,  pages 1637–1646 ( 2022 ) Cite this article

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• Lung cancer
• Risk factors

Genetic variation increases the risk of lung cancer, but the extent to which smoking amplifies this effect remains unknown. Therefore, we aimed to investigate the risk of lung cancer in people with different genetic risks and smoking habits.

This prospective cohort study included 345,794 European ancestry participants from the UK Biobank and followed up for 7.2 [6.5–7.8] years.

Overall, 26.2% of the participants were former smokers, and 9.8% were current smokers. During follow-up, 1687 (0.49%) participants developed lung cancer. High genetic risk and smoking were independently associated with an increased risk of incident lung cancer. Compared with never-smokers, HR per standard deviation of the PRS increase was 1.16 (95% CI, 1.11–1.22), and HR of heavy smokers (≥40 pack-years) was 17.89 (95% CI, 15.31–20.91). There were no significant interactions between the PRS and the smoking status or pack-years. Population-attributable fraction analysis showed that smoking cessation might prevent 76.4% of new lung cancers.

Conclusions

Both high genetic risk and smoking were independently associated with higher lung cancer risk, but the increased risk of smoking was much more significant than heredity. The combination of traditional risk factors and additional PRS provides realistic application prospects for precise prevention.

Lung cancer is the most commonly diagnosed cancer and has the highest mortality worldwide among the general population and males, and it has the second leading mortality and the third incidence among females. In 2018, there were more than 2 million new cases and 1.7 million deaths from lung cancer [ 1 ]. Tobacco exposure is the leading cause of lung cancer, despite differences in the intensity of smoking and the type of cigarettes, and ~90% of lung cancers are attributed to smoking [ 2 ]. In addition, genetic factors also play essential roles in cancer development. Twin studies [ 3 ] and heritability estimation based on genome-wide association studies (GWASs) [ 4 , 5 ] indicated that genetic factors contribute far less to incident lung cancer than environmental factors, including smoking. However, population-based prospective studies of smoking and genetic risk in lung cancer have not been fully validated.

Over the past decade, GWASs have identified multiple susceptibility loci associated with lung cancer risk, including TP63 , TERT , CDKN2A/B and CHRNA3/5 [ 6 , 7 , 8 , 9 ]. However, while consistently and significantly associated with the lung cancer risk, each common variant’s impact is modest. Aggregating multiple single-nucleotide polymorphisms (SNPs) with tiny functions to generate a composite polygenic risk score (PRS) may explain the genetic risk of complex diseases [ 10 ]. In addition, multiple genes, including CHRNA3/5 , were strongly associated with lung cancer, smoking behaviours [ 11 ], and nicotine addiction [ 12 ]. Although previous studies have reported a significant association with lung cancer based on case-control designs [ 13 , 14 ], the relevance of combining these risk scores and smoking for individual subjects and whether smoking and genetic risk have a synergistic effect remains uncertain. Therefore, we hypothesised that smoking and genetic risk are independently associated with incident lung cancer.

This study’s primary purpose was to investigate whether there are differences in the association between smoking and new-onset lung cancer among individuals with low, intermediate or high genetic risk in a large population-based cohort. The second aim was to investigate the possible interaction between genetic risk and smoking for incident lung cancer.

Study design

The UK Biobank study started in 2006 and, until 2010, recruited >500,000 participants aged 40–69 years from the general population at 22 assessment centres throughout the UK [ 15 ]. Participants provided information on smoking and other potentially health-related aspects through extensive baseline questionnaires, verbal interviews and physical measurements. Moreover, blood samples were collected for genotyping.

Participants were excluded if they withdrew from the study ( n  = 1298), their genotype data does not meet the quality control conditions, related to another one more than second-degree, or were non-European ancestry ( n  = 44,072). Besides, participants with missing data on smoking or covariates were excluded ( n  = 75,546). Participants with a history of cancer at baseline were also excluded ( n  = 35,814).

Polygenic risk score

Polygenic risk scores were created following an additive model for previously published common genetic variants associated with lung cancer. To identify relevant risk loci, we began by searching the NHGRI-EBI GWAS Catalog of published GWAS [ 16 ]. Then, we reviewed both the original manuscript and supplementary materials to identify SNPs, risk alleles, and effect sizes. SNPs were selected for each locus according to the criteria of independent ( r 2  < 0.1), common (minor allele frequencies [MAF] > 0.01 in 1000 Genomes Project European population), UK Biobank available, large sample size in the development cohort, and smallest P value. The number of risk alleles (0, 1 or 2) for everyone was summed after multiplication with the effect size between the SNPs and each trait. A total of 33 SNPs from eight studies were used (eTable  1 in the Supplement) [ 8 , 9 , 17 , 18 , 19 , 20 , 21 , 22 ]. This polygenic risk score was then z-standardised based on values for all individuals and categorised into low (lowest quintile), intermediate (quintiles 2–4) and high (highest quintile) risk.

Smoking status and pack-years

Touchscreen questionnaires collected information on smoking status and pack-years at baseline. Detailed definitions of smoking status and the pack-years of smoking were provided in eTable  2 in the Supplement. All participants were categorised as never, former or current smoking according to their smoking status, and as no (0), light (0.1–19.9), intermediate (20–39.9), or heavy (≥40) smoking according to the pack-years of smoking.

Participants with incident lung cancer were identified as having a diagnosis in national cancer registries after baseline assessment. Diagnoses were recorded using the International Classification of Diseases-9 (ICD-9) and ICD-10 coding system (eTable  3 in Supplement). Death was ascertained via linkage to death registries. We calculated the follow-up time from the date of attendance to the date of first diagnosis, date of death, March 31, 2016 for Wales and England, and October 31, 2015 for Scotland, whichever occurred first.

All models were adjusted for age, sex, education, socioeconomic status (household income and Townsend deprivation index [ 23 ]), body mass index (BMI), physical activity, diet, alcohol consumption, passive smoking, occupational exposure, the relatedness of individuals in the sample and first 20 principal components of ancestry. Body mass index (BMI) (kg/m 2 ) was calculated for all UK Biobank participants based on their measured weight and height. Duration and intensity of physical activity were ascertained by touchscreen questionnaires based on the validated International Physical Activity Questionnaire [ 24 ]. A healthy diet was calculated based on the Dietary Approaches to Stop Hypertension (DASH) recommendation, associated with multiple cancer types [ 25 , 26 ]. Alcohol consumption was calculated based on US Dietary Guidelines for Americans 2015–2020 [ 27 ]. Exposure to tobacco smoke from others at home or outside for more than an hour per week was considered passive smoking. Occupational exposure is based on self-reported exposure to asbestos, paints, thinners, glues, pesticides, diesel exhaust, or other chemical smog at work.

Statistical analyses

Baseline characteristics of participants were summarised across incident lung cancer status as a percentage for categorical variables, mean (standard deviation [SD]) for normally distributed variables, and median (interquartile range) for skewed variables. The association between genetic-risk categories, smoking categories, and the combination of genetic and smoking categories (nine categories with low genetic risk and never-smoking as a reference, 12 categories with low genetic risk and no smoking pack-years as a reference) and incident lung cancer were explored using multivariable Cox proportional hazard models. The assumption for proportional hazards was evaluated by tests based on Schoenfeld residuals [ 28 ]; violation of this assumption was not observed in our analyses. The area under the curve (AUC) of receiver operating characteristic (ROC) curves was used to assess each model’s predictive ability, including PRS, smoking, and the combination. The associations between PRS and incident lung cancer were evaluated on a continuous scale with restricted cubic spline curves based on multivariable Cox proportional hazards models. Moreover, interactions between polygenic risk scores and smoking status or pack-years were tested. The population-attributable fractions (PAFs), which estimate the proportion of events that would have been prevented if all individuals had been in the never-smoking category, were calculated [ 29 ]. The distribution of smoking status in the Health Survey for England (HSE) [ 30 ] and European Prospective Investigation into Cancer and Nutrition (EPIC) [ 31 ] with better representation to England and the European population were included in the analysis to deal with the incomplete representation of the UK Biobank [ 32 ].

Several sensitivity analyses were conducted to verify the robustness of the results. The risk of incident lung cancer was analysed using genetic-risk quintiles and pack-years of smoking in more subdivided groups. The association was also adjusted for self-reported and hospital diagnosed chronic obstructive pulmonary disease (COPD) and chronic pulmonary infections (definitions in eTable 3) at baseline, which may be important confounding factors [ 33 , 34 ]. The sensitivity analysis excluded participants who had third-degree or higher relatedness to further reduce non-random distribution of risk genes, developed outcomes within the first two years of follow-up to avoid reverse causality, and had a mismatch between calculation and self-reported never-smoking. Moreover, stratified analyses were performed to estimate potential modification effects according to sex (female or male), age (<60 or ≥60 years). Analyses were undertaken using R v3.6.1 (R Center for Statistical Computing, Vienna, Austria). P value < 0.05 (two-sided) was considered significant.

Participants characteristics

A total of 345,794 European individuals with a complete genotype and phenotype were included in the analysis of incident lung cancer, and their detailed information is shown in Fig.  1 . Their mean (SD) age was 56.3 (8.0) years, and 186,330 (53.9%) were female. The PRS was normally distributed among all participants (eFigure  1 in Supplement). There were 90,727 (26.2%) former smokers and 33,994 (9.8%) current smokers, among which 40,889 (11.8%) individuals had intermediate smoking exposure (20–39.9 pack-years) and 19,027 (5.5%) individuals had heavy smoking exposure (≥40 pack-years). The participant characteristics are provided in Table  1 .

BMI body mass index, TDI Townsend deprivation index.

Over 2,454,915 person-years of follow-up (median [interquartile range] length of follow-up, 7.2 [6.5–7.8] years), there were 1687 cases of incident lung cancer. Participants who developed incident lung cancer were slightly older, more likely to be male, had more smoking exposure, had less physical activity, and had an unhealthy diet. Meanwhile, they also had higher genetic risks.

Associations of genetic risk with incident lung cancer

With the increase in genetic risk, the incidence rate and hazard ratio (HR) of lung cancer gradually increased. After additional adjustment for smoking status or pack-years, the HRs of the high genetic-risk group were 1.73 (95% confidence interval [CI], 1.48–2.02) and 1.69 (95% CI, 1.44–1.97) compared with the low genetic-risk group, and the HRs per SD of PRS increase were 1.16 (95% CI, 1.11–1.22) and 1.16 (95% CI, 1.10–1.21). This result was almost the same as before the adjustment (Table  2 ). When genetic-risk quintiles were used instead of categories, the same results trend was observed (eTable  4 in Supplement). Figure  2a shows the cumulative risk of incident lung cancer in each genetic-risk group during follow-up.

Cumulative risk of incident lung cancer during follow-up according to genetic risk ( a ), smoking status ( b ) and smoking pack-years ( c ).

Associations of smoking with incident lung cancer

With the changing smoking status and increasing pack-years, the incidence and HR of lung cancer were also increased. After additional adjustment for PRS, the HRs of the current or heavy smoking group were 14.54 (95% CI, 12.47–16.94) and 17.80 (95% CI, 15.23–20.81), respectively, compared with the never-smoking group. This result was almost the same as before the adjustment (Table  3 ). When the number of smoking pack-years was given in more subdivided categories, the same trend of results was observed (eTable  5 in Supplement). Figure  2 b and c shows the cumulative risk of incident lung cancer in each smoking status and pack-year group during follow-up.

Associations of smoking and genetic risk with incident lung cancer

In each genetic-risk group, the incidence and HR of lung cancer increased with the smoking status deteriorating and pack-years increasing. Compared with the low genetic risk and never-smoking group, there was no significant difference of incident lung cancer risk in the high genetic risk but never-smoking group, while the HR of the low genetic risk but the current smoking group was 11.31 (95% CI, 7.84–16.33). A similar pattern was observed among genetic risk and smoking pack-year groups. The highest risks were observed among individuals with high genetic risk and current smoking (HR, 22.46 [95% CI, 15.99–31.53]) compared with low genetic risk and never-smoking. Individuals with high genetic risk and heavy smoking had a much higher risk of incident lung cancer (HR, 27.02 [95% CI, 19.28–37.88]) compared with those with low genetic risk and no smoking (Fig.  3 ). There was no significant interaction between the PRS and the smoking status or pack-years (both P for interaction > 0.05).

Risk of incident lung cancer according to genetic risk and smoking status ( a ) or genetic risk and smoking pack-years ( b ). The vertical line indicates the reference value of 1.

Further analyses stratified by genetic-risk category showed that the association between smoking and lung cancer appeared to increase with increasing genetic risk (Table  4 ). In the low, intermediate and high genetic-risk groups, the HRs of current smoking were 10.75 (95% CI, 7.28–15.88), 14.86 (95% CI, 12.22–18.07), and 16.85 (95% CI, 12.25–23.19), respectively, compared with never-smoking. Similarly, the HRs of heavy smoking were 16.22 (10.97–23.97), 17.06 (13.97–20.84) and 21.22 (15.34–29.35) compared with no smoking.

The same pattern of associations was observed in a series of sensitivity analyses with additional adjustment for COPD and chronic pulmonary infections, excluding participants who had third-degree or higher relatedness, excluding participants who developed outcomes within two years of baseline, and those who had a mismatch between calculation and self-reported never-smoking. (eTables  6 and 7 in the Supplement). Stratified analyses were performed by age and sex (eTables  8 and 9 in the Supplement), but the results were not markedly different among male and female or the <60 years and ≥60 years groups.

Population-attributable fractions

Since there was no significant interaction between PRS and smoking, the population-attributable fractions were calculated regardless of genetic risk. If all individuals had never smoked, 76.4% (95% CI, 73.4–79.2, based on smoking status) to 75.3% (95% CI, 72.0–78.2, based on smoking pack-years) new-onset lung cancer events might have been prevented during follow-up. If all current smokers quit smoking and the former smokers remained, the new-onset events might have been reduced by 26.4% (95% CI, 25.8–27.0). Further analyses stratified by genetic-risk category showed that 73.4% (95% CI, 64.5–80.4), 76.1% (95% CI, 72.2–79.6), and 79.1% (95% CI, 73.0–83.9) of incident lung cancer cases were attributed to smoking among the low, intermediate and high genetic-risk populations. When the smoking status proportional in HSE and EPIC were included, the PAFs of smoking were 83.2% (95% CI, 80.9–85.3) and 85.1% (95% CI, 83.1–87.0), respectively (eTable  10 in the Supplement).

In this large population-based prospective cohort study of more than 345,000 European individuals, high genetic risk and smoking status were independently associated with an increased risk of incident lung cancer events. Among never-smokers, there was no significant difference in the incident risk between each genetic group. The high genetic risk was two-fold higher than that of low genetic risk for current smokers. A similar pattern was observed for genetic risk and smoking pack-year groups. Meanwhile, there was no significant interaction between the PRS and smoking status or pack-years for incident lung cancer, and smoking cessation or reduction can provide similar protection against lung cancer regardless of genetic risk. The PAF analysis hypothesised that ~76% of new-onset lung cancer events might have been prevented if all individuals had never smoked.

To our knowledge, this study is by far the most extensive and fully adjusted prospective study of lung cancer incidence treating smoking as a single modifiable factor and incorporating multiple genetic-risk factors. Many common variants with minor effects have been identified as associated with a high risk of lung cancer, and the PRS can indicate their combined impact. Previous studies used 19 SNPs to construct a PRS for non-small cell lung cancer and showed predictive effects in a prospective study of 95,408 individuals [ 9 ]. Compared with this previous study, the present study included a larger sample size and more SNPs to increase the power for risk estimation. Meanwhile, we used the upper and lower quintiles to categorise the high and low genetic-risk groups [ 35 , 36 ], which may reduce the accuracy for the high genetic-risk group but warn a broader population that they need to carry out PRS-informed disease screening or life planning for life-threatening lung cancer. It also ensured that the comparison between the combined smoking and genetic-risk subgroups had sufficient statistical power.

Compared with another study based on the UK Biobank [ 37 ], the current PRS contains fewer highly independent SNPs in each locus to avoid overinflation of the GWAS summary results caused by many linkage disequilibrium SNPs. Therefore, this PRS may have better generalisations in other populations [ 38 ]. The current results showed similar HRs after adjusting for confounding factors (economic and social background, lifestyle factors, occupational exposure). Compared with case-control studies [ 39 , 40 ], prospective studies may lose some statistical power, but estimates of the absolute risk support using the PRS to predict incident lung cancer [ 10 , 41 ]. Regarding the role of PRS in never-smokers, our results suggest that their incident risk did not achieve statistical significance as the PRS group increased. Among never-smokers, the post hoc study powers for incident lung cancer in those with intermediate and high genetic risk were only 0.243–0.293. Therefore, we speculate that more outcome events may bring different results with the extension of follow-up time. To sum up, we believe that PRS could be a powerful tool for lung cancer risk assessment as it provides additional information independent of smoking and combining it with traditional risk factors could contribute to a better prediction of lung cancer.

We observed a strong association between smoking and incident lung cancer, independent of genetic risk, and the increased risk was much greater than the genetic risk. This means that smoking will significantly offset low genetic-risk benefits, consistent with a previous study [ 9 ]. However, we followed the same grouping method and found that the risk values were much more significant than those in a previous study (eTable  11 in the Supplement). Sample size, confounding factors, subtle differences in smoking habits, and outcome data sources may be the reasons for the differences. We observed similar associations between smoking and lung cancer with other relevant studies [ 42 , 43 ]. Based on a study of the contemporary population, although smoking, a long-recognised risk factor has undergone tremendous changes in production, composition and use method [ 44 ], it still plays a decisive role in lung cancer occurrence. Therefore, smoking cessation is still the most significant and cost-effective way to prevent lung cancer.

Previous studies believed that smoking was responsible for 80%~90% of lung cancer [ 2 , 43 , 45 ], and a study showed that 63.6% of lung cancer are attributable to comprehensive modifiable factors, including smoking and air pollution [ 37 ]. We found that the entire population would avoid 76.4% of lung cancer cases by becoming never-smokers. The slight reduction in this proportion is probably because of the reduction in smoking prevalence (23.3% of individuals were current smokers in The European Prospective Investigation into Cancer and Nutrition cohort [ 43 ]), manifesting the achievement of tobacco use control. In addition, differences in sample, methodology, and confounders’ representativeness also contribute to the different PAFs between studies. Furthermore, we also estimated the attribution of smoking by a more natural form of PAFs called the generalised impact fraction [ 46 ]. Our results showed that if all current smokers stop smoking and former smokers remain, the expected reduction in lung cancer cases would be 26%, again highlighting the efficiency of smoking cessation.

GWASs have shown that a locus may be simultaneously associated with smoking preference and lung cancer [ 12 , 47 , 48 ]. The interaction between smoking and genetic risk for lung cancer is a topic worth discussing, as it may help explain some of the missing heritability in lung cancer susceptibility [ 49 ]. Variants at the 15q25 locus have been confirmed by several studies associated with increased tobacco addiction and lung cancer risk [ 47 , 48 ], but a significant gene-environment interaction is controversial [ 50 , 51 ]. Some studies suggested that there were significant gene-smoking interactions at 10q25 [ 52 ], 14q22, 15q22 [ 53 ] and 19q13 [ 54 ]. In this study, there was no significant PRS-smoking interaction for lung cancer. This may be because the combination of multiple loci may mask the potential interaction, and the model selection and the specific definition of smoking habits may also affect the results. Besides, the number of positive cases observed in this cohort was far less than in large-scale GWASs, so there may be insufficient statistical power. However, based on the analysis of adjusting for extensive potential confounding factors and using the two smoking measures, we still believe that PRS and smoking promote lung cancer independently.

Strengths and limitations

This study has several strengths. Many participants from the UK Biobank study provided complete exposure information, and the extensive phenotype information provided many covariates that could be adjusted in the model to eliminate potential confounders. A more detailed grouping of lifetime tobacco exposure showed a typical dose-response relationship. Furthermore, the study population was utterly independent of previous GWASs that identified the risk loci and their effect sizes, which avoided overfitting to some extent.

Several limitations also need to be considered. First, the analysis was conducted on overall lung cancer without constructing PRS and assessing their effects for more detailed lung cancer classifications, which may mask their heterogeneity. Second, additional variants or genetic patterns associated with lung cancer are likely to be identified in the future, which may refine estimates of genetic risk. Third, PRS based on GWASs of European ancestry may limit its application in a larger population due to the differences in risk alleles, allele frequency, and the effect sizes of risk alleles. Fourth, smoking behaviours were self-reported and may have recall and misclassification bias, and there may be differences in the distribution of individuals excluded due to lacking smoking information. Fifth, smoking was not randomly assigned. Although analyses were adjusted for several covariates and sensitivity analyses, the possibility of unmeasured confounding remained. Sixth, the current study included 936 (0.27%) participants with inconsistent information on never-smoking and 0 pack-years of smoking. This may be due to the difference between the self-reported state and participants’ calculated state with minimal smoking exposure. Although we excluded these people in the sensitivity analysis, there may still be potential inconsistencies. Finally, the potential “healthy volunteer” selection bias in the UK biobank may be accompanied by a lower proportion of the smoking population and underestimated PAF. A mild increase in PAF was found using representative England and European population structures.

In conclusion, high genetic risk and smoking were independently associated with higher lung cancer risk, and there were no interactions between these risk factors. Polygenic risk assessment can provide important information beyond a variety of environmental exposures. This study provided new insights to quantitatively evaluate the role of smoking and genetics in lung cancer.

Data availability

The dataset supporting the conclusions of this article is available in the UK Biobank upon request ( https://www.ukbiobank.ac.uk/ ).

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Acknowledgements

We are grateful to UK Biobank participants. This research has been conducted using the UK Biobank resource ( https://www.ukbiobank.ac.uk ) under application number 43795.

This work was supported by the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2019), the National Natural Science Foundation of China (82103931 and 82003443), the Guangzhou Science and Technology Project (202002030255), and Young Elite Scientists Sponsorship Program by CAST (2019QNRC001). The funders had no role in the study design or implementation; data collection, management, analysis or interpretation; manuscript preparation, review or approval; or the decision to submit the manuscript for publication.

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Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China

Peidong Zhang, Pei-Liang Chen, Zhi-Hao Li, Xi-Ru Zhang, Yu-Jie Zhang, Dan Liu & Chen Mao

The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

Peidong Zhang

State Key Laboratory of Molecular Neuroscience and Center of Systems Biology and Human Health, Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China

Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

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Prof. Mao had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. PDZ and CM contributed to the study design and supervised the whole project. PDZ, ZHL, PLC, AZ and CM contributed to the data interpretation, data analysis, and manuscript writing. CM, PDZ, PLC, XRZ, YJZ and DL contributed to the data curation and funding acquisition. PDZ and PLC contributed equally to this work. All the authors reviewed or revised the manuscript.

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Zhang, P., Chen, PL., Li, ZH. et al. Association of smoking and polygenic risk with the incidence of lung cancer: a prospective cohort study. Br J Cancer 126 , 1637–1646 (2022). https://doi.org/10.1038/s41416-022-01736-3

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Immunotherapies work with the body's immune system to help fight cancer. They are a major focus in lung cancer treatment research today. Clinical trials are ongoing to look at new combinations of immunotherapies with or without chemotherapy  to treat  lung cancer.

Immune checkpoint inhibitor s are drugs that block an interaction between proteins on immune cells and cancer cells which, in turn, lowers the immune response to the cancer. Several immune checkpoint inhibitors have been approved for advanced lung cancer, including  p embrolizumab (Keytruda) . a tezolizumab (Tecentriq) , c emiplimab (Libtayo) , d urvalumab (Imfinzi) , and  n ivolumab (Opdivo) .

A key issue with immunotherapies is deciding which patients are most likely to benefit. There is some evidence that patients whose tumor cells have high levels of an immune checkpoint protein called PD-L1 may be more responsive to immune checkpoint inhibitors. Another  marker for immunotherapy response is tumor mutational burden , or TMB, which refers to the amount of mutations in the DNA of the cancer cells. In some lung cancer trials, positive responses to immune checkpoint inhibitors have been linked with a high TMB. However, these markers cannot always predict a response and there is ongoing work to find better markers.

To learn more, see Immunotherapy to Treat Cancer .

Targeted Therapies

Targeted treatments identify and attack certain types of cancer cells with less harm to normal cells. In recent years, many targeted therapies have become available for advanced lung cancer and more are in development. Targeted treatments for lung cancer include the below.

Anaplastic lymphoma kinase (ALK) Inhibitors

ALK inhibitors target cancer-causing rearrangements in a protein called ALK. These drugs continue to be refined for the 5% of NSCLC patients who have an ALK gene alteration. Approved treatments include   ceritinib (Zykadia) , alectinib (Alecensa) , brigatinib   (Alunbrig) , and lorlatinib  (Lorbrena) .

These ALK inhibitors are improvements from previous ones in their enhanced ability to cross the blood–brain barrier. This progress is critical because, in non-small cell lung cancer patients with  ALK  alterations, disease progression tends to occur in the brain.  

EGFR Inhibitors

• Lung Cancer Trial of Osimertinib Draws Praise—and Some Criticism

The drug improved survival in a large clinical trial, but some question the trial’s design.

EGFR inhibitors block the activity of a protein called epidermal growth factor receptor (EGFR). Altered forms of EGFR are found at high levels in some lung cancers, causing them to grow rapidly.  Osimertinib (Tagrisso) is the most effective and most widely used EGFR inhibitor. It is also used for adjuvant therapy after surgery for resectable NSCLC. Other drugs that target EGFR that are approved for treating NSCLC include afatinib (Gilotrif) , dacomitinib (Vizimpro) , erlotinib (Tarceva) , gefitinib (Iressa) . For people with Exon 20 mutations, amivantamab (Rybrevant)   is an approved targeted therapy.

ROS1 Inhibitors

The ROS1 protein is involved in cell signaling and cell growth. A small percentage of people with NSCLC have rearranged forms of the ROS1 gene. Crizotinib (Xalkori) and entrectinib (Rozlytrek) are approved as treatments for patients with these alterations.

BRAF Inhibitors

The B-Raf protein is involved in sending signals in cells and cell growth. Certain changes in the B-Raf gene can increase the growth and spread of NSCLC cells.

The combination of the B-Raf-targeted drug dabrafenib (Tafinlar)  and trametinib (Mekinist ), which targets a protein called MEK, has been approved as treatment for patients with NSCLC that has a specific mutation in the BRAF gene.

Encorafenib (Braftovi) combined with binimetinib (Mektovi) is approved for patients with metastatic NSCLC with a BRAF V600E mutation .

Other Inhibitors

Some NSCLCs have mutations in the genes NRTK-1 and NRTK-2 that can be treated with the targeted therapy larotrectinib (Vitrakvi). Those with certain mutations in the MET gene can be treated with tepotinib (Tepmetko) or capmatinib (Tabrecta) . And those with alterations in the RET gene are treated with selpercatinib (Retevmo)  and pralsetinib (Gavreto) . Inhibitors of other targets that drive some lung cancers are currently being tested in clinical trials.

See a complete list of  targeted therapies for lung cancer . 

NCI-Supported Research Programs

Many NCI-funded researchers at the NIH campus, and across the United States and the world, are seeking ways to address lung cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some is more clinical, seeking to translate basic information into improved patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in lung cancer.

Pragmatica-Lung Study Enrolling Patients

The simplified trial may serve as a model for future cancer clinical trials.

• The Pragmatica-Lung Study is a randomized trial that will compare the combination of the targeted therapy ramucirumab (Cyramza) and the immunotherapy pembrolizumab (Keytruda) with standard chemotherapy in people with advanced NSCLC whose disease has progressed after previous treatment with immunotherapy and chemotherapy. In addition to looking at an important clinical question, the trial will serve as a model for future trials because it is designed to remove many of the barriers that prevent people from joining clinical trials.
• Begun in 2014, ALCHEMIST is a multicenter NCI trial for patients with early stage non-small cell lung cancer. It tests to see whether adding a targeted therapy after surgery, based on the genetics of a patient’s tumor, will improve survival.
• The Lung MAP trial is an ongoing multicenter trial for patients with advanced non-small cell lung cancer who have not responded to earlier treatment. Patients are assigned to specific targeted therapies based on their tumor’s genetic makeup.
• The Small Cell Lung Cancer Consortium  was created to coordinate efforts and provide a network for investigators who focus on preclinical studies of small-cell lung cancer. The goal of the consortium is to accelerate progress on this disease through information exchange, data sharing and analysis, and face-to-face meetings.
• NCI funds eight  lung cancer Specialized Programs of Research Excellence (Lung SPOREs) . These programs are designed to quickly move basic scientific findings into clinical settings. Each SPORE has multiple lung cancer projects underway.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for both non-small cell lung cancer treatment  and small cell lung cancer treatment .

Lung Cancer Research Results

The following are some of our latest news articles on lung cancer research:

• Lung-Sparing Surgery Is Effective for Some with Early-Stage Lung Cancer
• Enhertu Marks First Targeted Therapy for HER2-Mutant Lung Cancer
• For Early-Stage Lung Cancer, Nivolumab and Chemo before Surgery Proves Effective
• Adjuvant Immunotherapy Approved for Some Patients with Lung Cancer
• Quitting Smoking Improves Survival in People with Lung Cancer

View the full list of Lung Cancer Research Results and Study Updates .

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Does Smoking Cause Cancer?

Smoking and cancer, lung cancer types, lung cancer stages, other risk factors, frequently asked questions.

The connection between smoking cigarettes and cancer has long been proven. Smoking cigarettes is the leading cause of preventable disease, disability, and death in the United States, and leads to 480,000 deaths in the U.S. each year.  

The Centers for Disease Control and Prevention (CDC) estimated that in 2019 approximately 34.1 million American adults were regular cigarette smokers, and more than 16 million were living with a smoking-related disease. Researchers defined a “current smoker” as someone who reported smoking at least 100 cigarettes in their lifetime or who reported smoking some days or every day.

Fortunately, the prevalence of smokers has gone down in recent years. In 2005, about 20.9% of American adults smoked, and in 2019 that number dropped to 14%.  

Verywell / Danie Drankwalter

While the link between cigarettes and cancer is well understood, there are other types of smoking that have not received the same amount of research. This article will describe the different types of smoking and how they are related to an increased risk for several different types of cancer.  

Smoking raises the risk of cancer because it damages the lungs and other bodily tissues. People who smoke experience damage to their airways and small air sacs in the lungs. Smoking is also associated with heart disease because it leads to damage to the blood vessels and the heart itself.  

Smoking tobacco is dangerous to our health because it raises the risk of cancer and other chronic health problems. It’s estimated that tobacco use causes one in five deaths in the United States, and we know that people who smoke die on average 10 years earlier than those who don’t.

Experts believe that smoking cigarettes or cigars causes about 20% of all cancers in the United States and is to blame for 30% of all cancer deaths. According to the American Cancer Society, about 80% of all lung cancers in the United States are caused by smoking. Lung cancer is still the leading cause of death in both men and women.  

Smoking cigarettes has been linked to an increased risk for the following cancers:

• Stomach 
• Bladder  
• Pancreas  
• Cervix  
• Rectum  

It is unclear if smoking marijuana raises the risk of lung cancer. However, we know that smoking marijuana causes lung damage. Research shows that marijuana smoking leads to inflammation in the airways. This inflammation can cause symptoms of chronic bronchitis and other respiratory problems. 

It is also possible that smoking marijuana affects the body’s immune system. Because marijuana has immune-suppressing properties, it may lead to an increased risk of lung infections like pneumonia . 

Marijuana smoke contains many of the same cancer-causing chemicals as cigarette smoke. It even has 50% more benzopyrene and 75% more benzanthracene than cigarette smoke.  

While marijuana is typically smoked less frequently than cigarettes, its smoke is usually inhaled deeper into the lungs and held for longer than cigarette smoke. Because of the different way it is smoked, marijuana smoke leads to four times the tar buildup in the lungs as cigarette smoke.  

E-Cigarettes

E-cigarettes are vaping devices that produce an aerosol by heating a liquid that contains nicotine. The risks associated with e-cigarettes are not as well understood as those of cigarettes. However, the information that is available indicates that e-cigarettes are very dangerous to our health. 

E-cigarettes are known to irritate the tissue in the lungs and cause damage to the heart. Like traditional cigarettes, e-cigarettes contain nicotine, which is known to be addictive. It may also harm the brain development of children and teenagers. 

Individuals who regularly vape have reported chronic symptoms including:

• Shortness of breath
• Nausea and vomiting
• Fatigue  
• Unintended weight loss

It is important to remember that e-cigarettes contain many of the same cancer-causing chemicals found in cigarettes. 

The most common signs and symptoms of lung cancer include:

• A persistent cough
• Coughing up blood or blood-tinged sputum
• Loss of appetite
• Fatigue 
• Respiratory infections that don’t improve
• New-onset wheezing 

Early Signs

Lung cancer does not always cause symptoms in the early stages. Often, symptoms present once cancer has begun to spread. As soon as you develop any signs or symptoms of lung cancer, it’s important to see your doctor right away. 

Lung cancer develops in the lung tissues and usually in the lining of the airways. The two most common types of lung cancer are small cell lung cancer and non-small cell lung cancer. Non-small cell lung cancer makes up about 80% to 85% of all lung cancer cases.  

Small Cell Lung Cancer (SCLC)

Small cell lung cancer makes up about 13% of all lung cancer cases. It can be classified into one of two stages:

• Limited stage : Cancer can be found in one area of the chest. It may have spread to the nearby lymph nodes. Treatment usually involves radiation therapy to one area of the body. If cancer has not spread to the lymph nodes yet, your medical team will most likely recommend surgery and chemotherapy. If cancer has reached the lymph nodes, radiation therapy is recommended as well. 
• Extensive stage : Cancer has spread to the entire lung and may have also spread to the other lung, the lymph nodes, the fluids surrounding the lungs, or distant areas of the body. Treatment usually includes chemotherapy and immunotherapy . The cancer has spread too far for surgery or radiation therapy to be helpful. 

Non-Small Cell Lung Cancer (NSCLC)

Non-small cell lung cancer is the most common type of lung cancer, and smoking is the major risk factor. Types of non-small cell lung cancer include squamous cell carcinoma , large cell carcinoma, and adenocarcinoma .  

Stages of non-small cell lung cancer range from stage 0, also known as carcinoma in situ , to stage 4. Typically, the lower the number of the stage, the less the cancer has spread throughout the body and the easier it is to treat.  

Lung cancer staging is a tool used to determine how advanced an individual’s lung cancer is. The lung cancer staging shows how far cancer cells have spread beyond the lungs and helps to develop the most effective treatment plan. 

In stage 1 lung cancer, the abnormal cells in the lining of the lungs have turned into cancer. Treatment for stage 1 non-small cell lung cancer usually starts with surgery to remove the cancerous portion of the lung. Your surgeon may recommend taking out the entire lobe, known as a lobectomy , or a smaller portion. During surgery, the surgeon will likely remove nearby lymph nodes to check them for cancer as well. 

In stage 2 lung cancer, cancer cells have begun to spread to nearby tissues. Treatment for stage 2 non-small lung cancer will depend on the exact size of the tumor and how far cancer cells have spread. The treatment plan usually starts with surgery to remove a lobe or the entire lung ( pneumonectomy ). Nearby lymph nodes are usually removed as well and then tested for cancer cells. After surgery, your medical team may recommend chemotherapy or radiation therapy to kill any remaining cancer cells.  

In stage 3 non-small cell lung cancer, the tumor has grown and possibly reached the lymph nodes. Treatment for stage 3 non-small cell lung cancer usually includes a combination of surgery, chemotherapy, and radiation therapy.

In the final stage, stage 4 non-small cell lung cancer , cancer cells have spread to distant tissues of the body such as the opposite lung, bones, brain, liver, or kidney. Stage 4 non-small cell lung cancer is difficult to treat and cure because of how advanced it is. Depending on how healthy you are otherwise, treatment may include surgery, chemotherapy, radiation therapy, targeted therapy , and immunotherapy .  

In addition to tobacco smoke, other known risk factors for lung cancer include:

• Radon : Radon is a naturally occurring radioactive gas that you cannot see, smell, or taste. It’s believed to be the second leading cause of lung cancer in people who do not smoke. 
• Asbestos : Asbestos is a group of naturally occurring minerals that are most likely to be found in mines, mills, textile plants, shipyards, and places where people work with insulation. Exposure to these minerals at work raises your risk for lung cancer, especially if you also smoke.
• Radiation : Receiving radiation to your chest is a risk factor for lung cancer, especially if you also smoke. People who may have a history of chest radiation include those treated for Hodgkin disease or breast cancer.
• Air pollution : It’s estimated that air pollution is to blame for about 5% of all lung cancer deaths worldwide. This risk factor is difficult to address because we as individuals usually do not have control over the quality of the air we breathe. 

The best way to prevent lung cancer is to avoid the risk factors that lead to it. Ways to prevent lung cancer include:

• Quit smoking.
• Avoid radon exposure.
• Protect yourself against asbestos exposure.
• Eat a healthy diet.

The treatment for lung cancer is individual and depends on several factors, including the stage of cancer, how advanced it is, and your overall health. Many treatment plans include surgery, radiation therapy, chemotherapy, immunotherapy, and targeted therapies.  

Smoking cigarettes is the leading cause of lung cancer and lung cancer deaths. Smoking marijuana and e-cigarettes is known to damage the lungs but has not been linked to an increased risk for lung cancer. 

Symptoms of lung cancer include a persistent cough, chest pain, coughing up blood, loss of appetite, shortness of breath, and fatigue. Treatment options include surgery, radiation, chemotherapy, immunotherapy, and targeted therapies. 

A Word From Verywell

The link between smoking cigarettes and cancer is well established, but that does not mean that quitting smoking is easy. If you have decided to reduce or eliminate your smoking habit, talk with your healthcare provider about resources in your area. It’s important to remember that while there is currently no proven link between marijuana smoke or e-cigarette smoke and cancer, all types of smoking cause damage to your lungs and raise your risk for chronic health problems. 

There is no known number of cigarettes that you can safely consume in a day. However, reducing the number of cigarettes that you currently smoke each day is still beneficial to your health. 

Most packs contain 20 cigarettes. 

Yes, it is possible to live with one lung. For most people, one lung is able to provide enough oxygen for the body. However, if the one lung is damaged, it may not be able to keep up with the body’s needs.  

Centers for Disease Control and Prevention. Current cigarette smoking among adults in the United States . Updated December 10, 2020.

Centers for Disease Control and Prevention. Tobacco-Related Mortality . Updated April 28, 2020.

American Cancer Society. Health risks of smoking tobacco . Updated October 28, 2020.

National Institute on Drug Access. What are marijuana's effects on lung health ? Updated July 2020.

American Lung Association. Marijuana and lung health . Updated December 17, 2020.

American Cancer Society. What do we know about E-cigarettes ? Updated September 9, 2020. 

American Cancer Society. Health risks of E-cigarettes . Updated October 28, 2020.

American Cancer Society. Lung cancer signs & symptoms . Updated October 1, 2019. 

American Lung Association. Lung cancer basics . Updated August 30, 2021.

American Cancer Society. Non-small cell lung cancer staging . Updated October 1, 2019.

American Cancer Society. Lung cancer statistics | How common is lung cancer ? Updated January 12, 2021.

American Cancer Society. Lung cancer treatment by stage . Updated March 3, 2021. 

Cancer Treatment Centers of America. Understand how lung cancer is staged and graded . 

National Cancer Institute. Definition of stage IIB non-small cell lung cancer . Updated July 15, 2021. 

American Cancer Society. Lung cancer risk factors . Updated October 1, 2019.

American Lung Association. Lung cancer causes & risk factors . Updated October 4, 2021. 

American Cancer Society. Lung cancer prevention . Updated October 1, 2019.

Centers for Disease Control and Prevention. How is lung cancer diagnosed and treated ? Updated October 18, 2021.

Johns Hopkins Medicine. Pneumonectomy .

By Carrie Madormo, RN, MPH Carrie Madormo, RN, MPH, is a health writer with over a decade of experience working as a registered nurse. She has practiced in a variety of settings including pediatrics, oncology, chronic pain, and public health.

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• Volume 8, Issue 10
• Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis
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• Linda M O’Keeffe 1 , 2 ,
• http://orcid.org/0000-0003-2185-0162 Gemma Taylor 1 , 2 , 3 , 4 ,
• Rachel R Huxley 5 , 6 ,
• Paul Mitchell 7 ,
• Mark Woodward 6 , 8 , 9 ,
• Sanne A E Peters 8
• 1 MRC Integrative Epidemiology Unit at the University of Bristol , Bristol Medical School, University of Bristol , Bristol , UK
• 2 Population Health Sciences , Bristol Medical School, University of Bristol , Bristol , UK
• 3 UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology , University of Bristol , Bristol , UK
• 4 Department of Psychology , University of Bath , Bath , UK
• 5 College of Science, Health and Engineering , La Trobe University , Melbourne , Australia
• 6 The George Institute for Global Health , University of New South Wales , Sydney , New South Wales , Australia
• 7 Olivia Newton-John Cancer and Wellness Centre , Austin Health and Olivia Newton-John Cancer Research Institute , Heidelberg , Victoria , Australia
• 8 The George Institute for Global Health , University of Oxford , Oxford , UK
• 9 Department of Epidemiology , John Hopkins University , Baltimore , Maryland , USA
• Correspondence to Dr Linda M O’Keeffe; linda.okeeffe{at}bristol.ac.uk

Objectives To investigate the sex-specific association between smoking and lung cancer.

Design Systematic review and meta-analysis.

Data sources We searched PubMed and EMBASE from 1 January 1999 to 15 April 2016 for cohort studies. Cohort studies before 1 January 1999 were retrieved from a previous meta-analysis. Individual participant data from three sources were also available to supplement analyses of published literature.

Eligibility criteria for selecting studies Cohort studies reporting the sex-specific relative risk (RR) of lung cancer associated with smoking.

Results Data from 29 studies representing 99 cohort studies, 7 million individuals and >50 000 incident lung cancer cases were included. The sex-specific RRs and their ratio comparing women with men were pooled using random-effects meta-analysis with inverse-variance weighting. The pooled multiple-adjusted lung cancer RR was 6.99 (95% Confidence Interval (CI) 5.09 to 9.59) in women and 7.33 (95% CI 4.90 to 10.96) in men. The pooled ratio of the RRs was 0.92 (95% CI 0.72 to 1.16; I 2 =89%; p<0.001), with no evidence of publication bias or differences across major pre-defined participant and study subtypes. The women-to-men ratio of RRs was 0.99 (95% CI 0.65 to 1.52), 1.11 (95% CI 0.75 to 1.64) and 0.94 (95% CI 0.69 to 1.30), for light, moderate and heavy smoking, respectively.

Conclusions Smoking yields similar risks of lung cancer in women compared with men. However, these data may underestimate the true risks of lung cancer among women, as the smoking epidemic has not yet reached full maturity in women. Continued efforts to measure the sex-specific association of smoking and lung cancer are required.

• systematic review
• lung cancer
• sex-specific

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/ .

http://dx.doi.org/10.1136/bmjopen-2018-021611

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Strengths and limitations of this study

Evidence on the sex-specific association of smoking and lung cancer was meta-analysed in over 7 million participants across 99 cohort studies.

Several subgroup analyses were performed to examine the robustness of findings across different population subgroups.

However, the smoking epidemic is not yet fully mature in women and risks of lung cancer in women may still be underestimated.

Detailed data on smoking behaviour and data on specific subtypes of lung cancer were not available.

Introduction 

Lung cancer is the leading cause of cancer death worldwide with 1.7 million global deaths attributed to cigarette smoking in 2015. 1 Tobacco use is the leading cause of lung cancer; 55% of lung cancer deaths in women and over 70% of lung cancer deaths in men are due to smoking. 1 These global estimates, however, mask major differences in smoking prevalence in men and women across populations, with rates below 5% for women in most Asian and African countries to 40% and above for men in many parts of Asia and Eastern Europe. 2 In addition, smoking behaviour varies significantly by sex. For example, compared with women, men smoke more cigars and pipes, 3 take puffs of longer duration and leave shorter butts, 4 which each could potentially predispose them to greater risks of smoking-related lung cancer. Substantial physiological differences between the sexes may also result in sex differences in the effects of smoking, particularly for women. For example, compared with men, women have a smaller lung size and different airway behaviour, 5 which may increase their susceptibility to lung cancer at lower levels of smoking. A recent meta-analysis showed that cigarette smoking confers a greater coronary hazard in women compared with men, which suggests the possibility that this may also be true for the risk of smoking-related lung cancer. 6

A study of 50-year trends in smoking-related mortality in the USA found that the relative risks of smoking-related lung cancer mortality were higher in men than women. 7 However, this sex difference was only apparent in the oldest cohorts with the longest follow-up, possibly reflecting greater cumulative tobacco exposure in men than in women. In contrast, a recent study in Korea, a population where smoking patterns continue to differ between the sexes, suggested that sex differences in the impact of smoking on lung cancer risk exist and differ by histological subtype. 8 Analyses of a large UK primary care database showed that moderate and heavy smoking more strongly increase the risks of lung cancer in women than in men. 9

Two recent meta-analyses examined the sex-specific association between smoking and lung cancer. In the most recent of these, men were found to have a greater risk of lung cancer associated with smoking compared with women. 10 However, virtually all data were from historical case–control studies, which have several limitations, and the three included prospective studies provided contradictory results. While a previous meta-analysis by Lee et al 11 included 287 cohort and case–control studies and provided sex-specific estimates, single-sex cohorts were also included, sex differences in the smoking-related risk of lung cancer were not formally compared within studies, and only studies published up to 1999 were included.

To resolve this uncertainty, we performed a systematic review and meta-analysis of prospective cohort studies published to date on the sex-specific association of smoking with the risk of fatal and non-fatal lung cancer. Our systematic review builds on these previous meta-analyses by adding literature from 1999 onwards and restricting the analyses to cohort studies, which are less prone to bias than case–control studies. In addition, we perform several predefined subgroup analyses which have not been performed in meta-analyses of cohort studies included in previous reviews and supplement our findings with results from three sources of individual participant data (IPD), not published previously. An important a priori consideration is the substantial sex difference in the maturity of the smoking epidemic with men being at a more advanced stage than women in most parts of the world. 2 This would be expected to translate into lower relative risk (RR) estimates for lung cancer in women than in men. Hence, the null hypothesis that smoking confers the same lung cancer hazard in both women and men, would be met if the ratio of the RRs (RRRs) for lung cancer (women:men) was less than unity (reflecting a greater hazard in men than women). However, if the RRRs were found to be unity (or higher) then this would suggest a greater hazard associated with tobacco exposure in women than in men.

Search strategy

This review was conducted using a predefined protocol and in accordance to the Meta-analysis Of Observational Studies in Epidemiology guidelines (online supplementary eappendix 1 ). We systematically searched PubMed and EMBASE for studies published between 1 January 1999 and 15 April 2016 that reported on the relationship between smoking and lung cancer in men and women from a general population. The computer-based searches combined medical subject headings and free-text terms related to ‘tobacco/smoking’, ‘cancer’, ‘sex’ and ‘cohort studies’. The full search criteria are available in online supplementary eappendix 2 . Articles published before 1 January 1999 were retrieved from a previous systematic review. 11 The reference lists of all relevant original research and review articles were scanned to capture missed studies. Two authors (LMOK and GT) independently conducted the screening of studies and any disagreement was mediated by a third author (SAEP).

Supplementary file 1

Data extraction.

Data were extracted, in duplicate, from studies deemed to meet the eligibility criteria. These included details on general study characteristics (study name, duration of follow-up, year of publication), information about the studied population (prevalence of smoking, mean age, number of men and women, incidence of lung cancer, whether lung cancer was fatal or non-fatal and level of adjustment for covariates). We extracted sex-specific adjusted measures of RR and 95% confidence intervals (CIs).

Study selection

Observational cohort studies were included if they reported sex-specific RRs or equivalent, on the relationship between smoking and lung cancer. Studies were excluded if the variability around the point estimate was not reported, if they had not been adjusted for at least age, or if the study was performed in a population selected on the basis of prior lung cancer or another major underlying chronic disease. In the case of duplicate reports from the same study, the report with the longest follow-up or the highest number of cases was included. IPD from studies available to the authors were also used; the Asia Pacific Cohort Studies Collaboration (APCSC), the National Health and Nutrition Examination Survey III (NHANES III) and the Scottish Heart Health Extended Cohort Study (SHHEC). The Newcastle-Ottawa Scale assessment (NOS) was used to assess the methodological quality of all included studies, on a 9-point scale (online supplementary eappendix 3 and etable 1 ). 12

Meta-analysis

The primary analysis was a comparison of the sex-specific RR of lung cancer (fatal or non-fatal) in current smokers versus non-smokers (defined either as former or never smokers). For each study, we obtained the natural log of the sex-specific RRs and calculated the differences. The differences were pooled across studies using random-effects meta-analysis which allows the RR of lung cancer to vary from study to study, weighted by the inverse of the variances of the log RRs and then back-transformed to obtain the pooled women-to-men RRRs. The SE of the log RRR was calculated as the square root of the sum of the variance of the two sex-specific log RRs for each study. Pooled RRRs were computed separately for studies with only age-adjusted estimates and then for those studies with multiple-adjusted estimates. The set of multiple adjustments made was allowed to vary by study, but had to include at least one other risk factor in addition to age. The I² statistic was used to estimate the percentage of variability across studies due to between-study heterogeneity. The presence of publication bias was graphically examined using contour funnel plots, plotting the natural log of the RRR against its SE and tested using Begg’s test. Predefined subgroup analyses were conducted to obtain the adjusted RRRs by study region (Asia or non-Asia and Asia, Europe, USA, and Australia and New Zealand (ANZ)), year of study baseline (pre-1985 or post-1985), study endpoint (fatal only or fatal and non-fatal combined), number of cigarettes smoked per day (>0 to 10, 10–20, >20), study quality ≤6 vs >6 points) and follow-up time (≤10 vs >10 years). Random-effects meta-analyses were used for all subgroup analyses and differences between subgroups were examined using meta-regression. To include the largest number of studies available, we combined the age-adjusted and multiple-adjusted estimates, taking the maximum adjustment set available. In secondary analyses, we obtained the sex-specific RRs and RRRs comparing former smokers to never smokers and performed the same set of subgroup analyses. All analyses were performed using Stata V.12.0.

Patient and public involvement

There were no patients or applicable public involved in this review.

Of the 9519 unique records that were identified through the systematic search, 227 qualified for full-text evaluation ( figure 1 ). Of these, 25 separate studies provided information about sex differences in the association between smoking and lung cancer. This database was extended with IPD from APCSC (separately for Asia and ANZ), NHANES III and SHHEC leading to a total of 29 individual estimates, representing a total of 99 cohort studies available for meta-analysis.

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Flow chart of study selection. IPD, individual participant data.

The characteristics of the included studies are described in table 1 . Overall, data were available from 99 cohorts, including 7 113 303 individuals (46% women)—not accounting for two cohorts that used Census data—and at least 51 161 incident cases of lung cancer (31% women). Forty-six cohorts were from Asia (61% of the individuals), 6 were from the USA (28%), 37 were from Europe (10%) and 10 were from ANZ (1%). Of 29 studies, 4 studies had a quality score of 5 out of 9, 9 studies had a score of 6, 12 studies had a score of 7 and 4 studies with a score of 8 (online supplementary etable 1 ).

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Characteristics of included studies

Eighteen studies reported on the prevalence of smoking, which varied widely by study, region and sex. The prevalence of smoking ranged from 1% to 47% in women and from 1% to 70% in men. In all but two studies, the prevalence of smoking was higher in men than women, especially in Asia where typically less than 10% of women were smokers compared with over 50% of men. Smoking cessation rates were also higher among men (7%–61%) than women (<1%–39%).

Risk of lung cancer in current smokers versus non-smokers

Compared with non-smoking, current smoking was associated with an age-adjusted RR of lung cancer of 7.48 (95% CI 5.29 to 10.60) in women and 8.78 (95% CI 6.13 to 12.57) in men ( table 2 and online supplementary efigure 1 ). The pooled age-adjusted women-to-men RRR was 0.81 (95% CI 0.62 to 1.04), with substantial between-study heterogeneity (I 2 =86%; p<0.001) ( table 2 and online supplementary efigure 2 ). The multiple-adjusted RR of lung cancer associated with current smoking was 6.99 (95% CI 5.09 to 9.59) in women and 7.33 (95% CI 4.90 to 10.96) in men ( table 2 and figure 2 ). The corresponding RRR was 0.92 (95% CI 0.72 to 1.16) and between-study heterogeneity was substantial (I 2 =89%; p<0.001) ( table 2 and figure 3 ). There was no evidence of publication bias based on the Begg’s test (p=0.75) (online supplementary efigure 3 ).

Multiple-adjusted relative risk (RR) for incident lung cancer in women and men, comparing current smokers to non-smokers. Multiple-adjusted includes anything that adjusted for more than just age. These covariates are listed in table 1 . Figures may contain less than 29 studies because we report age-adjusted and multiple-adjusted results separately. Some studies only contributed age-adjusted results whereas others only provided multiple-adjusted results. However, the count of unique studies that contributed to at least one of these analyses is 29. APCSC, Asia Pacific Cohort Studies Collaboration; ARIC, Atherosclerosis Risk in Communities study; CPS, Cancer Prevention Study; EHS, Elderly Health Services; EPIC, European Prospective Investigation into Cancer; JACC, Japan Collaborative Cohort Study; JPHC, Japan Public Health Centre Study; NHANES III, National Health And Nutrition Examination Survey III; NHIS, National Health Interview Survey; NIH-AARP, National Institutes of Health American Association of Retrired Persons Diet and Health Study; SHHEC, Scottish Heart Health Extended Cohort Study; TPCS, Three-Prefecture Cohort Study.

Multiple-adjusted women-to-men ratio of relative risks (RRR) for incident lung cancer, comparing current smokers to non-smokers. Multiple-adjusted includes anything that adjusted for more than just age. These covariates are listed in table 1 . Figures may contain less than 29 studies because we report age-adjusted and multiple-adjusted results separately. Some studies only contributed age-adjusted results whereas others only provided multiple-adjusted results. However, the count of unique studies that contributed to at least one of these analyses is 29. APCSC, Asia Pacific Cohort Studies Collaboration; ARIC, Atherosclerosis Risk in Communities study; CPS, Cancer Prevention Study; EHS, Elderly Health Services; EPIC, European Prospective Investigation into Cancer; JACC, Japan Collaborative Cohort Study; JPHC, Japan Public Health Centre Study; NHANES III, National Health And Nutrition Examination Survey III; NHIS, National Health Interview Survey; NIH-AARP, National Institutes of Health American Association of Retired Persons Diet and Health Study; SHHEC, Scottish Heart Health Extended Cohort Study; TPCS, Three-Prefecture Cohort Study.

Sex-specific pooled relative risks (RR) and ratio of relative risks (RRR) for lung cancer associated with smoking

The sex difference in the risk of smoking-related lung cancer in our main analysis did not differ in subgroup analyses stratified by the women-to-men ratio of current smokers (p=0.90), women-to-men ratio of lung cancer incidence in the studies (p=0.64), year of study baseline (p=0.66), study endpoint (p=0.21) or study region (p=0.73) ( table 3 ). The sex difference in the risk of smoking-related lung cancer in our main analysis also did not differ by follow-up time (p=0.83) or study quality (p=0.69). The RRR was 0.93 (95% CI 0.72 to 1.20) for studies from Asia and 0.87 (95% CI 0.66 to 1.14) for studies from USA, Europe or ANZ.

Maximally adjusted pooled women to men ratio of relative risks (RRR) for lung cancer associated with smoking, in subgroup analyses

The risk of smoking-related lung cancer increased according to the number of cigarettes smoked per day in both sexes ( table 2 ). In women, the RRs were 5.30 (95% CI 3.52 to 7.97), 10.67 (95% CI 7.43 to 15.33) and 17.09 (95% CI 12.11 to 24.11) across subgroups of <10, 10 to 20 and >20 cigarettes per day versus non-smoking, respectively. Corresponding RRs in men were 4.97 (95% CI 2.74 to 9.03), 8.93 (95% CI 4.90 to 16.28) and 14.61 (95% CI 8.33 to 25.59), respectively. The RRRs in these subgroups were 0.99 (95% CI 0.65 to 1.52), 1.11 (95% CI 0.75 to 1.64) and 0.94 (95% CI 0.69 to 1.30), respectively.

Risk of lung cancer in former smokers versus never smokers

Data from 89 cohorts, including 6 006 725 individuals and 38 244 cases of lung cancer, reported on the risk of lung cancer in former smokers compared with never smokers. The age-adjusted RR of lung cancer associated with former smoking was 2.82 (95% CI 2.25 to 3.54) in women and 3.01 (95% CI 2.23 to 4.08) in men ( table 2 and online supplementary efigure 4 ); the age-adjusted RRR was 0.88 (95% CI 0.69 to 1.14) (I 2 =64%; p<0.001) ( table 2 and online supplementary efigure 5 ). The corresponding multiple-adjusted RRs were 3.14 (95% CI 2.45 to 4.03) in women and 3.13 (95% CI 2.06 to 4.76) in men ( table 2 and online supplementary efigure 6 ). There was no statistical evidence that the effects of smoking cessation on risk of lung cancer differed between the sexes; the multiple-adjusted RRR was 0.89 (95% CI 0.69 to 1.13) (I 2 =69%; p<0.001) ( table 2 and online supplementary efigure 7 ). There was no evidence that the RRR differed across various subgroup analyses ( table 3 ).

In this systematic review and meta-analysis, comprising data from more than 7 million participants, 99 cohort studies and over 50 000 incident cases of lung cancer, there was no evidence for a difference in the risk of smoking-related lung cancer in women compared with men. This was true across a range of subgroup and sensitivity analyses. However, as smoking prevalence and intensity were higher in men compared with women in most studies included in this analysis, there may yet be an unrealised sex difference in the risk of smoking-related lung cancer that will only become fully manifest as the smoking epidemic reaches full maturity in women. 2

The sevenfold higher RRs of lung cancer associated with smoking found in the present meta-analysis are considerably smaller than the 20-fold increased risks reported in the Million Women’s Study 13 and the British Doctors Study. 14 Both of these studies had the advantage of capturing smoking-related risks in populations that had smoked for long enough for the effects to become fully manifest, highlighting the importance of taking into consideration the stage of the tobacco epidemic in each sex. The lack of any appreciable sex difference in the RRs of lung cancer is surprising given men’s greater cumulative exposure to smoking, in most populations, compared with women. In addition, men have a greater exposure to other risk factors for lung cancer including occupational carcinogens. 15 Men also smoke more cigars and pipes, 3 take longer puffs of longer duration and leave shorter butts compared with women. 4 Hence, it may be reasonable to surmise that the RR estimates of smoking-related lung cancer in women may eventually exceed those of men, once cumulative exposure to smoking in women is comparable to that in men. In a previous meta-analysis, using similar methodology, we found that smoking conferred a 25% greater RR of coronary heart disease (CHD) in women than in men. Two possible explanations for why a similar pattern is not observed for lung cancer are that, first, the lag-time between smoking and CHD is considerably shorter than for lung cancer, 16 and second the pathways by which smoking increases risk are different between CHD and lung cancer.

Although not assessed in this analysis, evidence suggests that there are sex differences in the pattern of lung cancer among never smokers, with a higher prevalence of lung cancer among never-smoking women than never-smoking men. 17 18 A US study among 500000 people found a 30% higher incidence of lung cancer in women never smokers compared with men never smokers. 19 An Australian study found the proportion of patients with lung cancer who had never smoked was approximately 18% in women and 3% of men. 20 The reasons for this sex difference are not clear, but women may have increased exposure to environmental tobacco smoke 21 or other environmental carcinogens such as indoor air pollution 22 or sex-related differences in the metabolism of environmental carcinogens. The possibility of greater exposure to environmental tobacco smoke and other environmental carcinogens in women compared with men could have resulted in a greater underestimation of the association between smoking and lung cancer in women than men. This, in turn, could have impacted the sex difference in risk of smoking-related lung cancer reported in this study.

Our study has several strengths including restriction to cohort studies which provide more robust evidence of the associations compared with case–control studies. Differences between case–control and cohort studies may also explain why a previous meta-analysis of case–control studies (which included only three cohort studies) showed a higher RR of lung cancer in men compared with women. 10 Other strengths to our study include an update of findings to include studies published after 1999, 11 with supplementation of published literature with IPD from three established population databases. We have also performed a range of prespecified sensitivity analyses and several subgroup analyses which were not performed in previous meta-analyses. Our results were consistent across regions and irrespective of the women-to-men smoking ratio, suggesting that underestimation of the association of smoking and lung cancer in women due to sex differences in smoking prevalence and under-reporting of smoking is unlikely. This is especially relevant for parts of Asia where the prevalence of smoking in women is typically <10% and where smoking among women remains relatively socially unacceptable. As the up-take of smoking continues among women in countries where significant sex differences in smoking prevalence exist, the sex-specific risks of lung cancer due to smoking may become further apparent. This is also true for Western countries where differences in prevalence between women and men have reduced substantially over time, with prevalence of smoking in younger cohorts of women and men approaching unity. 23 The limitations of this study include heterogeneity across studies in study design, study population, verification of smoking status and outcome ascertainment. Assessment of smoking status differed across studies and was generally self-reported, which may have introduced measurement error. 24 Notably, compared with men, women are more likely to under-report smoking status, and under-reporting is especially prevalent in countries where smoking among women is not culturally acceptable. 25 The lack of standardisation across studies in how smoking status was obtained, including how smoking dose and duration were measured is also a major limitation. In addition, there was insufficient data available to examine whether there were sex differences in the impact of age at smoking initiation and smoking duration on the risk of lung cancer. The reference group of non-smokers in our analysis of current smoking was composed of former and never smokers which may inflate the risks of smoking-related lung cancer risk among non-smokers. However, we have also examined former smoking compared with never smoking and demonstrated no appreciable sex differences in the risks of smoking-related lung cancer in this group, which provides some evidence that the inclusion of former smokers in the reference category is unlikely to have biased the sex difference in our main analysis. We quantified sex differences in the risk of lung cancer associated with smoking based on RRs rather than absolute risks. This might introduce a statistical artefact, in which the generally higher absolute risk for lung cancer in men, and the same risk difference subsequent to smoking in each sex, would translate to a greater RR in women than men. However, our previous meta-analyses on risk factors for cardiovascular diseases demonstrated that sex differences in RRs are not inevitable, 26 despite differences in absolute risks. Compared with absolute risks, RRs are more stable across populations with different background risks, which makes them suitable for meta-analyses. In addition, RRs are reported much more commonly than absolute risks. In our review, no studies reported adjusted absolute risks, with standard errors, that allow for meta-analyses. We, therefore, believe that use of RRs in the present analysis is appropriate. In addition, while we have aimed to assess study quality using the widely accepted and used NOS, the value and contribution of quality assessment scales such as this to systematic reviews and meta-analyses continues to be debated. 27–29 Finally, there are differences between men and women in histological subtypes of lung cancer. Adenocarcinoma is more common in women and squamous cell carcinoma is more common in men. 30 Smoking is more strongly associated with squamous cell carcinoma than adenocarcinoma. 30 Few studies reported the sex-specific association of smoking with histological subtypes of cancer, which precluded the examination of sex differences in the association of smoking-related lung cancer subtypes and this remains an important limitation of our review. 30 Further studies of the smoking-related risks of lung cancer in women and men are required as the smoking epidemic reaches its full maturity in women. Given the later up-take of smoking in women, studies which allow sufficient lag time for lung cancer to develop are essential. In addition, reducing under-reporting of smoking in women, using standardised and robust methods for the ascertainment of smoking status and smoking behaviours and more extensive measurement and adjustment for confounders which differ by sex (such as exposure to environmental tobacco smoke) is also important for future work, as well as examination of histological subtypes of lung cancer which was not possible in this review.

In conclusion, this meta-analysis, summarising all available literature to date, shows that the effect of smoking on risk of lung cancer is similar in women and men. However, these data may yet underestimate the true RR of smoking-related lung cancer in women, given later uptake and lower intensity of smoking in women. Although strides have been made in reducing smoking rates particularly in high-income countries, continuing efforts to measure the effects of smoking on disease outcomes are required, as the smoking epidemic has not yet reached its global peak, particularly among women. In addition, tobacco control programmes that dissuade both sexes from smoking but which also encourage individuals to quit remain a priority.

• 1. ↵ Institute for Health Metrics and Evaluation . Global burden of disease 2015 . 2015 http://vizhub.healthdata.org/gbd-compare/#
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LMO’K and GT contributed equally.

Contributors LMOK, GT, SAEP, RRH and MW designed the study. LMOK and GT performed systematic searches, retrieved literature and performed data extraction. SAEP performed the analysis of the data. LMOK and GT wrote the first draft of the article. RRH, MW and PM contributed important intellectual content and critical expertise and revisions to the manuscript.

Funding The MRC Integrative Epidemiology Unit at the University of Bristol is supported by the University of Bristol and the Medical Research Council [MC_UU_12013/2, MC_UU_12013/3, MC_UU_12013/4, MC_UU_12013/6, MC_UU_12013/9]. LMOK is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1). GT is funded by a Cancer Research UK Postdoctoral Fellowship (C56067/A21330). SAEP is supported by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1).

Competing interests None declared.

Patient consent Not required.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement Technical appendix, statistical code and dataset (of published data only) available from authors on request.

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• v.63(1); Jan-Feb 1990

Research on smoking and lung cancer: a landmark in the history of chronic disease epidemiology.

This paper describes the history of the epidemiologic research on lung cancer prior to 1970 and its effect on chronic disease epidemiology. In the 1930s, epidemiology was largely concerned with acute infectious diseases. As the evidence grew that the incidence of lung cancer was increasing among men, however, epidemiologists undertook research into the etiology of the disease. In 1950, Doll and Hill, in England, and Wynder and Graham, in the United States, published substantial case-control studies that implicated the use of tobacco as a major risk factor for the disease. A controversy developed over the credibility of this finding and was increased in 1954 when a cohort study by Doll and Hill and another by Hammond and Horn each gave estimates that the risk of lung cancer was greatly increased among smokers relative to the risk among comparable non-smokers. An account is given of the disputes surrounding these and related studies. The controversy had a stimulating effect in fostering the developing discipline of chronic disease and epidemiology.

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References .

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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Smoking and lung cancer

Affiliation.

• 1 Department of Chest Diseases, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. [email protected]
• PMID: 16100660

Nowadays, around one-third of adults are known to be smokers, and smoking rates are increasing among the female population. It is estimated that deaths attributable to tobacco use will rise to 10 million by 2025, and one-third of all adult deaths are expected to be related to cigarette smoking. The association between cigarettes and lung cancer has been proven by large cohort studies. Tobacco use has been reported to be the main cause of 90% of male and 79% of female lung cancers. 90% of deaths from lung cancer are estimated to be due to smoking. The risk of lung cancer development is 20-40 times higher in lifelong smokers compared to non-smokers. Environmental cigarette smoke exposure and different types of smoking have been shown to cause pulmonary carcinoma. DNA adducts, the metabolites of smoke carcinogens bound covalently with DNA, are regarded as an indicator of cancer risk in smokers. In recent decades, there has been a shift from squamous and small cell lung cancer types to adenocarcinoma, due to increasing rates of smoking among female population and rising light cigarette usage. After smoking cessation, the cumulative death risk from lung cancer decreases. Patients who continue smoking experience greater difficulties during cancer treatment. Stopping smoking may prolong survival in cancer patients, and also decreases the risk of recurrent pulmonary carcinoma. In order to save lives and prevent smoking related hazards, physicians should advise both healthy individuals and those with cancer of the benefits of stopping smoking.

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• Lung Neoplasms / etiology
• Lung Neoplasms / prevention & control*
• Smoking / adverse effects*
• Smoking Cessation*

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Lung cancer is the deadliest cancer in the U.S. and although new precision therapies have helped curb its high mortality rate, both smokers and nonsmokers continue to be diagnosed with various forms of this cancer due to commercial tobacco use, radon, air pollution and other drivers of the disease.

Preventive lung cancer screening, used to detect whether a tumor is beginning to grow, has been available for around a decade. The U.S. Preventive Services Task Force currently recommends adults between 50 and 80 who have a 20 pack-year smoking history and who currently smoke (or have quit within the past 15 years) receive a low-dose computed tomography (CT)  every year.

Unfortunately, recent research from Fred Hutchinson Cancer Center found nearly half of people with “positive” lung cancer screening CTs, (and positive is not good in cancer) had delays in their follow-up. As a result, some of these people had their cancers diagnosed at a later stage. Early detection works best when any suspicious findings caught on a scan are investigated.

But what about people who don’t smoke but live or work or play around those who do?   

A regular Fred Hutch News reader wondered if low-dose CT lung cancer screening was available for nonsmokers who grew up around people who smoked, a perfect question during November, Lung Cancer Awareness Month.

Is lung cancer screening recommended for individuals who did not smoke, but lived in a smoking household with second-hand smoke most of their life?               — Susan in Edmonds

For answers, we tapped Fred Hutch pulmonologist and cancer prevention researcher  Matthew Triplette, MD, MPH , who said this is not an uncommon question, but is one that “can be tough to give a satisfying answer to.”

“Essentially every test or procedure we do has both potential risks and potential benefits,” Triplette explained, going on to add low-dose CT screening for lung cancer has been demonstrated to be helpful in patients of a certain age with a personal high-risk smoking history, but that it has not yet been demonstrated to be equally helpful in other groups.

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Representatives can meet with you in person or remotely. This service is provided to all current Fred Hutch patients, caregivers and family members.  Click here  for more information on Tobacco Free Services. Or  search here to learn about research trials around quitting smoking. 

“While we know family history and second-hand smoke can contribute to lung cancer risk, the highest risk group remains those with a substantial smoking history,” he said. “We definitely worry about the potential harms of screening people at lower risk for lung cancer including radiation risk and procedural harms.”

Currently, Triplette said low-dose CT screening is only recommended for people who meet the smoking criteria, but said the criteria is under continuous evaluation.

“This is definitely something that’s worth bringing up with your primary care physician and having a more personalized discussion about,” he added.

Read more about the  signs, symptoms and causes  of lung cancer and/or check out the  latest lung cancer research  being done at Fred Hutch. 

Do you have a question about cancer? Send it  our way ! 

Diane Mapes is a staff writer at Fred Hutchinson Cancer Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at  doublewhammied.com  and tweets @double_whammied . Email her at  [email protected] . Just diagnosed and need information and resources? Visit our Patient Care page.

Are you interested in reprinting or republishing this story? Be our guest! We want to help connect people with the information they need. We just ask that you link back to the original article, preserve the author’s byline and refrain from making edits that alter the original context. Questions? Email us at  [email protected]

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How does smoking cause cancer?

• Smoking is the biggest cause of cancer in the UK, and worldwide.  
• Smoking damages the cells in our body and causes at least 15 different cancer types.  
• There is no safe level of smoking - s topping completely is the best thing you can do for your health, and there are tools and services to help you succeed.

What’s my cancer risk from smoking?

Smoking causes at least 15 different types of cancer and is the biggest cause of lung cancer in the UK. Smoking causes other diseases too, such as heart disease and various lung diseases.

If you smoke, stopping completely is the best thing you can do for your health.

Both the amount you smoke, and the length of time you’ve been smoking for, affect your cancer risk.

The more cigarettes you smoke a day, the higher your risk of cancer. So reducing the number of cigarettes you smoke a day is a good first step.

But the number of years you smoke for affects your cancer risk the most . So it’s important to make a plan to stop smoking completely.

The sooner you stop, the lower your risk of cancer. Everyone who smokes can benefit from stopping, and it’s never too late to stop - even if you’ve smoked for years. Speak to your doctor or pharmacist, free local stop smoking service, or visit NHS Smokefree to get support on how to stop smoking for good.

Find out more about how to stop smoking

What types of cancer does smoking cause?

The link between smoking and cancer is very clear. It causes at least 15 different types of cancer, including two of the most common types: lung cancer and bowel cancer.

Cancers caused by smoking include:

• nose and sinuses
• pharynx (upper throat)
• larynx (voice box)
• oesophagus (food pipe)
• some types of leukaemia

There is growing evidence that smoking also causes other types of cancer, including breast cancer. But we need more quality research to be able to say for certain that smoking causes breast cancer.

infographic_tobacco-related_cancers_uk_screen_1.png

Smoking causes cancer in multiple ways. The main way is by damaging the DNA in our cells.

DNA controls how our cells grow and behave. Damage to DNA causes cells to behave in ways that they’re not supposed to. And the build-up of DNA damage over time can lead to cancer.

how_smoking_causes_cancer_v4_002.png

Cigarette smoke contains over 5000 chemicals and many of these are harmful - we know at least 70 can cause cancer.

When smoking, the harmful chemicals enter our lungs and affect the entire body.

These chemicals damage our DNA, including parts of our DNA that protect us against cancer.

Chemicals in cigarette smoke also make it harder for our cells to repair DNA damage. This means DNA damage can build up.

It’s the build-up of DNA damage in the same cell over time that leads to cancer.

You can find more information on the chemicals in cigarettes that cause cancer and what smoking does to the body on our webpage.

What causes lung cancer?

Smoking is the biggest cause of lung cancer. And lung cancer is the most common cause of cancer death.

Smoking causes more than 7 in 10 lung cancer cases in the UK. Both active smoking and passive smoking cause lung cancer. Passive smoking is when a person breathes in someone else’s tobacco smoke. You can find out more about passive smoking on our webpage.

There are some other things that increase your risk of lung cancer, which you can learn more about on our causes of lung cancer page.

People who smoke sometimes have a cough. But coughing can be a sign of lung cancer, as well as other health conditions.  If you have a persistent cough, breathlessness or any other symptom that’s new for you or won’t go away, it’s important that you tell your doctor about it. If you have any doubts, don’t ignore it.

Remember, it’s never too late to stop smoking and reduce your risk of lung cancer. The best way to reduce your risk is to stop smoking completely.

Our tips and support to help you stop smoking for good .

Does light, occasional and social smoking cause cancer?

Yes, ‘light’, ‘occasional’, or ‘social smoking’ still increases your risk of cancer.

Even smoking fewer cigarettes than 1 a day increases the risk of dying early, compared to people who have never smoked. And studies looking at people who smoke fewer than 10 cigarettes per day show an increased risk of smoking-related cancers and other diseases.

Reducing the number of cigarettes you smoke a day is a good first step. But, there is no safe level of smoking. The best thing you can do for your health is to stop smoking completely, and it is never too late to stop.

Key references

Brown, K. F. et al. The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015. Br. J. Cancer. 118, 1130–1141 (2018).

Cancer Research UK. Lung cancer statistics. Cruk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer 

International Agency for Research on Cancer. Personal Habit and Indoor Combustion: Tobacco Smoking. 100 E, 377–504 (2012).

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Smoking and Lung Cancer: An Overview 1,2

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Lawrence A. Loeb , Virginia L. Emster , Kenneth E. Warner , John Abbotts , John Laszlo; Smoking and Lung Cancer: An Overview 1,2 . Cancer Res 1 December 1984; 44 (12_Part_1): 5940–5958.

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This position paper summarizes the overwhelming evidence that tobacco smoking is the cause of 30 to 40% of deaths from cancer. The focus is on lung cancer because of the sheer magnitude of this disease in males and the likelihood of a similar epidemic in females. There are two categories of evidence that indicate smoking to be the major cause of human lung cancer. Without exception, epidemiological studies have demonstrated a consistent association between smoking and lung cancer in men and now suggest a similar association in women. Chemical analyses of cigarette smoke reveal a multitude of known mutagens and carcinogens. Moreover, these chemicals are absorbed, are metabolized, and cause demonstrable genetic changes in smokers. Two consequences of smoking are evaluated. The results of treatment of lung cancer are not encouraging; despite vigorous therapy, the 5-year survival rate remains less than 10%. The social and economic costs of lung cancer and the smoking habit impinge on the productiveness of our society.

A position paper of the American Association for Cancer Research, Inc., commissioned by the Association's Scientific and Public Affairs Committee. Individual sections were prepared as follows: Epidemiology, V. L. Emster; Carcinogenesis, L. A. Loeb; Clinical Aspects of Lung Cancer, J. Laszlo; The Economics of Smoking and Lung Cancer, K. E. Warner.

Reprint requests for both individual and bulk orders should be addressed to: American Association for Cancer Research, Inc., Temple University School of Medicine, West Building, Room 301, Phila., PA 19140.

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Lung cancer still biggest cancer killer, but death rates are improving, report finds

Fastest decline in lung cancer mortality reported to date in canada.

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MaryAnn Bradley was bracing herself for a heart disease diagnosis when her cardiologist told her an X-ray showed a shadow on her right lung.

"I just thought I was going to die. That was it," she said.

Bradley, now 68, had been pushing doctors to find out what was behind an unrelenting pain in the left side of her neck.

The St. Catharines, Ont., woman was "completely devastated" to learn she had Stage 1 lung cancer, especially because her father had died of the disease years before.

'I've never looked back'

A few weeks later, a thoracic surgeon removed the tumour.

"Everything went fantastically well," Bradley said.

She's been cancer-free for 10 years now, and goes back for CT scans to make sure it's caught early if it ever returns.

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"I had a great recovery and I've never looked back," said Bradley, who now advocates for early detection of lung cancer and volunteers with Lung Cancer Canada as a peer mentor for others who get the diagnosis.

An annual report on cancer statistics released Wednesday says more people with lung cancer are surviving like Bradley.

Lung cancer death rates are declining faster than any other type of cancer in this country, according to Canadian Cancer Statistics 2023 , which is compiled by the Canadian Cancer Statistics Advisory Committee, along with the Canadian Cancer Society, Statistics Canada and the Public Health Agency of Canada.

Epidemiologist credits anti-smoking policies

Lung cancer death rates have decreased by 4.3 per cent per year since 2014 for males and 4.1 per cent per year since 2016 for females, the report says.

"To me, this finding really highlights the progress that has been made in reducing lung cancer incidence through commercial tobacco control," said Jennifer Gillis, an epidemiologist in Vancouver and senior manager of surveillance at the Canadian Cancer Society.

According to the cancer society, smoking tobacco is a factor in about 72 per cent of lung cancer deaths.

As of 2021, about 11.8 per cent of people age 12 and older in Canada smoked, Statistics Canada says.

WATCH | Driving down smoking rates:

Canadian smokers will soon see warnings printed on individual cigarettes

The Canadian Cancer Society aims to reduce the smoking rate to five per cent by 2035, estimating it could prevent more than 50,000 cancer cases.

Other risk factors that can increase someone's risk for lung cancer include radon gas, asbestos and air pollution, it said.

Still biggest cancer killer

More research is also needed on e-cigarettes and vaping to determine the long-term effects of the chemicals they contain, the report said. 

It's one of the great sadnesses I have that I meet people for the first time and we talk about that they may have lung cancer and there's so much self-blame there.

In addition to cutting down smoking rates, the report reflects progress in early screening and advances in treatment options, Gillis said.

"We're really improving outcomes for people who have been diagnosed and are affected by lung cancer," she said.

But despite the progress made, lung cancer is still responsible for about one in four cancer deaths in Canada, and remains the leading cause of cancer mortality, the report said.

The report estimates 20,600 people in Canada are expected to die from lung cancer in 2023.

Early screening is key

Statistics Canada estimates lung cancer survival rates are 62 per cent for people diagnosed at Stage 1, and 39 per cent at Stage 2. That drops to 16 per cent at Stage 3 and three per cent at Stage 4.

The report says colorectal cancer is expected to be the second leading cause of cancer death in 2023, followed by pancreatic cancer.

Early lung cancer screening through CT scans makes a "powerful" difference, said Dr. Christian Finley, a thoracic surgeon at McMaster University in Hamilton, and a member of the Canadian Cancer Statistics Advisory Committee.

• New regulations mean warnings like 'poison in every puff' will soon be on every cigarette
• AI shows major promise in breast cancer detection, new studies suggest

Ontario and British Columbia are running programs and several other provinces are trying to pilot them, he said.

Where lung cancer screening is available now, it's targeted to people with a long history of smoking, Finley said.

Reducing stigma around lung cancer is also critical, he said.

"It's one of the great sadnesses I have that I meet people for the first time and we talk about that they may have lung cancer and there's so much self-blame there," Finley said.

'You always have that bit of guilt'

Bradley has experienced that stigma first-hand.

Although she's not a regular smoker, "my workmates and I would go out on Friday evening after work and have a drink, and with that drink we would have a cigarette," she said.

"Was that the cause of my cancer? I don't know. There was nothing that pointed towards that," Bradley said.

• Analysis Canada has some of the highest teen vaping rates in the world, new data shows 
• Alcohol should have cancer warning labels, say doctors and researchers pushing to raise awareness of risk

"You always have that bit of guilt that maybe if I didn't do that, I wouldn't have gotten cancer."

Stigma around lung cancer is so damaging that it can even affect people's health-care decisions, Bradley said.

A couple of years ago, she volunteered as a peer mentor for a 48-year-old man in Thunder Bay, Ont., who had been diagnosed with lung cancer, she said.

He died and talking about him still brings her close to tears.

"He refused treatment because he blamed himself," Bradley said.

"He just said, 'No, I've done this to myself. I can't go through anything. I just can't because I did this to myself.' He was so depressed. It was really awful," she said.

Stigma and shame around lung cancer has also affected funding for research, prevention and treatment, said Finley.

Compared to other cancers, lung cancer is "dramatically underfunded," he said, which the society is working to change.

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November 17, 2023

This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility:

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Expert highlights the importance of lung cancer screening

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How lung cancer screening works

2023 Mayo Clinic News Network. Distributed by Tribune Content Agency, LLC.

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