Environmental tobacco smoke (ETS) exposure is hypothesized to influence survival after breast cancer, but few studies have examined this association

Bradshaw, Patrick T.

Conway, Kathleen

Engel, Lawrence S.

Gammon, Marilie D.

Neugut, Alfred I.

Parada, Humberto

Santella, Regina M.

Steck, Susan E.

Teitelbaum, Susan L.

English

PubMed

Carolina Digital Repository

Environmental Tobacco Smoke Exposure and Survival Following Breast CancerHumberto Parada Jr.a,*, Patrick T. Bradshawb, Lawrence S. Engela, Kathleen Conwaya, Susan E. Steckc, Susan L. Teitelbaumd, Alfred I. Neugute,f, Regina M. Santellag, and Marilie D. GammonaaDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAbDivision of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA, USAcDepartment of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC, USAdDepartment of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USAeDepartment of Epidemiology, Columbia University, New York, NY, USAfDepartment of Medicine, Columbia University, New York, NY, USAgDepartment of Environmental Health Sciences, Columbia University, New York, NY, USAAbstractBackground—Environmental tobacco smoke (ETS) exposure is hypothesized to influence survival after breast cancer, but few studies have examined this association.Methods—A population-based cohort of women (N=1,508) diagnosed with first primary invasive or in situ breast cancer in 1996–1997 was interviewed shortly after diagnosis and again approximately 5 years later to assess ETS exposure, and women were followed for over 18 years using the National Death Index; 597 deaths (237 associated with breast cancer) were identified. Multivariable Cox regression was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for mortality among women with breast cancer as related to at-diagnosis and at-/post-diagnosis changes in ETS exposure.Results—There was little or no association between at-diagnosis ETS exposure and all-cause (HR=1.04, 95% CI=0.78–1.40) or breast cancer-specific (HR=0.98, 95% CI=0.63–1.52) mortality. Mortality was elevated among women who reported cessation in post-diagnosis ETS exposure up to one year before the follow-up assessment, for all-cause (HR=1.81, 95% CI=0.87–3.74) and breast cancer mortality (HR=1.89, 95% CI=0.68–5.24); however, estimates were imprecise.Conclusions—We found little evidence of an association between at-diagnosis ETS exposure and mortality after breast cancer. Post-diagnosis cessation of ETS exposure was positively *Corresponding author: Humberto Parada; University of North Carolina at Chapel Hill, Department of Epidemiology, 2101 McGavran-Greenberg Hall, CB #7435, Chapel Hill, NC 27599-7435. Telephone: 919-636-9236. hparada@live.unc.edu. Conflicts of interest: None declaredHHS Public AccessAuthor manuscriptCancer Epidemiol Biomarkers Prev. Author manuscript; available in PMC 2018 February 01.Published in final edited form as:Cancer Epidemiol Biomarkers Prev. 2017 February ; 26(2): 278–280. doi:10.1158/1055-9965.EPI-16-0658.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptassociated with mortality, although we could not rule out chance and reverse causation as possible explanations.Impact—Exposure to ETS does not appear to influence mortality after breast cancer.Keywordsenvironmental tobacco smoke; second-hand smoke; passive smoke; breast cancer; mortality; survival analysisIntroductionFew studies (1–4) have examined whether environmental tobacco smoke (ETS) exposure increases the risk of mortality among women with breast cancer and no studies to date have prospectively examined the impact of post-diagnosis changes in ETS exposure on mortality. This study examined whether ETS exposure was associated with long-term all-cause and breast cancer-specific mortality among a population-based sample of women.Materials and MethodsParticipants of the Long Island Breast Cancer Study Project (LIBCSP), a population-based cohort of women newly diagnosed with breast cancer, were interviewed shortly after diagnosis and again about 5 years later, and now continue to be followed for vital status. Details of the LIBCSP have been published previously (2,5). Institutional Review Board approval was obtained from of all participating institutions.Environmental Tobacco Smoke Exposure AssessmentETS exposure was determined via structured interviews (2). Women were asked to report whether any members of the household smoked in their presence, the relationship of the smoker, the participant’s ages at first/last exposure, and any time periods the household member did not smoke. Duration of exposure was categorized as <15 years, ≥15–<30 years, and ≥30 years of exposure. Recency of exposure was categorized as <5 years, ≥5–<10 years, and ≥10 years.Covariate assessmentCovariates assessed via questionnaire included: age, menopausal status, annual household income, education, marital status, body mass index, physical activity, intake of alcoholic beverages, cigarette smoking, and treatment. Estrogen receptor status and nodal involvement were determined by medical record. Tumor size was obtained from the NY State Cancer Registry.Outcome AssessmentVital status of the 1,508 women diagnosed with breast cancer was determined using the National Death Index. Follow-up for mortality occurred from the date of diagnosis in 1996–1997 until December 31, 2014 (median=17.61 years). We identified 597 deaths; 234 were associated with breast cancer.Parada et al. Page 2Cancer Epidemiol Biomarkers Prev. Author manuscript; available in PMC 2018 February 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptStatistical AnalysisUsing multivariable Cox proportional regression models, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for the associations between at-diagnosis as well as at-/post-diagnosis changes in ETS exposure and mortality following breast cancer. Models restricted to women with invasive cancer only yielded similar results from those of all women; only the latter are shown. All analyses were conducted using IBM SPSS Statistics Version 22.0 (IBM Corp., Armonk, NY).In analyses of at-diagnosis ETS exposure, survival time began at the date of breast cancer diagnosis and ended on the date of death or, if alive, December 31, 2014. In analyses examining post-diagnosis ETS exposure, survival time began at the date of completion of the follow-up questionnaire and ended on the date of death or, if alive, December 31, 2014. Missing covariates were imputed in SPSS using 25 imputations with 1,000 iterations. The imputation models included age at diagnosis, menopausal status, income, education, marital status, BMI, physical activity, and alcohol intake, smoking status, post-diagnosis ETS exposure, disease characteristics (stage, tumor size, nodal involvement estrogen receptor status), treatment (radiation, chemotherapy, and hormone therapies), and the outcome (the event indicator and the Nelson-Aalen cumulative hazard estimator).ResultsApproximately 15% of women reported ETS exposure in the year before diagnosis and 14% reported current exposure at the follow-up questionnaire.At-Diagnosis Environmental Tobacco Smoke ExposureThere was little or no association between current ETS exposure and all-cause (HR=1.04, 95% CI=0.78–1.40) or breast cancer-specific (HR=0.98, 95% CI=0.63–1.52) mortality after adjustment for covariates (Table 1). Risk of mortality was slightly elevated for all-cause (HR=1.17, 95% CI=0.74–1.86) and breast cancer-specific (HR=1.13, 95% CI=0.57–2.27) mortality when we restricted the analyses to never smokers, though the corresponding estimates imprecise.At-/Post-Diagnosis Environmental Tobacco Smoke ExposureThough no associations were observed among women with ongoing ETS exposure, HRs were elevated 81% (HR=1.81, 95% CI=0.87–3.74) for all-cause mortality and 89% (HR=1.89, 95% CI=0.68–5.24) for breast cancer-specific mortality among women who reported cessation in post-diagnosis ETS exposure up to the year before the follow-up assessment (Table 2).DiscussionExposure to the constituents of tobacco smoke, either through active smoking or exposure to ETS, is hypothesized to influence breast cancer progression through several mechanisms, including directly by influencing cell proliferation and metastasis (6), and indirectly by disrupting the endocrine system (7). Additionally, because up to 70% of tar in ETS is in the Parada et al. Page 3Cancer Epidemiol Biomarkers Prev. Author manuscript; available in PMC 2018 February 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptvapor phase, whereas all of the tar in direct smoking is in the particulate phase, ETS may be an important source of exposure to carcinogens since particulate smoke is cleared into the mouth and swallowed, but vapor phase constituents are inhaled and absorbed into the bloodstream and lymph system (8). Despite these hypothesized mechanisms, the few studies conducted to date (1–4), including the sufficiently powered study reported here, provide limited or no evidence of an association between ETS exposure and survival after breast cancer. While we observed an elevated risk of mortality among women with post-diagnosis cessation of ETS exposure, we could not rule out chance and reverse causation as possible explanations.AcknowledgmentsGrant SupportThe Long Island Breast Cancer Study Project was funded by the National Cancer Institute and the National Institutes of Environmental Health Sciences grants UO1CA/ES66572 and UO1CA66572 awarded to M.D. Gammon. H. Parada was supported by T32 ES007018 and R25 CA057726.References1. Boone SD, Baumgartner KB, Baumgartner RN, Connor AE, John EM, Giuliano AR, et al. Active and passive cigarette smoking and mortality among Hispanic and non-Hispanic white women diagnosed with invasive breast cancer. Ann Epidemiol. 2015; 25:824–831. [PubMed: 26387598] 2. Sagiv SK, Gaudet MM, Eng SM, Abrahamson PE, Shantakumar S, Teitelbaum SL, et al. Active and passive cigarette smoke and breast cancer survival. Ann Epidemiol. 2007; 17:385–393. [PubMed: 17395485] 3. Kakugawa Y, Kawai M, Nishino Y, Fukamachi K, Ishida T, Ohuchi N, et al. Smoking and survival after breast cancer diagnosis in Japanese women: A prospective cohort study. Cancer Sci. 2015; 106:1066–1074. [PubMed: 26052951] 4. Wartenberg D, Calle EE, Thun MJ, Heath, Clark WJ, Lally C, Woodruff T. Passive smoking exposure and female breast cancer mortality. J Natl Cancer Inst. 2000; 92:1666–1673. [PubMed: 11036112] 5. Bradshaw PT, Ibrahim JG, Stevens J, Cleveland R, Abrahamson PE, Satia JA, et al. Postdiagnosis change in bodyweight and survival after breast cancer diagnosis. Epidemiology. 2012; 23:320–327. [PubMed: 22317813] 6. Dasgupta P, Rizwani W, Pillai S, Kinkade R, Kovacs M, Rastogi S, et al. Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines. Int J Cancer. 2009; 124:36–45. [PubMed: 18844224] 7. Bekki K, Toriba A, Tang N, Kameda T, Hayakawa K. Biological effects of polycyclic aromatic hydrocarbon derivatives. J UOEH. 2013; 35:17–24. [PubMed: 23475020] 8. Wells AJ. Breast cancer, cigarette smoking, and passive smoking. Am J Epidemiol. 1991; 133:208–210. [PubMed: 1985448] Parada et al. Page 4Cancer Epidemiol Biomarkers Prev. Author manuscript; available in PMC 2018 February 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptParada et al. Page 5Table 1Cox regression hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between pre-diagnosis and at-diagnosis environmental tobacco smoke (ETS) exposure and mortality in the LIBCSP women diagnosed with breast cancer in 1996–1997 (N=1,508).All-Cause Mortality (n deaths=597)Breast Cancer-Specific Mortality (n deaths=237)ETS ExposureAge-AdjustedMultivariable-AdjustedbAge-AdjustedMultivariable-AdjustedbAt-diagnosisDeathsCensoredHR (95% CI)HR (95% CI)DeathsCensoredHR (95% CI)HR (95% CI)ETS exposure statusa  Never1191761 (Ref.)1 (Ref.)492461 (Ref.)1 (Ref.)  Former3765851.00 (0.81–1.23)0.98 (0.80–1.22)1418200.87 (0.63–1.21)0.89 (0.64–1.24)  Current841381.25 (0.94–1.66)1.04 (0.78–1.40)381841.04 (0.68–1.59)0.98 (0.63–1.52)Duration of ETS exposure  Never1191761 (Ref.)1 (Ref.)492461 (Ref.)1 (Ref.)  Former    <15 years50911.05 (0.75–1.46)1.13 (0.80–1.59)241171.02 (0.62–1.66)1.10 (0.67–1.81)    ≥15–<30 years1312890.89 (0.69–1.14)0.90 (0.69–1.16)603600.84 (0.57–1.23)0.84 (0.57–1.24)    ≥30 years1751871.06 (0.84–1.34)1.00 (0.79–1.28)543080.90 (0.61–1.33)0.89 (0.60–1.33)  Current    <15 years771.74 (0.81–3.73)1.52 (0.70–3.27)<512--    ≥15–<30 years13221.59 (0.89–2.84)1.32 (0.74–2.36)6291.08 (0.46–2.55)0.97 (0.41–2.29)    ≥30 years621061.14 (0.83–1.55)0.93 (0.67–1.29)301381.07 (0.68–1.69)1.01 (0.63–1.61)ETS exposure recency  Never1191761 (Ref.)1 (Ref.)492461 (Ref.)1 (Ref.)  Former    <5 years26411.05 (0.69–1.60)0.95 (0.62–1.47)12551.07 (0.57–2.01)0.99 (0.52–1.87)    ≥5–<10 years47691.07 (0.77–1.51)1.00 (0.71–1.41)161000.82 (0.47–1.45)0.76 (0.43–1.35)    ≥10 years3034750.99 (0.80–1.22)0.99 (0.79–123)1136650.86 (0.62–1.21)0.90 (0.64–1.27)  Current841381.25 (0.94–1.66)1.04 (0.78–1.40)381841.04 (0.68–1.59)0.98 (0.63–1.53)Long Island Breast Cancer Study Project (LIBCSP) participants diagnosed with breast cancer between August 1, 1996 and July 31, 1997, followed-up for vital status through December 31, 2014.a ETS exposure status was defined as never, former, and current exposure to tobacco smoke from any household members.Cancer Epidemiol Biomarkers Prev. Author manuscript; available in PMC 2018 February 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptParada et al. Page 6b Adjusted for age at diagnosis, body mass index, marital status, income, alcohol intake, physical activity, and active cigarette smoking status.Cancer Epidemiol Biomarkers Prev. Author manuscript; available in PMC 2018 February 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor ManuscriptParada et al. Page 7Table 2Cox regression hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between at-/post-diagnosis environmental tobacco smoke exposure (ETS) and mortality in the LIBCSP women diagnosed with breast cancer in 1996–1997 (n=1,339).All-Cause Mortality (n deaths=428)Breast Cancer-Specific Mortality (n deaths=126)ETS ExposureAge-AdjustedMultivariable-AdjustedaAge-AdjustedMultivariable-AdjustedaAt-diagnosis/Post-diagnosisDeathsCensoredHR (95% CI)HR (95% CI)DeathsCensoredHR (95% CI)HR (95% CI)ETS exposure status  Never/Never791631 (Ref.)1 (Ref.)232191 (Ref.)1 (Ref.)  Never/Former10181.14 (0.44–2.94)0.94 (0.35–2.58)<524––  Former/Never2515291.03 (0.79–1.35)1.03 (0.78–1.36)697110.93 (0.56–1.54)0.92 (0.55–1.54)  Former/Former5140.96 (0.21–4.54)0.72 (0.14–3.58)<518––  Former/Current21481.32 (0.72–2.43)1.05 (0.56–1.99)8611.16 (0.43–3.18)0.87 (0.31–2.46)  Current/Never22431.29 (0.76–2.20)1.19 (0.67–2.09)6581.00 (0.38–2.63)0.88 (0.32–2.42)  Current/Former14181.99 (0.97–4.09)1.81 (0.87–3.74)6262.20 (0.81–5.97)1.89 (0.68–5.24)  Current/Current26781.18 (0.70–1.99)1.02 (0.59–1.77)8960.82 (0.33–2.06)0.66 (0.24–1.81)Long Island Breast Cancer Study Project (LIBCSP) participants diagnosed with breast cancer between August 1, 1996 and July 31, 1997, followed-up for vital status through December 31, 2014. Complete-case analyses exclude women who died within 5 years of breast cancer diagnosis (n=169)a Adjusted for age at diagnosis, body mass index, marital status, income, alcohol intake, physical activity, stage, tumor size, nodal involvement, estrogen receptor status, chemotherapy treatment, and post-diagnosis active cigarette smoking status.Cancer Epidemiol Biomarkers Prev. Author manuscript; available in PMC 2018 February 01.

Environmental Tobacco Smoke Exposure and Survival Following Breast Cancer

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Environmental Tobacco Smoke Exposure and Survival Following Breast Cancer

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