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Associations of sex steroid hormones with mortality in women with breast cancer

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Epidemiological studies have demonstrated associations between circulating levels of sex steroid hormones and risk of breast cancer in postmenopausal women. However, data on associations with breast cancer survival are limited. We measured levels of estradiol, estrone, testosterone, and sex hormone-binding globulin (SHBG), in serum collected on average 30 months after diagnosis from 358 postmenopausal women diagnosed with stage I-IIIA breast cancer between 1995 and 1998 who participated in a multiethnic, prospective cohort study. Women were followed through December, 2012. We evaluated associations between log-transformed analytes and breast cancer-specific and all-cause mortality fitting multivariable Cox proportional hazards models. Over a median of 14.5 years of follow-up, 102 deaths occurred; 43 of these were due to breast cancer. In models adjusted for ethnicity/study site, age, body mass index, and tumor stage, increased levels of log-transformed SHBG were associated with reduced risk of both breast cancer-specific mortality (hazard ratio, HR 0.48; 95 % confidence interval, CI 0.26–0.89) and all-cause mortality (HR 0.64, 95 % CI 0.43–0.97). There were no associations between levels of estradiol, estrone, or testosterone for either endpoint. In subgroup analyses, after correction for multiple testing, increased estrone was significantly associated with reduced risk for breast cancer-specific mortality among participants with ER-negative tumors (HR 0.16, 95 % CI 0.05–0.63) but not among participants with ER-positive tumors. Increased serum levels of SHBG were associated with decreased risk of breast cancer-specific and all-cause mortality in women with breast cancer. These results should be confirmed in larger breast cancer survivor cohorts.

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Sex steroid hormone-binding globulin


Estrogen receptor


Progesterone receptor


Health, eating, activity, and lifestyle study


Surveillance, epidemiology, and end results


Hazard ratio


Hormone replacement therapy


Confidence interval


  1. Key T, Appleby P, Barnes I, Reeves G (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94(8):606–616

    Article  CAS  PubMed  Google Scholar 

  2. Chlebowski R, Hendrix S, Langer R, Stefanick M, Gass M, Lane D, Rodabough R, Gilligan M, Cyr M, Thomson C, Khandekar J, Petrovitch H, McTiernan A, Investigators W (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA J Am Med Assoc 289(24):3243–3253

    Article  CAS  Google Scholar 

  3. Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, Lane DS, Hubbell FA, Assaf AR, Sarto GE, Schenken RS, Yasmeen S, Lessin L, Chlebowski RT, Investigators WHI (2006) Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA J Am Med Assoc 295(14):1647–1657. doi:10.1001/jama.295.14.1647

    Article  CAS  Google Scholar 

  4. Burstein HJ, Prestrud AA, Seidenfeld J, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Malin J, Mamounas EP, Rowden D, Solky AJ, Sowers MR, Stearns V, Winer EP, Somerfield MR, Griggs JJ, American Society of Clinical O (2010) American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 28(23):3784–3796. doi:10.1200/jco.2009.26.3756

    Article  PubMed  Google Scholar 

  5. Rock CL, Flatt SW, Laughlin GA, Gold EB, Thomson CA, Natarajan L, Jones LA, Caan BJ, Stefanick ML, Hajek RA, Al-Delaimy WK, Stanczyk FZ, Pierce JP, Women’s Healthy E, Living Study G (2008) Reproductive steroid hormones and recurrence-free survival in women with a history of breast cancer. Cancer Epidemiol Biomarkers Prev 17(3):614–620. doi:10.1158/1055-9965.epi-07-0761

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Berrino F, Pasanisi P, Bellati C, Venturelli E, Krogh V, Mastroianni A, Berselli E, Muti P, Secreto G (2005) Serum testosterone levels and breast cancer recurrence. Int J Cancer 113(3):499–502. doi:10.1002/ijc.20582

    Article  CAS  PubMed  Google Scholar 

  7. Lonning P, Helle S, Johannessen D, Ekse D, Aldercreutz H (1996) Influence of plasma estrogen levels on the length of the disease-free interval in postmenopausal women with breast cancer. Br Cancer Res Treat 39:335–341

    Article  CAS  Google Scholar 

  8. McTiernan A, Rajan KB, Tworoger SS, Irwin M, Bernstein L, Baumgartner R, Gilliland F, Stanczyk FZ, Yasui Y, Ballard-Barbash R (2003) Adiposity and sex hormones in postmenopausal breast cancer survivors. J Clin Oncol 21(10):1961–1966

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Sodergard R, Backstrom T, Shanbhag V, Carstensen H (1982) Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem 16(6):801–810

    Article  CAS  PubMed  Google Scholar 

  10. Ma H, Sullivan-Halley J, Smith AW, Neuhouser ML, Alfano CM, Meeske K, George SM, McTiernan A, McKean-Cowdin R, Baumgartner KB, Ballard-Barbash R, Bernstein L (2011) Estrogenic botanical supplements, health-related quality of life, fatigue, and hormone-related symptoms in breast cancer survivors: a HEAL study report. BMC Complement Altern Med 11:109. doi:10.1186/1472-6882-11-109

    Article  PubMed Central  PubMed  Google Scholar 

  11. Doria-Rose VP, Marcus PM (2009) Death certificates provide an adequate source of cause of death information when evaluating lung cancer mortality: an example from the Mayo Lung Project. Lung Cancer 63(2):295–300

    Article  PubMed Central  PubMed  Google Scholar 

  12. Engel LW, Strauchen JA, Chiazze L Jr, Heid M (1980) Accuracy of death certification in an autopsied population with specific attention to malignant neoplasms and vascular diseases. Am J Epidemiol 111(1):99–112

    CAS  PubMed  Google Scholar 

  13. Cox DR (1972) Regression models and life tables (with discussion). JR Stat Soc B 34:187–220

    Google Scholar 

  14. Micheli A, Meneghini E, Secreto G, Berrino F, Venturelli E, Cavalleri A, Camerini T, Di Mauro MG, Cavadini E, De Palo G, Veronesi U, Formelli F (2007) Plasma testosterone and prognosis of postmenopausal breast cancer patients. J Clin Oncol 25(19):2685–2690. doi:10.1200/jco.2006.09.0118

    Article  CAS  PubMed  Google Scholar 

  15. Kaaks R, Rinaldi S, Key TJ et al (2005) Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 12(4):1071–1082

    Article  CAS  PubMed  Google Scholar 

  16. He XY, Liao YD, Yu S, Zhang Y, Wang R (2015) Sex hormone binding globulin and risk of breast cancer in postmenopausal women: a meta-analysis of prospective studies. Horm Metab Res 47(7):485–490. doi:10.1055/s-0034-1395606

    Article  CAS  PubMed  Google Scholar 

  17. Fortunati N, Becchis M, Catalano MG, Comba A, Ferrera P, Raineri M, Berta L, Frairia R (1999) Sex hormone-binding globulin, its membrane receptor, and breast cancer: a new approach to the modulation of estradiol action in neoplastic cells. J Steroid Biochem Mol Biol 69(1–6):473–479

    Article  CAS  PubMed  Google Scholar 

  18. Kahn SM, Li YH, Hryb DJ, Nakhla AM, Romas NA, Cheong J, Rosner W (2008) Sex hormone-binding globulin influences gene expression of LNCaP and MCF-7 cells in response to androgen and estrogen treatment. Adv Exp Med Biol 617:557–564. doi:10.1007/978-0-387-69080-3_57

    Article  CAS  PubMed  Google Scholar 

  19. Fazzari A, Catalano MG, Comba A, Becchis M, Raineri M, Frairia R, Fortunati N (2001) The control of progesterone receptor expression in MCF-7 breast cancer cells: effects of estradiol and sex hormone-binding globulin (SHBG). Mol Cell Endocrinol 172(1–2):31–36

    Article  CAS  PubMed  Google Scholar 

  20. Catalano MG, Frairia R, Boccuzzi G, Fortunati N (2005) Sex hormone-binding globulin antagonizes the anti-apoptotic effect of estradiol in breast cancer cells. Mol Cell Endocrinol 230:31–37

    Article  CAS  PubMed  Google Scholar 

  21. Fortunati N, Catalano MG (2006) Sex hormone-binding globulin (SHBG) and estradiol cross-talk in breast cancer cells. Horm Metab Res 38(4):236–240

    Article  CAS  PubMed  Google Scholar 

  22. Fortunati N, Catalano MG, Boccuzzi G, Frairia R (2010) Sex Hormone-Binding Globulin (SHBG), estradiol and breast cancer. Mol Cell Endocrinol 316(1):86–92. doi:10.1016/j.mce.2009.09.012

    Article  CAS  PubMed  Google Scholar 

  23. Ma H, Wang Y, Sullivan-Halley J, Weiss L, Burkman RT, Simon MS, Malone KE, Strom BL, Ursin G, Marchbanks PA, McDonald JA, Spirtas R, Press MF, Bernstein L (2009) Breast cancer receptor status: do results from a centralized pathology laboratory agree with SEER registry reports? Cancer Epidemiol Biomarkers Prev 18(8):2214–2220. doi:10.1158/1055-9965.epi-09-0301

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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We would like to thank the HEAL participants for their dedication to this study


National Cancer Institute (N01-CN-75036-20, N01-CN-05228, N01-PC-67010, U54-CA116847, U54CA116848, R25-CA94880); National Institutes of Health (M01-RR-00037); University of New Mexico (NCRR M01-RR-0997); National Institute of Child Health and Human Development (N01-HD-3-3175); California Department of Health Services (050Q-8709-S1528).

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Correspondence to Catherine Duggan.

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The authors declare that they have no conflict of interest.

Ethical Statement

This study was performed with the approval of the Institutional Review Boards of participating centers in accordance with assurances filed with and approved by the U.S. Department of Health and Human Services.

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Duggan, C., Stanczyk, F., Campbell, K. et al. Associations of sex steroid hormones with mortality in women with breast cancer. Breast Cancer Res Treat 155, 559–567 (2016).

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