Lung Cancer in People Who Have Never Smoked
Heather Wakelee, MD
Lung cancer is the leading cause of cancer death for both men and women in the United States, and globally it is the leading cause of cancer death in men and the second leading cause in women.1 Smoking is the most common cause of lung cancer, but there are many people who have never smoked who develop lung cancer. Lung cancer in people who have never smoked is more common in Asia, especially women.1 The causes of lung cancer in people who have never smoked are not well understood. Lung cancer treatments can work differently in people who have never smoked.
People who have never smoked (“never-smokers”) are defined as people who have smoked < 100 cigarettes in their lifetime. The information about how many people develop cancer each year comes from cancer registries that have information about the type of cancer and age of the person, but no information may be available about smoking history. Therefore, it is unknown exactly how many people with lung cancer do or do not smoke. We can make estimates though about how many people with lung cancer have developed the disease without a smoking history.
Worldwide, approximately 15% to 20% of men with lung cancer, and 50% of women with lung cancer, are people who have never smoked.1 In the United States, approximately 1 in 10 men, and 1 in 5 women, with lung cancer are people who have never smoked.2 The number of men who have never smoked and who develop lung cancer each year is similar to the number of men who develop multiple myeloma, a cancer of the immune system. The number of women who have never smoked and who develop lung cancer each year is similar to the number of women who develop cervical cancer.
It is unknown whether the frequency of developing lung cancer is increasing in people who have never smoked. A study in Swedish construction workers who had never smoked showed an increased frequency of lung cancer in the 1990’s compared with the 1970’s.3 In the United States, more women who had never smoked died of lung cancer in the 1980’s and 1990’s than in the 1960’s.4 However, there is no other evidence of an increased incidence of lung cancer in people who have never smoked, and some studies show no increase.5-6 These types of studies are difficult to do because we do not have smoking information available in the same databases that capture information about the number of patients who develop lung cancer. There is a sense among doctors who treat lung cancer that the number of people with lung cancer who have never smoked is increasing. Studies are being done to try to get a better answer to that question, but at this time it remains uncertain.
There are several known differences between lung cancer in smokers and people who have never smoked, including the specific type of cancer. Lung cancer in smokers frequently is often a type called “small cell lung cancer” or a form of “non-small cell lung cancer (NSCLC)” known as “squamous cell carcinoma”. Adenocarcinoma, a different type of NSCLC, is more common in people who have never smoked.1, 7 However, people with a smoking history can also develop adenocarcinoma of the lung and those who have never smoked are rarely diagnosed with squamous cell lung cancer or small cell lung cancer. The only way to know what kind of lung cancer it is for sure is to have a biopsy that is examined by a pathology doctor.
It is also known that lung cancer in people from certain racial/ethnic groups is more often seen in never-smokers than in other racial groups. This is true for people of Asian ancestry and Hispanics.8-10 Most of the risk is seen in women. We know that the percentage of women with lung cancer who have never smoked is higher than the percentage of men with lung cancer who have never smoked.2 The reason for these differences is not known. People are looking at air pollution as a cause of lung cancer in never-smokers.
Tumors from patients who have never smoked frequently have different changes in the DNA than the tumors from smokers, including changes in a protein known as the epidermal growth factor receptor (EGFR).11-16 Tumors with specific changes in the EGFR protein are more likely to shrink when treated with drugs that attack the EGFR protein, (such as erlotinib, gefitinib and afatinib). Another change that is more common in people with no smoking history who develop lung cancer is with the Anaplastic Lymphoma Kinase (ALK) gene.17-18 The drugs crizotinib, ceritinib and alectinib are used to treat lung cancer patients who have the ALK gene rearrangement.19
Other changes in DNA are frequently different between lung cancer tumors from smokers and people who have never smoked, and the major DNA change that is important for the cancer can be identified in approximately half of patients in research studies. Most commonly, patients have only a single major change in the DNA, and a patient with a change in the EGFR gene usually does not also have an ALK gene rearrangement. Testing for these DNA changes is now considered standard for patients who have been diagnosed with non-small cell lung cancer, especially adenocarcinoma, to help guide treatment and better understand the disease in each individual. There are lung cancer patients who have never smoked who do not have any of these gene mutations. However, it is important that testing is done to look for EGFR, ALK and ROS1 at a minimum in lung cancer patients who have never-smoked. The number of other gene mutations or gene rearrangements that can lead to changes in treatment are rapidly growing. In addition to EGFR, ALK and ROS1 we now can look for changes in BRAF, RET, MET, and HER2 and can offer specific “targeted” therapy when identified in tumors of patients with metastatic disease. These gene changes can also be seen in patients with a smoking history who develop lung cancer, but they seem to be more common in patients without a smoking history.
The causes of lung cancer in people who have never smoked are unknown, but several factors may increase the risk (Table 1).20 Second hand smoke may cause 20% of the lung cancers in people who have never smoked21-22 Air pollution may cause 5% of cases of the disease.23 Indoor air pollution, such as fumes from cooking oil and smoke from burning coal, may increase lung cancer risk, especially in Asia.24
Radon is a colorless, odorless, radioactive gas that occurs naturally in some parts of the United States and other countries. Some homes have high levels of radon, and this can be tested with home kits. People who live in homes with high levels of radon are at a higher risk of developing lung cancer, whether or not they smoke.25-26
Jobs that expose people to toxic substances, such as uranium, asbestos, chromium, and arsenic, may increase the risk of developing lung cancer.27-29 Arsenic may be present in drinking water in some areas such as Taiwan and Chile.30-31 Nutritional deficiencies may contribute to the development of cancer, and people who eat more fruits and vegetables may be at lower risk for developing lung cancer.32-35
Lung damage from radiation therapy may increase the risk of developing lung cancer. Furthermore,
lung cancer risk may be increased in people who have the human papilloma virus, but not everyone agrees with that risk.36 At this time there is no proof that human papilloma virus causes lung cancer. People with family members who have lung cancer have a slightly higher risk of developing lung cancer, but the magnitude and cause of this risk are unknown.20, 37-40Research is being done to try to find what changes in the DNA (genes) may make certain families at higher risk for lung cancer. So far we don’t know any DNA changes that are definitely linked to a higher risk of lung cancer in families and we don’t have a test to help people know if they are at risk. This research is ongoing.
Table 1. Possible Causes of Lung Cancer in People Who Have Never Smoked
- Second hand smoke
- Radon exposure
- Other toxins (asbestos, chromium, or arsenic)
- Dietary factors (diet deficient in fruits and vegetables)
- Air pollution (including cooking fumes)
- Radiation therapy to the chest
- Other lung diseases such as idiopathic pulmonary fibrosis
- Human papilloma virus (controversial)
- Other family members with lung cancer
- Differences in ability to fix DNA damage
Treatment of Lung Cancer in People Who Have Never Smoked
People with lung cancer who have never smoked may live longer, but may or may not respond better to chemotherapy, than smokers with lung cancer. Basic treatment usually is similar for people with lung cancer whether or not they have a smoking history.
People who have never smoked and who have lung cancer are more likely to have changes in specific genes. Though we do not know what causes the changes, we do know that specific gene changes can be the driving force in a cancer. These gene changes are not seen in the normal cells from a person with lung cancer, only in the cancer cells.
The gene changes we know the most about that are more common in the lung cancer of people who are never smoked are in the genes Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK) and ROS1. In recent years more gene changes that can be the driving force behind lung cancer in never smokers have been discovered. There are specific treatments available for people with lung cancer with changes in some of these genes such as erlotinib, gefitinib or afatinib for EGFR gene mutations and crizotinib, ceritinib or alectinib for ALK gene changes.13-14 Crizotinib is also active in ROS1. In addition to EGFR, ALK and ROS1 we now can look for changes in BRAF, RET, MET, and HER2 and can offer specific “targeted” therapy when identified in tumors of patients with metastatic disease. Specific BRAF inhibitors approved for use in melanoma including vemurafenib or the combination of dabrafenib/trametinib are active with many BRAF mutations. HER2 active drugs include afatinib and trastuzumab. Multiple drugs are active for RET including cabozantinib and vandetinib and cabozantinib is also active for METexon 14 splice site variations, as is crizotinib.
For most people diagnosed with stage IV (also called metastatic or advanced stage) non-small cell lung cancer the first treatment is chemotherapy. Chemotherapy can also work very well for patients with tumors with specific gene mutations; however, if we find the gene mutation before chemotherapy is started we usually start with a drug “targeted” to treat the gene mutation. It is very important for all patients with advanced stage lung cancer, especially patients who are never-smokers where it is more common, to have their tumor tested for the gene changes.
Patients with metastatic lung cancer who have specific EGFR gene changes should receive erlotinib, gefitinib, or afatinib as the initial treatment, even before the typical chemotherapy regimen, based on studies that have shown that they have a higher chance of shrinking the tumor than chemotherapy for these patients.13, 41-42 People who start therapy with a “targeted” drug also have a longer time before the cancer starts to regrow and new treatment is needed. Chemotherapy can be further delayed with the approval of osimertinib for patients who have tumors with EGFR mutations who have initially responded to an EGFR drug and then became resistant due to a resistance mutation called T790M in EGFR. For ALK positive tumors we now have 3 drugs approved which can be used in sequence and many others are in development.
Erlotinib is not usually added to chemotherapy because the results of combining chemotherapy and erlotinib or gefitinib are not better than giving the chemotherapy alone as the first course of treatment. Recent studies looked at whether or not to continue the “targeted” drug after it stops working as well. Usually at that time chemotherapy is started and the question was whether the targeted drug should be continued when chemotherapy is started. The recent IMPRESS trial showed that it is not good in the majority of patiients to continue the targeted drug when chemotherapy is started. We now also have 3rd generation EGFR targeted drugs like osimertinib that work for the majority of patients (especially if the T790M mutation has developed) when the initial drug (erlotinib, gefitinib or afatinib) stop working. Current research is also evaluating whether erlotinib or gefitinib may help prevent the return of cancer in people with early stage lung cancer that has been removed with surgery. So far the studies have not proven that erlotinib or gefitnib after surgery leads to improved chance of cure. There are studies being done in Asia and the United States though to explore that question.
For patients who have the ALK gene rearrangement (most common in lung cancer patients who have never smoked), the drug crizotinib is now available to be given either after completion of chemotherapy in patients with metastatic non-small cell lung cancer, or before the chemotherapy is started.42 We know that crizotinib works better than chemotherapy as the first treatment in patients with the ALK gene rearrangement in their tumor.43 In 2014 the drug ceritinib (LDK378) was approved in the United States for patients with tumors with ALK gene rearrangements whose tumor was growing after the use of crizotinib.44 Alectinib was approved in 2015 for patients after crizotinib and there are studies to determine if it is better to start with alectinib instead of crizotinib. There are now many other drugs being developed for use in ALK+ lung cancer.
Other mutations that can be the driving force behind lung cancer and offer other treatment options if they are found are also being investigated.
Many other gene changes that can lead to lung cancer have been discovered in the past few years as outlined above.43-44 Some of these are also known to be cancer causing in other cancers like melanoma (BRAF mutations) and many have other targeted therapy available (HER2 mutations) as outlined above. Regardless of smoking status, the gene mutation profile of a lung cancer is now important for deciding on the best treatment. The gene mutations that have specific therapies are more common in cancer in never smokers. Many of the exciting developments in lung cancer starting in 2015 are related to immune targeted therapy. Those drugs have been shown to work in lung cancer regardless of smoking history, but perhaps less in patients with no smoking history. Efforts to get immune therapy to work in patients with limited smoking history are ongoing with multiple combination drug studies. At this point it is standard to offer immune therapy such as nivolumab or pembrolizumab to patients who have previously received chemotherapy and have developed progression of disease.45-47 The use of these drugs as first line therapy in selected patients is likely to become standard soon. How to best utilize these treatments in patients who develop lung cancer as never-smokers, and in patients with molecularly targeted mutations, is under investigation.20, 37-40
Lung cancer can happen to anybody, whether or not that person has ever smoked. Though, overall, lung cancer is very similar in patients whether or not they have a history of smoking, there are some differences. These include the types of people with the disease (never-smokers with lung cancer are more likely to be women, Asian, or Hispanic and potentially younger), and the type of lung cancer (adenocarcinoma is more common in never-smokers).
Some causes of lung cancer other than smoking have been identified, including second-hand smoke, radon exposure, cooking fumes, family history, and others. We know that patients with the disease who are never smokers are more likely to have mutations in the EGFR gene, ALK gene rearrangements or other gene changes in the tumor that can change treatment plans. Patients who have specific EGFR gene changes have a better response to EGFR blocking drugs like erlotinib and afatinib, and patients with the ALK gene rearrangement usually respond well to crizotinib, alectinib or ceritinib. Further research will provide more information about the cause of this type of lung cancer and how to best treat patients with this illness. People who want to know more about this topic can look at recent reviews that have been written for doctors.7, 48
1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90.
2. Wakelee HA, Chang ET, Gomez SL, et al. Lung cancer incidence in never smokers. J Clin Oncol. 2007;25:472-8.
3. Boffetta P, Järvholm B, Brennan P, et al. Incidence of lung cancer in a large cohort of non-smoking men from Sweden. Int J Cancer. 2001;94:591-3.
4. Thun MJ, Henley SJ, Burns D, et al. Lung cancer death rates in lifelong nonsmokers. J Natl Cancer Inst. 2006;98:691-9.
5. Peto R, Darby S, Deo H, et al. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ. 2000;321:323-9.
6. Kawaguchi T, Matsumura A, Fukai S, et al. Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and Southern California Regional Cancer Registry databases. J Thorac Oncol. 2010;5:1001-10.
7. Subramanian J, Govindan R. Lung cancer in ‘Never-smokers’: a unique entity. Oncology (Williston Park). 2010;24:29-35.
8. Ou SI, Ziogas A, Zell JA. Epidemiology study of people who have never smoked with non-small cell lung cancer (NSCLC): High percentages of Asian and Hispanic female people who have never smoked and the significance of Asian ethnicity. J Clin Oncol. 2008;26:425s (Abstr #8004).
9. Epplein M, Schwartz SM, Potter JD, et al. Smoking-adjusted lung cancer incidence among AsianAmericans (United States). Cancer Causes Control. 2005;16:1085-90.
10. Gomez SL, Chang ET, Shema SJ, et al. Survival following non-small cell lung cancer among Asian/Pacific Islander, Latina, and Non-Hispanic white women who have never smoked. Cancer Epidemiol Biomarkers Prev. 2011;20:545-54.
11. Sonobe M, Manabe T, Wada H, et al. Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer. 2005;93:355-63.
12. Kosaka T, Yatabe Y, Endoh H, et al. Mutations of the epidermal growth factor receptor gene in lung
cancer: biological and clinical implications. Cancer Res. 2004;64:8919-23.
13. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer – molecular and clinical predictors of
outcome. N Engl J Med. 2005;353:133-44.
14. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from
“never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad
Sci U S A. 2004;101:13306-11.
15. Pham D, Kris MG, Riely GJ, et al. Use of cigarette-smoking history to estimate the likelihood of
mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin
16. Tam IY, Chung LP, Suen WS, et al. Distinct epidermal growth factor receptor and KRAS mutation
patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic
features. Clin Cancer Res. 2006;12:1647-53.
17. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALKrearranged
lung adenocarcinoma in the western population. Clin Cancer Res. 2009;15:5216-23.
18. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with nonsmall-cell
lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-53.
19. Crinò L, Ahn MJ, De Marinis F, et al. Multicenter Phase II Study of Whole-Body and Intracranial
Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously
Treated With Chemotherapy and Crizotinib: Results From ASCEND-2.
20. Brenner DR, Hung RJ, Tsao MS, et al. Lung cancer risk in never-smokers: a population-based casecontrol
study of epidemiologic risk factors. BMC Cancer. 2010;10:285.
21. Wu A. Carcinogenic effects, in Shopland DR, Zeise L, Dunn A (eds): Health Effects of Exposure to
Enrironmental Tobacco Smoke. Bethesda, MD, National Cancer Institute, 1999.
22. Vineis P, Alavanja M, Buffler P, et al. Tobacco and cancer: recent epidemiological evidence. J Natl
Cancer Inst. 2004;96:99-106.
23. Vineis P, Hoek G, Krzyzanowski M, et al. Lung cancers attributable to environmental tobacco smoke
and air pollution in non-smokers in different European countries: a prospective study. Environ Health.
24. Kleinerman RA, Wang Z, Wang L, et al. Lung cancer and indoor exposure to coal and biomass in
rural China. J Occup Environ Med. 2002;44:338-44.
25. Krewski D, Lubin JH, Zielinski JM, et al. A combined analysis of North American case-control
studies of residential radon and lung cancer. J Toxicol Environ Health A. 2006;69:533-97.
26. Darby S, Hill D, Auvinen A, et al. Radon in homes and risk of lung cancer: collaborative analysis of
individual data from 13 European case-control studies. BMJ. 2005;330:223.
27. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer: looking to the future. J Clin Oncol.
28. Gottschall EB. Occupational and environmental thoracic malignancies. J Thorac Imaging. 2002;17:189-
29. Neuberger JS, Field RW. Occupation and lung cancer in nonsmokers. Rev Environ Health.
30. Chen CL, Hsu LI, Chiou HY, et al. Ingested arsenic, cigarette smoking, and lung cancer risk: a followup
study in arseniasis-endemic areas in Taiwan. JAMA. 2004;292:2984-90.
31. Ferreccio C, González C, Milosavjlevic V, et al. Lung cancer and arsenic concentrations in drinking
water in Chile. Epidemiology. 2000;11:673-9.
32. Wakai K, Ando M, Ozasa K, et al. Updated information on risk factors for lung cancer: findings from
the JACC Study. J Epidemiol. 2005;15 Suppl 2:S134-9.
33. Feskanich D, Ziegler RG, Michaud DS, et al. Prospective study of fruit and vegetable consumption
and risk of lung cancer among men and women. J Natl Cancer Inst. 2000;92:1812-23.
34. Galeone C, Negri E, Pelucchi C, et al. Dietary intake of fruit and vegetable and lung cancer risk: a
case-control study in Harbin, northeast China. Ann Oncol. 2007;18:388-92.
35. Gorlova OY, Weng SF, Hernandez L, et al. Dietary patterns affect lung cancer risk in never smokers.
Nutr Cancer. 2011;63:842-9.
36. Cheng YW, Chiou HL, Sheu GT, et al. The association of human papillomavirus 16/18 infection
with lung cancer among nonsmoking Taiwanese women. Cancer Res. 2001;61:2799-803.
37. Wu AH, Fontham ET, Reynolds P, et al. Family history of cancer and risk of lung cancer among
lifetime nonsmoking women in the United States. Am J Epidemiol. 1996;143:535-42.
38. Brownson RC, Alavanja MC, Caporaso N, et al. Family history of cancer and risk of lung cancer in
lifetime non-smokers and long-term ex-smokers. Int J Epidemiol. 1997;26:256-63.
39. Gorlova OY, Zhang Y, Schabath MB, et al. Never smokers and lung cancer risk: a case-control study
of epidemiological factors. Int J Cancer. 2006;118:1798-804.
40. Bailey-Wilson JE, Amos CI, Pinney SM, et al. A major lung cancer susceptibility locus maps to
chromosome 6q23-25. Am J Hum Genet. 2004;75:460-74.
41. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary
adenocarcinoma. N Engl J Med. 2009;361:947-57.
42. Mok T, Kim DW, Wu YL, Solomon BJ, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, et
al. First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients with
advanced ALK-positive non-squamous non-small cell lung cancer: Results of a phase III study
(Profile 1004) Proceeding of ASCO 2014, abstr 8002
43. YL, Solomon BJ, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, et al. First-line crizotinib
versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients with advanced ALK-positive nonsquamous
non-small cell lung cancer: Results of a phase III study (Profile 1004) Proceeding of ASCO
2014, abstr 8002
44. Shaw AT et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar
45. Borghaei H, Paz-Ares L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-SmallCell
Lung Cancer. JR. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643.
Epub 2015 Sep 27. PMID: 26412456 :
46. Brahmer J, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung
Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31.
47. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-
positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet.
2016 Apr 9;387(10027):1540-50. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19. PMID:
48. Rudin CM, Avila-Tang E, Harris CC, et al. Lung cancer in never smokers: molecular profiles and
therapeutic implications. Clin Cancer Res. 2009;15:5646-61.