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Cigarette smoking and endometrial carcinoma risk: the role of effect modification and tumor heterogeneity

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Abstract

Purpose

The inverse relationship between cigarette smoking and endometrial carcinoma risk is well established. We examined effect modification of this relationship and associations with tumor characteristics in the National Institutes of Health–AARP Diet and Health Study.

Methods

We examined the association between cigarette smoking and endometrial carcinoma risk among 110,304 women. During 1,029,041 person years of follow-up, we identified 1,476 incident endometrial carcinoma cases. Multivariable Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95 % confidence intervals (CIs) for the association between smoking status, years since smoking cessation, and endometrial carcinoma risk overall and within strata of endometrial carcinoma risk factors. Effect modification was assessed using likelihood ratio test statistics. Smoking associations by histologic subtype/grade and stage at diagnosis were also evaluated.

Results

Reduced endometrial carcinoma risk was evident among former (RR 0.89, 95 % CI 0.80, 1.00) and current (RR 0.65, 95 % CI 0.55, 0.78) smokers compared with never smokers. Smoking cessation 1–4 years prior to baseline was significantly associated with endometrial carcinoma risk (RR 0.65, 95 % CI 0.48, 0.89), while cessation ≥10 years before baseline was not. The association between smoking and endometrial carcinoma risk was not significantly modified by any endometrial carcinoma risk factor, nor did we observe major differences in risk associations by tumor characteristics.

Conclusion

The cigarette smoking–endometrial carcinoma risk relationship was consistent within strata of important endometrial carcinoma risk factors and by clinically relevant tumor characteristics.

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References

  1. Terry PD, Rohan TE, Franceschi S, Weiderpass E (2002) Cigarette smoking and the risk of endometrial cancer. Lancet Oncol 3(8):470–480

    Article  CAS  PubMed  Google Scholar 

  2. Services USDoHaH (2006), The health consequences of involuntary exposure to tobacco smoke: A Report of the Surgeon General. Atlanta, GA

  3. Zhou B, Yang L, Sun Q, Cong R, Gu H et al (2008) Cigarette smoking and the risk of endometrial cancer: a meta-analysis. Am J Med 121(6):501–508

    Article  CAS  PubMed  Google Scholar 

  4. Terry PD, Miller AB, Rohan TE (2002) A prospective cohort study of cigarette smoking and the risk of endometrial cancer. Br J Cancer 86(9):1430–1435

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Viswanathan AN, Feskanich D, De Vivo I, Hunter DJ, Barbieri RL et al (2005) Smoking and the risk of endometrial cancer: results from the Nurses’ Health Study. Int J Cancer 114(6):996–1001

    Article  CAS  PubMed  Google Scholar 

  6. Loerbroks A, Schouten LJ, Goldbohm RA, van den Brandt PA (2007) Alcohol consumption, cigarette smoking, and endometrial cancer risk: results from the Netherlands Cohort Study. Cancer Causes Control 18(5):551–560

    Article  PubMed Central  PubMed  Google Scholar 

  7. Nordlund LA, Carstensen JM, Pershagen G (1997) Cancer incidence in female smokers: a 26-year follow-up. Int J Cancer 73(5):625–628

    Article  CAS  PubMed  Google Scholar 

  8. Al-Zoughool M, Dossus L, Kaaks R, Clavel-Chapelon F, Tjonneland A et al (2007) Risk of endometrial cancer in relationship to cigarette smoking: results from the EPIC study. Int J Cancer 121(12):2741–2747

    Article  CAS  PubMed  Google Scholar 

  9. Kaaks R, Lukanova A, Kurzer MS (2002) Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev 11(12):1531–1543

    CAS  PubMed  Google Scholar 

  10. Bradlow HL, Telang NT, Sepkovic DW, Osborne MP (1996) 2-hydroxyestrone: the ‘good’ estrogen. J Endocrinol 150(Suppl):S259–S265

    CAS  PubMed  Google Scholar 

  11. Michnovicz JJ, Hershcopf RJ, Naganuma H, Bradlow HL, Fishman J (1986) Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med 315(21):1305–1309

    Article  CAS  PubMed  Google Scholar 

  12. Longcope C, Johnston CC Jr (1988) Androgen and estrogen dynamics in pre- and postmenopausal women: a comparison between smokers and nonsmokers. J Clin Endocrinol Metab 67(2):379–383

    Article  CAS  PubMed  Google Scholar 

  13. Mattison DR, Thorgeirsson SS (1978) Smoking and industrial pollution, and their effects on menopause and ovarian cancer. Lancet 1(8057):187–188

    Article  CAS  PubMed  Google Scholar 

  14. Gaudet MM, Gapstur SM, Sun J, Diver WR, Hannan LM et al (2013) Active smoking and breast cancer risk: original cohort data and meta-analysis. J Natl Cancer Inst 105(8):515–525

    Article  CAS  PubMed  Google Scholar 

  15. Porta M (2008) A dictionary of epidemiology, 5th edn. Oxford University Press, New York, NY

  16. Lawrence C, Tessaro I, Durgerian S, Caputo T, Richart R et al (1987) Smoking, body weight, and early-stage endometrial cancer. Cancer 59(9):1665–1669

    Article  CAS  PubMed  Google Scholar 

  17. Levi F, la Vecchia C, Decarli A (1987) Cigarette smoking and the risk of endometrial cancer. Eur J Cancer Clin Oncol 23(7):1025–1029

    Article  CAS  PubMed  Google Scholar 

  18. Brinton LA, Barrett RJ, Berman ML, Mortel R, Twiggs LB et al (1993) Cigarette smoking and the risk of endometrial cancer. Am J Epidemiol 137(3):281–291

    CAS  PubMed  Google Scholar 

  19. Parazzini F, La Vecchia C, Negri E, Moroni S, Chatenoud L (1995) Smoking and risk of endometrial cancer: results from an Italian case–control study. Gynecol Oncol 56(2):195–199

    Article  CAS  PubMed  Google Scholar 

  20. Newcomer LM, Newcomb PA, Trentham-Dietz A, Storer BE (2001) Hormonal risk factors for endometrial cancer: modification by cigarette smoking (United States). Cancer Causes Control 12(9):829–835

    Article  CAS  PubMed  Google Scholar 

  21. Chang SC, Lacey JV Jr, Brinton LA, Hartge P, Adams K et al (2007) Lifetime weight history and endometrial cancer risk by type of menopausal hormone use in the NIH–AARP diet and health study. Cancer Epidemiol Biomarkers Prev 16(4):723–730

    Article  CAS  PubMed  Google Scholar 

  22. Polesel J, Serraino D, Zucchetto A, Lucenteforte E, Dal Maso L et al (2009) Cigarette smoking and endometrial cancer risk: the modifying effect of obesity. Eur J Cancer Prev 18(6):476–481

    Article  CAS  PubMed  Google Scholar 

  23. Yang HP, Brinton LA, Platz EA, Lissowska J, Lacey JV Jr et al (2010) Active and passive cigarette smoking and the risk of endometrial cancer in Poland. Eur J Cancer 46(4):690–696

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Weiss NS, Farewall VT, Szekely DR, English DR, Kiviat N (1980) Oestrogens and endometrial cancer: effect of other risk factors on the association. Maturitas 2(3):185–190

    Article  CAS  PubMed  Google Scholar 

  25. Franks AL, Kendrick JS, Tyler CW Jr (1987) Postmenopausal smoking, estrogen replacement therapy, and the risk of endometrial cancer. Am J Obstet Gynecol 156(1):20–23

    Article  CAS  PubMed  Google Scholar 

  26. Schatzkin A, Subar AF, Thompson FE, Harlan LC, Tangrea J et al (2001) Design and serendipity in establishing a large cohort with wide dietary intake distributions : the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Am J Epidemiol 154(12):1119–1125

    Article  CAS  PubMed  Google Scholar 

  27. Assaf AR, Parker D, Lapane KL, McKenney JL, Carleton RA (2002) Are there gender differences in self-reported smoking practices? Correlation with thiocyanate and cotinine levels in smokers and nonsmokers from the Pawtucket Heart Health Program. J Womens Health (Larchmt) 11(10):899–906

    Article  Google Scholar 

  28. Petitti DB, Friedman GD, Kahn W (1981) Accuracy of information on smoking habits provided on self-administered research questionnaires. Am J Public Health 71(3):308–311

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Trabert B, Wentzensen N, Yang HP, Sherman ME, Hollenbeck AR, et al. (2013) Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk? Int J Cancer 132(2):417–426

    Google Scholar 

  30. Michaud D, Midthuner D, Hermansen S, Leitzmann MF, Harlan LC et al (2005) Comparison of cancer registry case ascertainment with SEER estimates and self-reporting in a subset of the NIH–AARP Diet and Health Study. J Registry Manag 32(2):6

    Google Scholar 

  31. Yang HP, Wentzensen N, Trabert B, Gierach GL, Felix AS et al (2013) Endometrial cancer risk factors by 2 main histologic subtypes: the NIH–AARP Diet and Health Study. Am J Epidemiol 177(2):142–151

    Article  PubMed Central  PubMed  Google Scholar 

  32. Brinton LA, Felix AS, McMeekin DS, Creasman WT, Sherman ME et al (2013) Etiologic heterogeneity in endometrial cancer: evidence from a gynecologic oncology group trial. Gynecol Oncol 129(2):277–284

    Article  PubMed  Google Scholar 

  33. Folsom AR, Demissie Z, Harnack L, Iowa Women’s Health S (2003) Glycemic index, glycemic load, and incidence of endometrial cancer: the Iowa women’s health study. Nutr Cancer 46(2):119–124

    Article  PubMed  Google Scholar 

  34. Lacey JV Jr, Leitzmann MF, Chang SC, Mouw T, Hollenbeck AR et al (2007) Endometrial cancer and menopausal hormone therapy in the National Institutes of Health–AARP Diet and Health Study cohort. Cancer 109(7):1303–1311

    Article  CAS  PubMed  Google Scholar 

  35. Jensen J, Christiansen C, Rodbro P (1985) Cigarette smoking, serum estrogens, and bone loss during hormone-replacement therapy early after menopause. N Engl J Med 313(16):973–975

    Article  CAS  PubMed  Google Scholar 

  36. Baron JA (1984) Smoking and estrogen-related disease. Am J Epidemiol 119(1):9–22

    CAS  PubMed  Google Scholar 

  37. Weiderpass E, Baron JA (2001) Cigarette smoking, alcohol consumption, and endometrial cancer risk: a population-based study in Sweden. Cancer Causes Control 12(3):239–247

    Article  CAS  PubMed  Google Scholar 

  38. MacMahon B, Trichopoulos D, Cole P, Brown J (1982) Cigarette smoking and urinary estrogens. N Engl J Med 307(17):1062–1065

    Article  CAS  PubMed  Google Scholar 

  39. Friedman AJ, Ravnikar VA, Barbieri RL (1987) Serum steroid hormone profiles in postmenopausal smokers and nonsmokers. Fertil Steril 47(3):398–401

    CAS  PubMed  Google Scholar 

  40. Khaw KT, Tazuke S, Barrett-Connor E (1988) Cigarette smoking and levels of adrenal androgens in postmenopausal women. N Engl J Med 318(26):1705–1709

    Article  CAS  PubMed  Google Scholar 

  41. Schlemmer A, Jensen J, Riis BJ, Christiansen C (1990) Smoking induces increased androgen levels in early post-menopausal women. Maturitas 12(2):99–104

    Article  CAS  PubMed  Google Scholar 

  42. Berta L, Frairia R, Fortunati N, Fazzari A, Gaidano G (1992) Smoking effects on the hormonal balance of fertile women. Horm Res 37(1–2):45–48

    Article  CAS  PubMed  Google Scholar 

  43. Key TJ, Pike MC, Brown JB, Hermon C, Allen DS et al (1996) Cigarette smoking and urinary oestrogen excretion in premenopausal and post-menopausal women. Br J Cancer 74(8):1313–1316

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Law MR, Cheng R, Hackshaw AK, Allaway S, Hale AK (1997) Cigarette smoking, sex hormones and bone density in women. Eur J Epidemiol 13(5):553–558

    Article  CAS  PubMed  Google Scholar 

  45. Lucero J, Harlow BL, Barbieri RL, Sluss P, Cramer DW (2001) Early follicular phase hormone levels in relation to patterns of alcohol, tobacco, and coffee use. Fertil Steril 76(4):723–729

    Article  CAS  PubMed  Google Scholar 

  46. Fishman J, Schneider J, Hershcope RJ, Bradlow HL (1984) Increased estrogen-16 alpha-hydroxylase activity in women with breast and endometrial cancer. J Steroid Biochem 20(4B):1077–1081

    Article  CAS  PubMed  Google Scholar 

  47. Fuhrman BJ, Schairer C, Gail MH, Boyd-Morin J, Xu X et al (2012) Estrogen metabolism and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 104(4):326–339

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Zeleniuch-Jacquotte A, Shore RE, Afanasyeva Y, Lukanova A, Sieri S et al (2011) Postmenopausal circulating levels of 2- and 16alpha-hydroxyestrone and risk of endometrial cancer. Br J Cancer 105(9):1458–1464

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Barbieri RL, McShane PM, Ryan KJ (1986) Constituents of cigarette smoke inhibit human granulosa cell aromatase. Fertil Steril 46(2):232–236

    CAS  PubMed  Google Scholar 

  50. Lesko SM, Rosenberg L, Kaufman DW, Helmrich SP, Miller DR et al (1985) Cigarette smoking and the risk of endometrial cancer. N Engl J Med 313(10):593–596

    Article  CAS  PubMed  Google Scholar 

  51. Smith EM, Sowers MF, Burns TL (1984) Effects of smoking on the development of female reproductive cancers. J Natl Cancer Inst 73(2):371–376

    CAS  PubMed  Google Scholar 

  52. Stockwell HG, Lyman GH (1987) Cigarette smoking and the risk of female reproductive cancer. Am J Obstet Gynecol 157(1):35–40

    Article  CAS  PubMed  Google Scholar 

  53. CW Tyler Jr, Webster LA, Ory HW, Rubin GL (1985) Endometrial cancer: how does cigarette smoking influence the risk of women under age 55 years having this tumor? Am J Obstet Gynecol 151(7):899–905

    Article  Google Scholar 

  54. Mlynarcikova A, Fickova M, Scsukova S (2005) Ovarian intrafollicular processes as a target for cigarette smoke components and selected environmental reproductive disruptors. Endocr Regul 39(1):21–32

    CAS  PubMed  Google Scholar 

  55. Vanderhyden BC (2005) Loss of ovarian function and the risk of ovarian cancer. Cell Tissue Res 322(1):117–124

    Article  PubMed  Google Scholar 

  56. Duskova M, Simunkova K, Hill M, Velikova M, Kubatova J et al (2012) Chronic cigarette smoking alters circulating sex hormones and neuroactive steroids in premenopausal women. Physiol Res 61(1):97–111

    CAS  PubMed  Google Scholar 

  57. Felix AS, Weissfeld JL, Stone RA, Bowser R, Chivukula M et al (2010) Factors associated with Type I and Type II endometrial cancer. Cancer Causes Control 21(11):1851–1856

    Article  PubMed Central  PubMed  Google Scholar 

  58. Sherman ME (2000) Theories of endometrial carcinogenesis: a multidisciplinary approach. Mod Pathol 13(3):295–308

    Article  CAS  PubMed  Google Scholar 

  59. Sherman ME, Sturgeon S, Brinton LA, Potischman N, Kurman RJ et al (1997) Risk factors and hormone levels in patients with serous and endometrioid uterine carcinomas. Mod Pathol 10(10):963–968

    CAS  PubMed  Google Scholar 

  60. Setiawan VW, Yang HP, Pike MC, McCann SE, Yu H, et al. (2013) Type I and II endometrial cancers: have they different risk factors? J Clin Oncol 31(20):2607–2618

    Google Scholar 

  61. Lawrence C, Tessaro I, Durgerian S, Caputo T, Richart RM et al (1989) Advanced-stage endometrial cancer: contributions of estrogen use, smoking, and other risk factors. Gynecol Oncol 32(1):41–45

    Article  CAS  PubMed  Google Scholar 

  62. Daniell HW (1993) More advanced-stage tumors among smokers with endometrial cancer. Am J Clin Pathol 100(4):439–443

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract to the Department of Health. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or the Florida Department of Health. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions.

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Authors and Affiliations

  1. Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, MD, 20892-9774, USA

    Ashley S. Felix, Hannah P. Yang, Gretchen L. Gierach & Louise A. Brinton

  2. Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Ashley S. Felix

  3. Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Yikyung Park

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  1. Ashley S. Felix
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Correspondence to Ashley S. Felix.

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Felix, A.S., Yang, H.P., Gierach, G.L. et al. Cigarette smoking and endometrial carcinoma risk: the role of effect modification and tumor heterogeneity. Cancer Causes Control 25, 479–489 (2014). https://doi.org/10.1007/s10552-014-0350-1

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