APIK Journal of Internal Medicine

: 2022  |  Volume : 10  |  Issue : 3  |  Page : 143--145

Lung cancer in never smokers: The smoke beyond tobacco

K Govind Babu1, Aparna Sreevatsa2,  
1 Health Care Global (HCG) Hospital and St. John's Medical College Hospital, Bengaluru, Karnataka, India
2 Health Care Global (HCG) Hospital, Nanjappa Hospitals, Shimoga, Karnataka, India

Correspondence Address:
K Govind Babu
8/1, 3rd Cross, 1st R Block, Rajajinagar, Bengaluru - 560 010, Karnataka

How to cite this article:
Babu K G, Sreevatsa A. Lung cancer in never smokers: The smoke beyond tobacco.APIK J Int Med 2022;10:143-145

How to cite this URL:
Babu K G, Sreevatsa A. Lung cancer in never smokers: The smoke beyond tobacco. APIK J Int Med [serial online] 2022 [cited 2022 Sep 28 ];10:143-145
Available from: https://www.ajim.in/text.asp?2022/10/3/143/350751

Full Text

Lung cancer is the most common cause of cancer-related death worldwide (Globocan 2020).[1] In India, lung cancer is one among the top five cancers in both incidence and mortality. Although majority of lung cancers are caused by smoking tobacco, a significant number of patients are never smokers. Never smokers are those who smoked less than 100 cigarettes in their lifetime.[2] Lung cancer in never smokers (LCINS) is a distinct entity with significant differences in terms of epidemiology, pathology, molecular biology, natural history, and response to treatment compared to lung cancer in smokers. Public health measures taken to curb the menace of smoking have led to decreased incidence of lung cancer as evidenced by the Surveillance, Epidemiology, and End Results (SEER) program that has epidemiological data collected from 1930. The developing countries continue to struggle with even the basic diagnostic issues such as clearly differentiating squamous carcinoma and adenocarcinomas, when advanced techniques such as next-generation sequencing are becoming the essential step to dissect out the various subtypes of lung cancer and institute personalized therapies.

Tobacco smoking has several reasons to become an addiction; the end result is enslaving the person to nicotine and the associated ill effects of all the carcinogenic and other chemicals. The SEER database also shows a disturbing increasing trend of tobacco use in women, while there is a fall in male tobacco users worldwide. The filter-less cigarettes of the past caused more of squamous cell carcinomas, while the filtered ones have led to a change from squamous to adenocarcinomas. The change in these smoking habits associated with this addition of varied filters has also led to change in location of lung tumors from being central to more peripheral ones. The arrival of electronic cigarettes is a challenge; although its relationship to causation of lung cancer is unclear, it seems to renormalize the smoking behavior by rather taking away the social stigma attached with tobacco smoking.

Studies suggest that the incidence of LCINS is on the rise.

Nonsmokers are exposed to inhaled carcinogens from environmental, domestic, and occupational exposures. Secondhand smoke (SHS) is a mixture of side stream smoke and exhaled mainstream smoke that nonsmokers inhale at home, workplace, or leisure activities.[3] We also have tertiary or third-hand smoking (THS), which is the smoke and its contents released after they have settled on several house articles such as blankets, towels, and napkins. Exposure to SHS and THS is difficult to quantify.

Genetic susceptibility to inhaled carcinogens due to enzymes involved in the metabolism of carcinogens might be important. Occupational exposure to asbestos, arsenic, and silica is associated with chronic irritation, inflammation, and carcinogenesis.[4] Domestic exposure to irritants is an unrecognized cause of lung cancer in women.[5] Using biomass fuel and coal for cooking in poorly ventilated kitchens is a risk factor for LCINS. Stir-frying, deep-frying, and pan-frying in open pans, which involve heating oil to high temperatures, lead to volatilization of oils and can be carcinogenic. Women may also be at a higher risk due to hormonal predisposition. Indoor exposure to radon is another risk factor for LCINS.

Adenocarcinoma is the most common histology seen in LCINS. Small cell lung cancer (SCLC) is rare in nonsmokers.[6] LCINS is more commonly associated with oncogenic driver mutations such as Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK) and Rous Sarcoma virus / Orphan Receptor kinase (ROS) rearrangements, and Human Epidermal Receptor 2 ( HER2) compared to lung cancer in smokers.[7] Smokers are more commonly associated with Kirsten Rat Sarcoma (K RAS), Mesenchymal Epidermal Transition Factor Receptor (MET), and Rapidly Activated Fibrosarcoma Homolog B1 (BRAF) compared to nonsmokers. Targeted therapy in addition to chemotherapy has changed the natural history of LCINS and improved survival of patients even in metastatic disease.

Screening for lung cancer with low-dose computed tomography (CT) is more beneficial in women compared to men and needs further emphasis.[8] Circulating tumor DNA analysis of volatile organic compounds in breath and artificial intelligence-enhanced interpretation of CT scans might improvise the screening efforts in the days to come.

The last decade has seen tremendous progress in the management of lung cancer, leading to the median survival on metastatic disease having a dismal 5-year survival of 4%–5% converting to over 30%–40%. All this has been possible due to our better understanding of the disease contributed by advances in molecular biology techniques, rapid improvement in bioinformatics, more sensitive imaging modalities, and better drugs that include chemotherapy, targeted therapy, and immunotherapy and vastly, strengthened supportive care measures.

Early-stage non-SCLC (NSCLC) is assessed for surgical resection and lobectomy is the standard of care in fit patients. In unfit patients, radiotherapy (RT) (stereotactic ablative body RT) is the preferred treatment. For resected NSCLC stage IB to III, adjuvant chemotherapy is the standard of care. In patients who are EGFR positive, adjuvant osimertinib following adjuvant chemotherapy has shown to improve disease-free survival (ADAURA).[9]

Stage III unresectable NSCLC is treated with concurrent chemoradiotherapy but has high risk of disease relapse. Adjuvant durvalumab for 12 months following CT-Computerized tomography, RT- Radiotherapy (CT RT) has shown improved progression-free survival (PFS) and overall survival (OS) (PACIFIC).[10]

In metastatic NSCLC, treatment options are guided by the EGFR, ALK, ROS, and PD L1 status. There is geographical variation in the prevalence of EGFR mutations.[11] First-generation (gefitinib and erlotinib) and second-generation (afatinib and dacomitinib) EGFR tyrosine kinase inhibitors (TKIs) have significantly improved PFS compared to chemotherapy doublets. Osimertinib is a third-generation EGFR TKI with activity against mutant EGFR and the most common EGFR TKI resistance mutation, Thr790Met. Osimertinib crosses blood–brain barrier (BBB) and improves OS compared to geftinib and erlotinib. Lazertinib, a third-generation EGFR TKI, and amivantamab, an EGFR-MET antibody, have also shown promising activity in patients who are treatment naïve and those who progressed on Onib.[12]

ALK gene rearrangement is seen in 3%–5% of NSCLC. Crizotinib was the first ALK TKI shown to be superior to chemotherapy with OS up to 4 years. Second-generation TKIs alectinib, ceretinib, brigatinib, and ensartinib cross BBB. Alectinib and brigatinib are approved for first-line use ALK-positive NSCLC. Lorlatinib is a novel third-generation ALK TKI, which has activity against ALK resistance mutations.[13]

ROS1 rearrangement is seen in 1%–2% of NSCLC. Crizotinib and entrectinib are FDA approved in patients with ROS-positive NSCLC.[14] Lorlatinib and repotrectinib are more potent inhibitors of ROS and are effective in patients resistant to crizotinib and entrectinib.

Patients with HER2 positive by immunohistochemistry (IHC) or HER2 amplification by Flourescent In situ Hybridization (FISH) benefit from trastuzumab deruxtecan and trastuzumab emtansine.

Patients progressing on first-line or second-line targeted agents are candidates for immune check point inhibitors. Anti-Programmed Death Receptor (PD) Programmed Death Receptor Ligand 1 (PD L1) antibodies are shown to be superior to second-line chemotherapy in patients progressing on second-line EGFR TKIs.

LCINS is an unrecognized disease entity which is a major health problem. SHS needs public health measures and commitment by lawmakers. Parents should consider the ill effects of SHS on the growing children and take action about their tobacco indulgence. There is unmet need for research in understanding of LCINS women and health effects of domestic exposure to carcinogens.

Screening efforts are required by primary care physicians for early detection of lung cancer. The screening programs do carry a substantial cost, but doing program for the high risk population is cost-effective. The most effective method remains to date is increased awareness not only in the general public but also in the primary care physicians, especially in developing countries where pulmonary tuberculosis is rampant and every prolonged cough and shadow on the chest X-ray is empirically treated as tuberculosis without the basic workup to rule out other possible causes.

Ajit Harsha et al. in their paper “Spectrum of Non-Peripheral Lung Tumors in Rural Areas in Tertiary Medical Center,” in this issue document and describe their experience of lung tumors in their center over a span of 8 years from 2012 to 2020, an impressive data collection indeed. They have essentially captured the essence in the difference of lung tumors, especially lung cancer occurring in smokers versus nonsmokers also documenting the shift in histology of the tumors. As described in this Editorial, the shift in histology has various reasons including smoking pattern changes, differences in the choice of using beedies, and unfiltered and filtered cigarettes. Yet, another important issue is of the trained pathologists to emphatically categorize the histology.

The tissue obtained here is an endobronchial biopsy which definitely yields less tissue than a trucut core biopsy. I state this because in today's age of precision medicine – tissue is the issue. We need adequate tissue to get adequate molecular data for instituting the right treatment for our patients. Many times, our pulmonology friends have been able to obtain enough tissue on the endobronchial route, but it needs a discussion between the specialists involved. Tumors located centrally are more of squamous histology, with the peripheral ones being adenocarcinomas. The preponderance of squamous histology in this data set is thus expected. The pathologists are most often than not able to categorize the histology of the tumor based on the typical characteristics on hematoxylin and eosin stains but when in doubt IHC markers of TTF1 and P63 can help. Today's practice of lung cancer is incomplete without molecular profiling of the lung cancers, as the targeted therapies play a major role. We also know that these targetable mutations are more often seen in nonsmokers and they will benefit with these drugs. We in India are fortunate to have many of these generic and biosimilar drugs that are fairly affordable, hence the emphasis on molecular testing. The data set in this paper consists of 294 smokers and 92 nonsmokers; a treatment history and follow-up would have been very useful. Moreover, as the authors confess, the staging procedures were inadequate and all were endobronchial biopsies.

The targeted therapies and immunotherapies are now being exploited to downstage inoperable lung cancers to an operable, one which can lead to increasing number of patients being cured.

The nihilism that exists for lung cancer needs to end as data show that these patients are living longer as against in the past, and therefore, every patient should be getting a fair chance of leading a meaningful lifespan.


1Howlader N, Forjaz G, Mooradian MJ, Meza R, Kong CY, Cronin KA, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med 2020;383:640-9.
2Scagliotti GV, Longo M, Novello S. Nonsmall cell lung cancer in never smokers. Curr Opin Oncol 2009;21:99-104.
3Toyooka S, Matsuo K, Shigematsu H, Kosaka T, Tokumo M, Yatabe Y, et al. The impact of sex and smoking status on the mutational spectrum of epidermal growth factor receptor gene in non small cell lung cancer. Clin Cancer Res 2007;13:5763-8.
4Samet JM, Avila-Tang E, Boffetta P, Hannan LM, Olivo-Marston S, Thun MJ, et al. Lung cancer in never smokers: Clinical epidemiology and environmental risk factors. Clin Cancer Res 2009;15:5626-45.
5North CM, Christiani DC. Women and lung cancer: What's new? Semin Thorac Cardiovasc Surg 2013;25:87-94.
6Travis WD, Brambilla E, Burke A, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015.
7Kalemkerian GP, Narula N, Kennedy EB, Biermann WA, Donington J, Leighl NB, et al. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline update. J Clin Oncol 2018;36:911-9.
8de Koning HJ, van der Aalst CM, de Jong PA, Scholten ET, Nackaerts K, Heuvelmans MA, et al. Reduced lungcancer mortality with volume CT screening in a randomized trial. N Engl J Med 2020;382:503-13.
9Wu YL, Herbst RS, Mann H, Rukazenkov Y, Marotti M, Tsuboi M. ADAURA: Phase III, double-blind, randomized study of osimertinib versus placebo in EGFR mutation-positive early-stage NSCLC after complete surgical resection. Clin Lung Cancer 2018;19:e533-6.
10Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379:2342-50.
11Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: A systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 2015;5:2892-911.
12Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet 2021;398:535-54.
13Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Solomon B, et al. Lorlatinib vs. crizotinib in the first-line treatment of patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC): Results of the phase III CROWN study. Ann Oncol 2020;31:S1180-81.
14Drilon A, Siena S, Dziadziuszko R, Barlesi F, Krebs MG, Shaw AT, et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: Integrated analysis of three phase 1-2 trials. Lancet Oncol 2020;21:261-70.