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Effect of estradiol as a continuous variable on breast cancer survival by menopausal status: a cohort study in China


High levels of circulating estradiol (E2) are associated with increased risk of breast cancer, whereas its relationship with breast cancer prognosis is still unclear. We evaluated the effect of E2 concentration on survival endpoints among 8766 breast cancer cases diagnosed between 2005 and 2017 from the Tianjin Breast Cancer Cases Cohort. Levels of serum E2 were measured in pre-menopausal and post-menopausal women. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between quartile of E2 levels and overall survival (OS) and progression-free survival (PFS) of breast cancer. The penalized spline was then used to test for non-linear relationships between E2 (continuous variable) and survival endpoints. 612 deaths and 982 progressions occurred over follow-up through 2017. Compared to women in the quartile 3, the highest quartile of E2 was associated with reduced risk of both PFS in pre-menopausal women (HR 1.79, 95% CI 1.17–2.75, P = 0.008) and OS in post-menopausal women (HR 1.35, 95% CI 1.04–1.74, P = 0.023). OS and PFS in pre-menopausal women exhibited a nonlinear relation (“L-shaped” and “U-shaped”, respectively) with E2 levels. However, there was a linear relationship in post-menopausal women. Moreover, patients with estrogen receptor-negative (ER-negative) breast cancer showed a “U-shaped” relationship with OS and PFS in pre-menopausal women. Pre-menopausal breast cancer patients have a plateau stage of prognosis at the intermediate concentrations of E2, whereas post-menopausal patients have no apparent threshold, and ER status may have an impact on this relationship.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.



Body mass index


Confidence intervals




Estrogen receptor


Human epidermal growth factor receptor-2


Hospital information system


Hazard ratios




Overall survival


Progression-free survival


Progesterone receptor


Tianjin Breast Cancer Cases Cohort


  1. Zhang S, Sun K, Zheng R et al (2021) Cancer incidence and mortality in China, 2015. J Natl Cancer Center 1(1):2–11.

    CAS  Article  Google Scholar 

  2. Lei S, Zheng R, Zhang S et al (2021) Breast cancer incidence and mortality in women in China: temporal trends and projections to 2030. Cancer Biol Med.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 3(71):209–249.

    Article  Google Scholar 

  4. Burstein HJ, Griggs JJ, Prestrud AA et al (2010) American society of clinical oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Oncol Pract 5(6):243–246.

    Article  Google Scholar 

  5. Gruber CJ, Tschugguel W, Schneeberger C et al (2002) Production and actions of estrogens. N Engl J Med 5(346):340–352.

    Article  Google Scholar 

  6. Folkerd E, Dowsett M (2013) Sex hormones and breast cancer risk and prognosis. Breast 22(Suppl 2):S38-43.

    Article  PubMed  Google Scholar 

  7. Hankinson SE, Manson JE, Spiegelman D et al (1995) Reproducibility of plasma hormone levels in postmenopausal women over a 2-3-year period. Cancer Epidemiol Biomarkers Prev 6(4):649–654

    Google Scholar 

  8. Tamimi RM, Byrne C, Colditz GA et al (2007) Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst 15(99):1178–1187.

    CAS  Article  Google Scholar 

  9. Eliassen AH, Missmer SA, Tworoger SS et al (2006) Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst 19(98):1406–1415.

    Article  Google Scholar 

  10. Kaaks R, Berrino F, Key T et al (2005) Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 10(97):755–765.

    CAS  Article  Google Scholar 

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

    Article  Google Scholar 

  12. Kensler KH, Eliassen AH, Rosner BA et al (2019) Pre-diagnostic sex hormone levels and survival among breast cancer patients. Breast Cancer Res Treat 3(174):749–758.

    CAS  Article  Google Scholar 

  13. Duggan C, Stanczyk F, Campbell K et al (2016) Associations of sex steroid hormones with mortality in women with breast cancer. Breast Cancer Res Treat 3(155):559–567.

    CAS  Article  Google Scholar 

  14. Kim JY, Han W, Moon HG et al (2013) Prognostic effect of preoperative serum estradiol level in postmenopausal breast cancer. BMC Cancer 13:503.

  15. Li J, Liu L, Feng Z et al (2020) Tumor markers CA15-3, CA125, CEA and breast cancer survival by molecular subtype: a cohort study. Breast Cancer 4(27):621–630.

    Article  Google Scholar 

  16. Zhang L, Huang Y, Feng Z et al (2019) Comparison of breast cancer risk factors among molecular subtypes: a case-only study. Cancer Med 4(8):1882–1892.

    CAS  Article  Google Scholar 

  17. Wang L, Zhou B, Zhao Z et al (2021) Body-mass index and obesity in urban and rural China: findings from consecutive nationally representative surveys during 2004–18. Lancet 10294(398):53–63.

    Article  Google Scholar 

  18. Untch M, Gerber B, Harbeck N et al (2013) 13th st. Gallen International breast cancer conference 2013: primary therapy of early breast cancer evidence, controversies, consensus—opinion of a german team of experts (zurich 2013). Breast Care (Basel) 3(8):221–229.

    Article  Google Scholar 

  19. Farhat GN, Cummings SR, Chlebowski RT et al (2011) Sex hormone levels and risks of estrogen receptor-negative and estrogen receptor-positive breast cancers. J Natl Cancer Inst 7(103):562–570.

    CAS  Article  Google Scholar 

  20. Meira-Machado L, Cadarso-Suarez C, Gude F et al (2013) SmoothHR: an R package for pointwise nonparametric estimation of hazard ratio curves of continuous predictors. Comput Math Methods Med 2013:745742.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Eskelinen M, Nordén T, Lindgren A et al (2004) Preoperative serum levels of follicle stimulating hormone (FSH) and prognosis in invasive breast cancer. Eur J Surg Oncol 5(30):495–500.

    Article  Google Scholar 

  22. Clark GM, Osborne CK, McGuire WL (1984) Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer. J Clin Oncol 10(2):1102–1109.

    Article  Google Scholar 

  23. Lonning PE, Helle H, Duong NK et al (2009) Tissue estradiol is selectively elevated in receptor positive breast cancers while tumour estrone is reduced independent of receptor status. J Steroid Biochem Mol Biol 1–3(117):31–41.

    CAS  Article  Google Scholar 

  24. Vermeulen A, Deslypere JP, Paridaens R et al (1986) Aromatase, 17 beta-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. Eur J Cancer Clin Oncol 4(22):515–525.

    Article  Google Scholar 

  25. Bonney RC, Reed MJ, Davidson K et al (1983) The relationship between 17 beta-hydroxysteroid dehydrogenase activity and oestrogen concentrations in human breast tumours and in normal breast tissue. Clin Endocrinol (Oxford) 6(19):727–739.

    Article  Google Scholar 

  26. Germain D (2011) Estrogen carcinogenesis in breast cancer. Endocrinol Metab Clin North Am 3(40):473–484.

    CAS  Article  Google Scholar 

  27. Missmer SA, Eliassen AH, Barbieri RL et al (2004) Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst 24(96):1856–1865.

    CAS  Article  Google Scholar 

  28. Cummings SR, Lee JS, Lui LY et al (2005) Sex hormones, risk factors, and risk of estrogen receptor-positive breast cancer in older women: a long-term prospective study. Cancer Epidemiol Biomarkers Prev 5(14):1047–1051.

    Article  Google Scholar 

  29. Micheli A, Meneghini E, Secreto G et al (2007) Plasma testosterone and prognosis of postmenopausal breast cancer patients. J Clin Oncol 19(25):2685–2690.

    CAS  Article  Google Scholar 

  30. Pasanisi P, Berrino F, De Petris M et al (2006) Metabolic syndrome as a prognostic factor for breast cancer recurrences. Int J Cancer 1(119):236–238.

    CAS  Article  Google Scholar 

  31. Haynes BP, Viale G, Galimberti V et al (2013) Expression of key oestrogen-regulated genes differs substantially across the menstrual cycle in oestrogen receptor-positive primary breast cancer. Breast Cancer Res Treat 1(138):157–165.

    CAS  Article  Google Scholar 

  32. Dunbier AK, Anderson H, Ghazoui Z et al (2010) Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women. J Clin Oncol 7(28):1161–1167.

    CAS  Article  Google Scholar 

  33. Rock CL, Flatt SW, Laughlin GA et al (2008) Reproductive steroid hormones and recurrence-free survival in women with a history of breast cancer. Cancer Epidemiol Biomarkers Prev 3(17):614–620.

    CAS  Article  Google Scholar 

  34. Lonning PE, Helle SI, Johannessen DC et al (1996) Influence of plasma estrogen levels on the length of the disease-free interval in postmenopausal women with breast cancer. Breast Cancer Res Treat 3(39):335–341.

    Article  Google Scholar 

  35. Folkerd EJ, Dowsett M (2010) Influence of sex hormones on cancer progression. J Clin Oncol 26(28):4038–4044.

    CAS  Article  Google Scholar 

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This study was supported by the National Key Research and Development Program of China (Grant No. 2018YFC1315600), and National Natural Science Foundation of China (Grant Nos. 81974439, 81974488).

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Authors and Affiliations



JL and CL designed the study, did the statistical analysis and drafted the manuscript. FS reviewed and revised the manuscript. All authors made contribution to the establishment of TBCCC and approved the final version.

Corresponding authors

Correspondence to Fengju Song or Kexin Chen.

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The authors declare that they have no competing interests.

Ethical approval

The investigators in TBCCC obtained informed consent from each breast cancer patient and participants or their guardians. The current study was in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments and it was approved by the research ethics board of the Tianjin Medical University Cancer Institute and Hospital.

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Li, J., Li, C., Feng, Z. et al. Effect of estradiol as a continuous variable on breast cancer survival by menopausal status: a cohort study in China. Breast Cancer Res Treat 194, 103–111 (2022).

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  • Breast cancer
  • Estradiol
  • Survival
  • Menopause status
  • ER status