Modeling the complex smoking exposure history in assessment of pan-cancer risk

Abstract

This study used UK Biobank data from ~500 000 participants to examine how smoking intensity and duration jointly shape the risk of 12 smoking-related cancers. We modeled excess relative risks (ERRs) per pack-year, separating the effect of smoking intensity while holding total pack-years constant to compare low-intensity/long-duration with high-intensity/short-duration patterns. For the same cumulative exposure, cancer risk increases differed across these smoking patterns, indicating that pack-years alone do not fully capture carcinogenic risk. We further evaluated time since cessation (TSC) and found that longer TSC was associated with lower ERR/pack-year for most cancers. Lifestyle factors modified these associations: participants with favorable behaviors (e.g., regular physical activity and healthier diet) generally had lower ERRs/pack-year than those with unfavorable behaviors. Overall, our findings show that smoking pattern and cessation history meaningfully influence pan-cancer risk beyond cumulative exposure, supporting the incorporation of detailed smoking histories—intensity, duration, and cessation—into risk stratification, screening eligibility, and prevention strategies.

Keywords

pan-cancer / complex smoking exposure / excess relative risk / prospective cohort / effect modification

References

[1] Siegel RL , Giaquinto AN , Jemal A . Cancer statistics, 2024. CA Cancer J Clin 2024; 74(1): 12–49

[2] Thomson B , Emberson J , Lacey B , Lewington S , Peto R , Islami F . Association of smoking initiation and cessation across the life course and cancer mortality: prospective study of 410 000 US adults. JAMA Oncol 2021; 7(12): 1901–1903

[3] Tu H , Ye Y , Huang M , Xie K , Chow WH , Zhao H , Wu X . Smoking, smoking cessation, and survival after cancer diagnosis in 128, 423 patients across cancer types. Cancer Commun (Lond) 2022; 42(12): 1421–1424

[4] Thun MJ , Carter BD , Feskanich D , Freedman ND , Prentice R , Lopez AD , Hartge P , Gapstur SM . 50-year trends in smoking-related mortality in the United States. N Engl J Med 2013; 368(4): 351–364

[5] Baris D , Karagas MR , Verrill C , Johnson A , Andrew AS , Marsit CJ , Schwenn M , Colt JS , Cherala S , Samanic C , Waddell R , Cantor KP , Schned A , Rothman N , Lubin J , Fraumeni JF , Hoover RN , Kelsey KT , Silverman DT . A case—control study of smoking and bladder cancer risk: emergent patterns over time. J Natl Cancer Inst 2009; 101(22): 1553–1561

[6] Lubin JH , Virtamo J , Weinstein SJ , Albanes D . Cigarette smoking and cancer: intensity patterns in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finnish men. Am J Epidemiol 2008; 167(8): 970–975

[7] Lubin JH , Caporaso NE . Cigarette smoking and lung cancer: modeling total exposure and intensity. Cancer Epidemiol Biomarkers Prev 2006; 15(3): 517–523

[8] Lubin JH , Gaudet MM , Olshan AF , Kelsey K , Boffetta P , Brennan P , Castellsague X , Chen C , Curado MP , Dal Maso L , Daudt AW , Fabianova E , Fernandez L , Wünsch-Filho V , Franceschi S , Herrero R , Koifman S , La Vecchia C , Lazarus P , Levi F , Lissowska J , Mates IN , Matos E , McClean M , Menezes A , Morgenstern H , Muscat J , Eluf Neto J , Purdue MP , Rudnai P , Schwartz SM , Shangina O , Sturgis EM , Szeszenia-Dabrowska N , Talamini R , Wei Q , Winn D , Zhang ZF , Hashibe M , Hayes RB . Body mass index, cigarette smoking, and alcohol consumption and cancers of the oral cavity, pharynx, and larynx: modeling odds ratios in pooled case-control data. Am J Epidemiol 2010; 171(12): 1250–1261

[9] Lubin JH , Couper D , Lutsey PL , Woodward M , Yatsuya H , Huxley RR . Risk of cardiovascular disease from cumulative cigarette use and the impact of smoking intensity. Epidemiology 2016; 27(3): 395–404

[10] Lubin JH , Caporaso N , Wichmann HE , Schaffrath-Rosario A , Alavanja MC . Cigarette smoking and lung cancer: modeling effect modification of total exposure and intensity. Epidemiology 2007; 18(5): 639–648

[11] Vlaanderen J , Portengen L , Schüz J , Olsson A , Pesch B , Kendzia B , Stücker I , Guida F , Brüske I , Wichmann HE , Consonni D , Landi MT , Caporaso N , Siemiatycki J , Merletti F , Mirabelli D , Richiardi L , Gustavsson P , Plato N , Jöckel KH , Ahrens W , Pohlabeln H , Tardón A , Zaridze D , Field JK , ’t Mannetje A , Pearce N , McLaughlin J , Demers P , Szeszenia-Dabrowska N , Lissowska J , Rudnai P , Fabianova E , Stanescu Dumitru R , Bencko V , Foretova L , Janout V , Boffetta P , Forastiere F , Bueno-de-Mesquita B , Peters S , Brüning T , Kromhout H , Straif K , Vermeulen R . Effect modification of the association of cumulative exposure and cancer risk by intensity of exposure and time since exposure cessation: a flexible method applied to cigarette smoking and lung cancer in the SYNERGY Study. Am J Epidemiol 2014; 179(3): 290–298

[12] Lubin JH , Alavanja MC , Caporaso N , Brown LM , Brownson RC , Field RW , Garcia-Closas M , Hartge P , Hauptmann M , Hayes RB , Kleinerman R , Kogevinas M , Krewski D , Langholz B , Letourneau EG , Lynch CF , Malats N , Sandler DP , Schaffrath-Rosario A , Schoenberg JB , Silverman DT , Wang Z , Wichmann HE , Wilcox HB , Zielinski JM . Cigarette smoking and cancer risk: modeling total exposure and intensity. Am J Epidemiol 2007; 166(4): 479–489

[13] Lubin JH , Kogevinas M , Silverman D , Malats N , Garcia-Closas M , Tardón A , Hein DW , Garcia-Closas R , Serra C , Dosemeci M , Carrato A , Rothman N . Evidence for an intensity-dependent interaction of NAT2 acetylation genotype and cigarette smoking in the Spanish Bladder Cancer Study. Int J Epidemiol 2007; 36(1): 236–241

[14] van Osch FHM , Vlaanderen J , Jochems SHJ , Bosetti C , Polesel J , Porru S , Carta A , Golka K , Jiang X , Stern MC , Zhong WD , Kellen E , Pohlabeln H , Tang L , Marshall J , Steineck G , Karagas MR , Johnson KC , Zhang ZF , Taylor JA , La Vecchia C , Bryan RT , van Schooten FJ , Wesselius A , Zeegers MP . Modeling the complex exposure history of smoking in predicting bladder cancer: a pooled analysis of 15 case-control studies. Epidemiology 2019; 30(3): 458–465

[15] Flanders WD , Lally CA , Zhu BP , Henley SJ , Thun MJ . Lung cancer mortality in relation to age, duration of smoking, and daily cigarette consumption: results from Cancer Prevention Study II. Cancer Res 2003; 63(19): 6556–6562

[16] Sudlow C , Gallacher J , Allen N , Beral V , Burton P , Danesh J , Downey P , Elliott P , Green J , Landray M , Liu B , Matthews P , Ong G , Pell J , Silman A , Young A , Sprosen T , Peakman T , Collins R . UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med 2015; 12(3): e1001779

[17] Centers for Disease Control and Prevention. Health effects of cigarettes: cancer 2024. Available at the website of www. cdc. gov/tobacco/about/cigarettes-and-cancer. html

[18] Liu M , Jiang Y , Wedow R , Li Y , Brazel DM , Chen F , Datta G , Davila-Velderrain J , McGuire D , Tian C , Zhan X , Choquet H , Docherty AR , Faul JD , Foerster JR , Fritsche LG , Gabrielsen ME , Gordon SD , Haessler J , Hottenga JJ , Huang H , Jang SK , Jansen PR , Ling Y , Mägi R , Matoba N , McMahon G , Mulas A , Orrù V , Palviainen T , Pandit A , Reginsson GW , Skogholt AH , Smith JA , Taylor AE , Turman C , Willemsen G , Young H , Young KA , Zajac GJM , Zhao W , Zhou W , Bjornsdottir G , Boardman JD , Boehnke M , Boomsma DI , Chen C , Cucca F , Davies GE , Eaton CB , Ehringer MA , Esko T , Fiorillo E , Gillespie NA , Gudbjartsson DF , Haller T , Harris KM , Heath AC , Hewitt JK , Hickie IB , Hokanson JE , Hopfer CJ , Hunter DJ , Iacono WG , Johnson EO , Kamatani Y , Kardia SLR , Keller MC , Kellis M , Kooperberg C , Kraft P , Krauter KS , Laakso M , Lind PA , Loukola A , Lutz SM , Madden PAF , Martin NG , McGue M , McQueen MB , Medland SE , Metspalu A , Mohlke KL , Nielsen JB , Okada Y , Peters U , Polderman TJC , Posthuma D , Reiner AP , Rice JP , Rimm E , Rose RJ , Runarsdottir V , Stallings MC , Stančáková A , Stefansson H , Thai KK , Tindle HA , Tyrfingsson T , Wall TL , Weir DR , Weisner C , Whitfield JB , Winsvold BS , Yin J , Zuccolo L , Bierut LJ , Hveem K , Lee JJ , Munafò MR , Saccone NL , Willer CJ , Cornelis MC , David SP , Hinds DA , Jorgenson E , Kaprio J , Stitzel JA , Stefansson K , Thorgeirsson TE , Abecasis G , Liu DJ , Vrieze S . Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet 2019; 51(2): 237–244

[19] Sedgwick P . Poisson regression. BMJ 2014; 349: g6150

[20] Biobank UK. 2017 UK Physical activity guidelines. 2017. Available at the website of biobank. ctsu. ox. ac. uk/crystal/field. cgi?id=22036

[21] Mozaffarian D . Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review. Circulation 2016; 133(2): 187–225

[22] Lourida I , Hannon E , Littlejohns TJ , Langa KM , Hyppönen E , Kuzma E , Llewellyn DJ . Association of lifestyle and genetic risk with incidence of dementia. JAMA 2019; 322(5): 430–437

[23] Ussher MH , Faulkner GEJ , Angus K , Hartmann-Boyce J , Taylor AH . Exercise interventions for smoking cessation. Cochrane Libr 2019; 2019(10): CD00229

[24] Patriota P , Guessous I , Marques-Vidal P . No changes in dietary intake after quitting smoking; a prospective study in Switzerland. BMC Nutr 2021; 7(1): 34

[25] Frome EL , Checkoway H . Use of Poisson regression models in estimating incidence rates and ratios. Am J Epidemiol 1985; 121(2): 309–323

[26] Richardson DB . A simple approach for fitting linear relative rate models in SAS. Am J Epidemiol 2008; 168(11): 1333–1338

[27] Park E , Kang HY , Lim MK , Kim B , Oh JK . Cancer risk following smoking cessation in Korea. JAMA Netw Open 2024; 7(2): e2354958

[28] Colamesta V , D’Aguanno S , Breccia M , Bruffa S , Cartoni C , La Torre G. . Do the smoking intensity and duration, the years since quitting, the methodological quality and the year of publication of the studies affect the results of the meta-analysis on cigarette smoking and acute myeloid leukemia (AML) in adults?. Crit Rev Oncol Hematol 2016; 99: 376–388

[29] Krebs NM , Chen A , Zhu J , Sun D , Liao J , Stennett AL , Muscat JE . Comparison of puff volume with cigarettes per day in predicting nicotine uptake among daily smokers. Am J Epidemiol 2016; 184(1): 48–57

[30] Zhang P , Chen PL , Li ZH , Zhang A , Zhang XR , Zhang YJ , Liu D , Mao C . Association of smoking and polygenic risk with the incidence of lung cancer: a prospective cohort study. Br J Cancer 2022; 126(11): 1637–1646

[31] Etter JF , Perneger TV . Measurement of self reported active exposure to cigarette smoke. J Epidemiol Community Health 2001; 55(9): 674–680

[32] Sugden K , Hannon EJ , Arseneault L , Belsky DW , Broadbent JM , Corcoran DL , Hancox RJ , Houts RM , Moffitt TE , Poulton R , Prinz JA , Thomson WM , Williams BS , Wong CCY , Mill J , Caspi A . Establishing a generalized polyepigenetic biomarker for tobacco smoking. Transl Psychiatry 2019; 9(1): 92

[33] Hecht SS . Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 2003; 3(10): 733–744

[34] Liu Y , Lu L , Yang H , Wu X , Luo X , Shen J , Xiao Z , Zhao Y , Du F , Chen Y , Deng S , Cho CH , Li Q , Li X , Li W , Wang F , Sun Y , Gu L , Chen M , Li M . Dysregulation of immunity by cigarette smoking promotes inflammation and cancer: a review. Environ Pollut 2023; 339: 122730

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