Pre-diagnostic sex hormone levels and survival among breast cancer patients
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Higher levels of circulating sex steroid hormones are associated with increased breast cancer risk, though their association with prognosis remains unclear. We evaluated the association between circulating sex hormone levels and breast cancer survival in two large cohorts.
We evaluated this association among 2073 breast cancer cases from the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) cohorts. Women in this analysis provided a blood sample in 1989–1990 (NHS) or in 1996–1999 (NHSII) and were subsequently diagnosed with breast cancer. Levels of estradiol (postmenopausal women only), testosterone, dehydroepiandrosterone-sulfate (DHEAS), and sex hormone-binding globulin (SHBG) were measured in plasma. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for survival, adjusting for patient and tumor characteristics.
A total of 639 deaths and 160 breast cancer deaths occurred over follow-up through 2015. Compared to women in the lowest quartile, postmenopausal women in the highest quartile of estradiol experienced a 1.43-fold overall mortality rate (HR 1.43, 95% CI 1.03–1.97, P-trend = 0.04) and a nonsignificantly higher breast cancer mortality rate (HR 1.50, 95% CI 0.75–2.98, P-trend = 0.12). Higher DHEAS levels were nonsignificantly associated with better overall survival (HRQ4vsQ1=0.79, 95% CI 0.57–1.10, P-trend = 0.05), though not with breast cancer survival. No associations were observed between testosterone or SHBG and survival.
Pre-diagnostic postmenopausal circulating estradiol levels were modestly associated with worse survival among breast cancer patients. Further studies should evaluate whether circulating hormone levels at diagnosis predict cancer prognosis or treatment response.
KeywordsBreast cancer Prognosis Estradiol Testosterone DHEAS SHBG
We would like to thank the participants and staff of the Nurses’ Health Study and Nurses’ Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.
This work was supported by the National Cancer Institute at the National Institute of Health (P50CA168504, UM1CA186107, UM1CA176726, P01CA87969, R01CA49449, R01CA67262). KHK was supported through National Research Service Awards F31CA192462 and T32CA009001 by the National Cancer Institute. MB is supported by the Breast Cancer Research Foundation. The study sponsors had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.
Compliance with ethical standards
Conflict of interest
MB receives sponsored research support from and has been a consultant to Novartis. MB has served on the scientific advisory board of Gtx, Inc. and currently serves on the scientific advisory board of Kronos Bio. The remaining authors declare they have no conflict of interest.
- 3.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 (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. https://doi.org/10.1200/jco.2009.26.3756 Google Scholar
- 4.Dimitrakakis C, Zhou J, Bondy CA (2002) Androgens and mammary growth and neoplasia. Fertil Steril 77(Suppl 4):S26–S33Google Scholar
- 5.Liao DJ, Dickson RB (2002) Roles of androgens in the development, growth, and carcinogenesis of the mammary gland. J Steroid Biochem Mol Biol 80(2):175–189Google Scholar
- 6.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):606–616Google Scholar
- 8.Woolcott CG, Shvetsov YB, Stanczyk FZ, Wilkens LR, White KK, Caberto C, Henderson BE, Le Marchand L, Kolonel LN, Goodman MT (2010) Plasma sex hormone concentrations and breast cancer risk in an ethnically diverse population of postmenopausal women: the multiethnic cohort study. Endocr Relat Cancer 17(1):125–134. https://doi.org/10.1677/erc-09-0211 Google Scholar
- 9.Zeleniuch-Jacquotte A, Shore RE, Koenig KL, Akhmedkhanov A, Afanasyeva Y, Kato I, Kim MY, Rinaldi S, Kaaks R, Toniolo P (2004) Postmenopausal levels of oestrogen, androgen, and SHBG and breast cancer: long-term results of a prospective study. Br J Cancer 90(1):153–159. https://doi.org/10.1038/sj.bjc.6601517 Google Scholar
- 10.Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PH, Biessy C, Dossus L, Lukanova A, Bingham S, Khaw KT, Allen NE, Bueno-de-Mesquita HB, van Gils CH, Grobbee D, Boeing H, Lahmann PH, Nagel G, Chang-Claude J, Clavel-Chapelon F, Fournier A, Thiebaut A, Gonzalez CA, Quiros JR, Tormo MJ, Ardanaz E, Amiano P, Krogh V, Palli D, Panico S, Tumino R, Vineis P, Trichopoulou A, Kalapothaki V, Trichopoulos D, Ferrari P, Norat T, Saracci R, Riboli E (2005) Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 12(4):1071–1082. https://doi.org/10.1677/erc.1.01038 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. https://doi.org/10.1200/jco.2006.09.0118 Google Scholar
- 15.Duggan C, Stanczyk F, Campbell K, Neuhouser ML, Baumgartner RN, Baumgartner KB, Bernstein L, Ballard R, McTiernan A (2016) Associations of sex steroid hormones with mortality in women with breast cancer. Breast Cancer Res Treat 155(3):559–567. https://doi.org/10.1007/s10549-016-3704-4 Google Scholar
- 16.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 (2008) Reproductive steroid hormones and recurrence-free survival in women with a history of breast cancer. Cancer Epidemiol Biomark Prev 17(3):614–620. https://doi.org/10.1158/1055-9965.epi-07-0761 Google Scholar
- 17.Lonning PE, Helle SI, Johannessen DC, Ekse D, Adlercreutz H (1996) Influence of plasma estrogen levels on the length of the disease-free interval in postmenopausal women with breast cancer. Breast Cancer Res Treat 39(3):335–341Google Scholar
- 18.Venturelli E, Orenti A, Fabricio ASC, Garrone G, Agresti R, Paolini B, Bonini C, Gion M, Berrino F, Desmedt C, Coradini D, Biganzoli E (2018) Observational study on the prognostic value of testosterone and adiposity in postmenopausal estrogen receptor positive breast cancer patients. BMC Cancer 18(1):651. https://doi.org/10.1186/s12885-018-4558-4 Google Scholar
- 19.Colditz GA, Manson JE, Hankinson SE (1997) The Nurses’ Health Study: 20-year contribution to the understanding of health among women. J Womens Health 6(1):49–62Google Scholar
- 20.Stampfer MJ, Willett WC, Speizer FE, Dysert DC, Lipnick R, Rosner B, Hennekens CH (1984) Test of the National death index. Am J Epidemiol 119(5):837–839Google Scholar
- 21.Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, Barbieri RL, Speizer FE (1998) Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90(17):1292–1299Google Scholar
- 23.Hankinson SE, Manson JE, Spiegelman D, Willett WC, Longcope C, Speizer FE (1995) Reproducibility of plasma hormone levels in postmenopausal women over a 2–3 year period. Cancer Epidemiol Biomark Prev 4(6):649–654Google Scholar
- 26.Prentice RL, Kalbfleisch JD (1979) Hazard rate models with covariates. Biometrics 35(1):25–39Google Scholar
- 27.Lunn M, McNeil D (1995) Applying Cox regression to competing risks. Biometrics 51(2):524–532Google Scholar
- 31.Dimitrakakis C, Zhou J, Wang J, Belanger A, LaBrie F, Cheng C, Powell D, Bondy C (2003) A physiologic role for testosterone in limiting estrogenic stimulation of the breast. Menopause 10(4):292–298. https://doi.org/10.1097/01.gme.0000055522.67459.89 Google Scholar
- 32.Birrell SN, Bentel JM, Hickey TE, Ricciardelli C, Weger MA, Horsfall DJ, Tilley WD (1995) Androgens induce divergent proliferative responses in human breast cancer cell lines. J Steroid Biochem Mol Biol 52(5):459–467Google Scholar
- 34.Key TJ, Appleby PN, Reeves GK, Travis RC, Alberg AJ, Barricarte A, Berrino F, Krogh V, Sieri S, Brinton LA, Dorgan JF, Dossus L, Dowsett M, Eliassen AH, Fortner RT, Hankinson SE, Helzlsouer KJ, Hoff man-Bolton J, Comstock GW, Kaaks R, Kahle LL, Muti P, Overvad K, Peeters PH, Riboli E, Rinaldi S, Rollison DE, Stanczyk FZ, Trichopoulos D, Tworoger SS, Vineis P (2013) Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol 14(10):1009–1019. https://doi.org/10.1016/s1470-2045(13)70301-2 Google Scholar
- 35.Lonning PE, Helle H, Duong NK, Ekse D, Aas T, Geisler J (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 117(1–3):31–41. https://doi.org/10.1016/j.jsbmb.2009.06.005 Google Scholar
- 36.Vermeulen A, Deslypere JP, Paridaens R, Leclercq G, Roy F, Heuson JC (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 22(4):515–525Google Scholar
- 37.Bonney RC, Reed MJ, Davidson K, Beranek PA, James VH (1983) The relationship between 17 beta-hydroxysteroid dehydrogenase activity and oestrogen concentrations in human breast tumours and in normal breast tissue. Clin Endocrinol (Oxf) 19(6):727–739Google Scholar
- 38.Dunbier AK, Anderson H, Ghazoui Z, Folkerd EJ, A’Hern R, Crowder RJ, Hoog J, Smith IE, Osin P, Nerurkar A, Parker JS, Perou CM, Ellis MJ, Dowsett M (2010) Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women. J Clin Oncol 28(7):1161–1167. https://doi.org/10.1200/jco.2009.23.9616 Google Scholar
- 39.Mady EA, Ramadan EE, Ossman AA (2000) Sex steroid hormones in serum and tissue of benign and malignant breast tumor patients. Dis Mark 16(3–4):151–157Google Scholar
- 40.Recchione C, Venturelli E, Manzari A, Cavalleri A, Martinetti A, Secreto G (1995) Testosterone, dihydrotestosterone and oestradiol levels in postmenopausal breast cancer tissues. J Steroid Biochem Mol Biol 52(6):541–546Google Scholar
- 41.Thijssen JH, Blankenstein MA (1989) Endogenous oestrogens and androgens in normal and malignant endometrial and mammary tissues. Eur J Cancer Clin Oncol 25(12):1953–1959Google Scholar
- 42.Key TJ, Appleby PN, Reeves GK, Roddam AW, Helzlsouer KJ, Alberg AJ, Rollison DE, Dorgan JF, Brinton LA, Overvad K, Kaaks R, Trichopoulou A, Clavel-Chapelon F, Panico S, Duell EJ, Peeters PH, Rinaldi S, Fentiman IS, Dowsett M, Manjer J, Lenner P, Hallmans G, Baglietto L, English DR, Giles GG, Hopper JL, Severi G, Morris HA, Hankinson SE, Tworoger SS, Koenig K, Zeleniuch-Jacquotte A, Arslan AA, Toniolo P, Shore RE, Krogh V, Micheli A, Berrino F, Barrett-Connor E, Laughlin GA, Kabuto M, Akiba S, Stevens RG, Neriishi K, Land CE, Cauley JA, Lui LY, Cummings SR, Gunter MJ, Rohan TE, Strickler HD (2011) Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies. Br J Cancer 105(5):709–722. https://doi.org/10.1038/bjc.2011.254 Google Scholar