Abstract
Lung cancer is the most common cause of cancer-related deaths globally. Although smoking-related lung cancers continue to account for the majority of diagnoses, smoking rates have been decreasing for several decades. Lung cancer in individuals who have never smoked (LCINS) is estimated to be the fifth most common cause of cancer-related deaths worldwide in 2023, preferentially occurring in women and Asian populations. As smoking rates continue to decline, understanding the aetiology and features of this disease, which necessitate unique diagnostic and treatment paradigms, will be imperative. New data have provided important insights into the molecular and genomic characteristics of LCINS, which are distinct from those of smoking-associated lung cancers and directly affect treatment decisions and outcomes. Herein, we review the emerging data regarding the aetiology and features of LCINS, particularly the genetic and environmental underpinnings of this disease as well as their implications for treatment. In addition, we outline the unique diagnostic and therapeutic paradigms of LCINS and discuss future directions in identifying individuals at high risk of this disease for potential screening efforts.
Key points
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The global incidence of lung cancer is decreasing in parallel with declining smoking rates in developed countries; however, the incidence of lung cancer in individuals who have never smoked (LCINS) is stable or increasing.
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LCINS is the eighth leading cause of cancer-related mortality in the USA and the fifth most common cause of cancer-related deaths worldwide.
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LCINS has histological and epidemiological distinctions from smoking-related lung cancers, occurring almost exclusively as adenocarcinomas and most commonly in women and individuals of Asian ancestry.
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LCINS are highly enriched for targetable oncogenic alterations, have low tumour mutational burden and low rates of PD-L1 positivity, and lack mutational signatures, even in patients who report passive, secondhand smoke exposure.
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LCINS development probably involves interactions between genetic risk, mediated by common and rare germline variants, and environmental exposures, including air pollution and particulate matter, with potential opportunities for broader lung cancer screening.
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In the era of precision oncology, the biological underpinnings of LCINS necessitate unique diagnostic and treatment paradigms and warrant consideration of this disease as an important and distinct clinical entity.
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The authors gratefully acknowledge M. Makarem, R. Collins, I. Odintsov and B. Johnson (at the Dana-Farber Cancer Institute) for their careful review of the manuscript and/or thoughtful discussions as well as Z. Wei and A. Tramontano (at the Dana-Farber Cancer Institute) and A. Shtein and Y. Wei (at the Harvard School of Public Health) for their assistance with data gathering and visualization.
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P.A.J. declares consultancy roles for Abbvie, Accutar Biotech, Allorion Therapeutics, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Chugai Pharmaceuticals, Daiichi Sankyo, DualityBio, Eisai, Eli Lilly, Frontier Medicines, Hongyun Biotechnology, Merus, Mirati Therapeutics, Monte Rosa, Novartis, Nuvalent, Pfizer, Roche/Genentech, Sanofi, Scorpion Therapeutics, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, Takeda Oncology, Transcenta and Voronoi; stock ownership in Gatekeeper Pharmaceuticals; research funding from AstraZenenca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA Biotechnology, Revolution Medicines and Takeda Oncology; and post-marketing royalties from Dana-Farber Cancer Institute-owned intellectual property relating to EGFR mutations that has been licensed to Lab Corp. The other authors declare no competing interests.
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LoPiccolo, J., Gusev, A., Christiani, D.C. et al. Lung cancer in patients who have never smoked — an emerging disease. Nat Rev Clin Oncol 21, 121–146 (2024). https://doi.org/10.1038/s41571-023-00844-0
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DOI: https://doi.org/10.1038/s41571-023-00844-0
