Main Article Content
Breast cancer, Hormone replacement therapy (HRT), Steroid
Background: The carcinogenic effect of exogenous steroid hormones on the breasts is a matter of debate, causing confusion for physicians at the time of making prescriptions. This article, as part of a quadruple series about exogenous sex hormones and breast disorders, reviews the association of breast cancer and hormone replacement therapy (HRT) in the general population, women with benign breast disorders, women with personal or family history of breast cancer, and BRCA carriers.
Methods: We accomplished an extensive search of the literature by using relevant keywords to identify pertinent cohort studies, clinical trials, and reviews. Then, we extracted all points regarding the question.
Results: An extensive literature exists on the risk of breast cancer following HRT in the general population, and HRT has been mentioned as a risk factor for breast cancer, especially in recent, long-term users of combined formulations. However, there is still no consensus about it. Conversely, few studies have considered challenging issues like the use of HRT in breast cancer survivors and high-risk women.
Conclusion: HRT up to 5 years can safely be used for management of menopausal symptoms in healthy women, and those with low-risk benign breast disorders. On the contrary, its use in high-risk women should be limited to refractory menopausal symptoms after describing potential harms to the patient.
2. Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 1998; 90:1292-9.
3. Armstrong K, Popik S, Guerra C, Ubel PA. Beliefs about breast cancer risk and use of postmenopausal hormone replacement therapy. Medical Decision Making. 2000; 20:308-13.
4. Fleming R. Do women taking hormone replacement therapy (HRT) have a higher incidence of breast cancer than women who do not? Integrative cancer therapies. 2003; 2:235-7.
5. Bouchardy C, Usel M, Verkooijen HM, Fioretta G, Benhamou S, Neyroud-Caspar I, et al. Changing pattern of age-specific breast cancer incidence in the Swiss canton of Geneva. Breast cancer research and treatment. 2010; 120:519-23.
6. Narod SA. Hormone replacement therapy and the risk of breast cancer. Nature reviews Clinical oncology. 2011; 8:669.
7. Alipour S, Eskandari A. Prescribing Oral Contraceptives in Women With Breast Diseases: A Matter of Concern for the Gynecologist. Archives of Breast Cancer. 2019:55-68.
8. Hulka B. Hormone?replacement therapy and the risk of breast cancer. CA: a cancer journal for clinicians. 1990; 40:289-96.
9. Stahlberg C, Pedersen AT, Lynge E, Ottesen B. Hormone replacement therapy and risk of breast cancer: the role of progestins. Acta obstetricia et gynecologica Scandinavica. 2003; 82:335-44.
10. Porch JV, Lee I-M, Cook NR, Rexrode KM, Buring JE. Estrogen–progestin replacement therapy and breast cancer risk: the Women's Health Study (United States). Cancer Causes & Control. 2002; 13:847-54.
11. Collaborators MWS. Breast cancer and hormone-replacement therapy in the Million Women Study. The Lancet. 2003; 362:419-27.
12. Chlebowski RT, Manson JE, Anderson GL, Cauley JA, Aragaki AK, Stefanick ML, et al. Estrogen plus progestin and breast cancer incidence and mortality in the Women’s Health Initiative Observational Study. Journal of the National Cancer Institute. 2013; 105:526-35.
13. Tjønneland A, Christensen J, Thomsen BL, Olsen A, Overvad K, Ewertz M, et al. Hormone replacement therapy in relation to breast carcinoma incidence rate ratios: a prospective Danish cohort study. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2004; 100:2328-37.
14. Shapiro S, Farmer RD, Stevenson JC, Burger HG, Mueck AO, Gompel A. Does hormone replacement therapy (HRT) cause breast cancer? An application of causal principles to three studies. J Fam Plann Reprod Health Care. 2013; 39:80-8.
15. Stevenson J, Hodis H, Pickar J, Lobo R. HRT and breast cancer risk: a realistic perspective. Climacteric. 2011; 14:633-6.
16. Antoine C, Ameye L, Paesmans M, Rozenberg S. Systematic review about breast cancer incidence in relation to hormone replacement therapy use. Climacteric. 2014; 17:116-32.
17. La Vecchia C, Negri E, Franceschi S, Favero A, Nanni O, Filiberti R, et al. Hormone replacement treatment and breast cancer risk: a cooperative Italian study. British journal of cancer. 1995; 72:244.
18. Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA, Rossing MA. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. Jama. 1995; 274:137-42.
19. Schuurman AG, van den Brandt PA, Goldbohm RA. Exogenous hormone use and the risk of postmenopausal breast cancer: results from The Netherlands Cohort Study. Cancer Causes & Control. 1995; 6:416-24.
20. Tavani A, Braga C, La Vecchia C, Negri E, Franceschi S. Hormone replacement treatment and breast cancer risk: an age-specific analysis. Cancer Epidemiology and Prevention Biomarkers. 1997; 6:11-4.
21. Ewertz M, Mellemkjaer L, Poulsen A, Friis S, Sørensen H, Pedersen L, et al. Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study. British journal of cancer. 2005; 92:1293.
22. Olsson HL, Ingvar C, Bladström A. Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2003; 97:1387-92.
23. Chlebowski RT, Anderson GL, Aragaki AK, Prentice R. Breast cancer and menopausal hormone therapy by race/ethnicity and body mass index. Journal of the National Cancer Institute. 2015; 108:djv327.
24. Li R, Gilliland FD, Baumgartner K, Samet J. Hormone replacement therapy and breast carcinoma risk in Hispanic and non?Hispanic women. Cancer. 2002; 95:960-8.
25. Coombs NJ, Taylor R, Wilcken N, Fiorica J, Boyages J. Hormone replacement therapy and breast cancer risk in California. The breast journal. 2005; 11:410-5.
26. Dinger JC, Heinemann LA, Möhner S, Assmann A. Breast cancer risk associated with different HRT formulations: a register-based case-control study. BMC women's health. 2006; 6:13.
27. Weiss LK, Burkman RT, Cushing-Haugen KL, Voigt LF, Simon MS, Daling JR, et al. Hormone replacement therapy regimens and breast cancer risk. Obstetrics & Gynecology. 2002; 100:1148-58.
28. Borgquist S, Anagnostaki L, Jirström K, Landberg G, Manjer J. Breast tumours following combined hormone replacement therapy express favourable prognostic factors. International journal of cancer. 2007; 120:2202-7.
29. O'connor IF, Shembekar MV, Shousha S. Breast carcinoma developing in patients on hormone replacement therapy: a histological and immunohistological study. Journal of clinical pathology. 1998; 51:935-8.
30. Biglia N, Sgro L, Defabiani E, De Rosa G, Ponzone R, Marenco D, et al. The influence of hormone replacement therapy on the pathology of breast cancer. European Journal of Surgical Oncology (EJSO). 2005; 31:467-72.
31. Kenemans P, Bosman A. Breast cancer and post-menopausal hormone therapy. Best Practice & Research Clinical Endocrinology & Metabolism. 2003; 17:123-37.
32. Antoine C, Liebens F, Carly B, Pastijn A, Rozenberg S. Influence of HRT on prognostic factors for breast cancer: a systematic review after the Women’s Health Initiative trial. Human reproduction. 2004; 19:741-56.
33. Fletcher A, Erbas B, Kavanagh A, Hart S, Rodger A, Gertig D. Use of hormone replacement therapy (HRT) and survival following breast cancer diagnosis. The Breast. 2005; 14:192-200.
34. Magnusson C, Holmberg L, Nordén T, Lindgren A, Persson I. Prognostic characteristics in breast cancers after hormone replacement therapy. Breast cancer research and treatment. 1996; 38:325-34.
35. Bonnier P, Bessenay F, Sasco AJ, Beedassy B, Lejeune C, Romain S, et al. Impact of menopausal hormone?replacement therapy on clinical and laboratory characteristics of breast cancer. International journal of cancer. 1998; 79:278-82.
36. Pappo I, Meirshon I, Karni T, Siegelmann-Danielli N, Stahl-Kent V, Sandbank J, et al. The characteristics of malignant breast tumors in hormone replacement therapy users versus nonusers. Annals of surgical oncology. 2004; 11:52-8.
37. Chen WY, Hankinson SE, Schnitt SJ, Rosner BA, Holmes MD, Colditz GA. Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma. Cancer. 2004; 101:1490-500.
38. Li CI, Malone KE, Porter PL, Weiss NS, Tang M-TC, Cushing-Haugen KL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. Jama. 2003; 289:3254-63.
39. Lobo RA. Hormone-replacement therapy: current thinking. Nature Reviews Endocrinology. 2017; 13:220.
40. Coombs NJ, Taylor R, Wilcken N, Boyages J. HRT and breast cancer: impact on population risk and incidence. European Journal of Cancer. 2005; 41:1775-81.
41. Jacobs H. Hormone replacement therapy and breast cancer. Endocrine-related cancer. 2000; 7:53-61.
42. Marsden J, Society BM. British Menopause Society consensus statement: The risks and benefits of HRT before and after a breast cancer diagnosis. Post reproductive health. 2019; 25:33-7.
43. Branchini G, Schneider L, Cericatto R, Capp E, Brum IS. Progesterone receptors A and B and estrogen receptor alpha expression in normal breast tissue and fibroadenomas. Endocrine. 2009; 35:459-66.
44. Dion L, Racin A, Brousse S, Beltjens F, Cauchois A, Levêque J, et al. Atypical epithelial hyperplasia of the breast: state of the art. Expert review of anticancer therapy. 2016; 16:943-53.
45. Hwang H, Sahoo S. Chapter 14- Atypical Lobular Hyperplasia and Lobular Carcinoma In Situ In: Shin SJ, editor. A Comprehensive Guide to Core Needle Biopsies of the Breast: Springer; 2016. p. 561 -94.
46. Kader T, Hill P, Rakha EA, Campbell IG, Gorringe KL. Atypical ductal hyperplasia: update on diagnosis, management, and molecular landscape. Breast Cancer Research. 2018; 20:39.
47. Tzingounis V, Cardamakis E, Ginopoulos P, Argiropoulos G. Incidence of benign and malignant breast disorders in women taking hormones (contraceptive pill or hormonal replacement therapy). Anticancer research. 1996; 16:3997-4000.
48. Rohan TE, Miller A. Hormone replacement therapy and risk of benign proliferative epithelial disorders of the breast. European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP). 1999; 8:123-30.
49. Rohan TE, Negassa A, Chlebowski RT, Lasser NL, McTiernan A, Schenken RS, et al. Estrogen plus progestin and risk of benign proliferative breast disease. Cancer Epidemiology and Prevention Biomarkers. 2008; 17:2337-43.
50. Friedenreich C, Bryant H, Alexander F, Hugh J, Danyluk J, Page D. Risk factors for benign proliferative breast disease. International journal of epidemiology. 2000; 29:637-44.
51. Berkowitz GS, Kelsey JL, Holford TR, Livolsi VA, Merino MJ, Beck GJ, et al. Estrogen replacement therapy and fibrocystic breast disease in postmenopausal women. American journal of epidemiology. 1985; 121:238-45.
52. Trapido EJ, Brinton LA, Schairer C, Hoover R. Estrogen replacement therapy and benign breast disease. Journal of the National Cancer Institute. 1984; 73:1101-5.
53. Canny PF, Berkowitz GS, Kelsey J, Livolsi VA. Fibroadenoma and the use of exogenous hormones: a case-control study. American Journal of epidemiology. 1988; 127:454-61.
54. Cahn MD, Tran T, Theur CP, Butler JA. Hormone replacement therapy and the risk of breast lesions that predispose to cancer. The American surgeon. 1997; 63:858-60.
55. Zera RT, Danielson D, Van Camp JM, Schmidt-Steinbrunn B, Hong J, McCoy M, et al. Atypical hyperplasia, proliferative fibrocystic change, and exogenous hormone use. Surgery. 2001; 130:732-7.
56. Dupont WD, Page DL, Parl FF, Plummer Jr WD, Schuyler PA, Kasami M, et al. Estrogen replacement therapy in women with a history of proliferative breast disease. Cancer. 1999; 85:1277-83.
57. Kenemans P, Scheele F, Burger C. Hormone replacement therapy and breast cancer morbidity, mortality and recurrence. European Journal of Obstetrics & Gynecology and Reproductive Biology. 1997; 71:199-203.
58. Deli T, Orosz M, Jakab A. Hormone Replacement Therapy in Cancer Survivors - Review of the Literature. Pathology oncology research : POR. 2019.
59. Wi?niewska I, Jochymek B, Lenart-Lipi?ska M, Chabowski M. The pharmacological and hormonal therapy of hot flushes in breast cancer survivors. Breast Cancer. 2016; 23:178-82.
60. Biglia N, Cozzarella M, Cacciari F, Ponzone R, Roagna R, Maggiorotto F, et al. Menopause after breast cancer: a survey on breast cancer survivors. Maturitas. 2003; 45:29-38.
61. Holmberg L, Iversen O-E, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. Journal of the National Cancer Institute. 2008; 100:475-82.
62. Fahlén M, Fornander T, Johansson H, Johansson U, Rutqvist L-E, Wilking N, et al. Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial. European journal of cancer. 2013; 49:52-9.
63. Natrajan PK, Gambrell Jr RD. Estrogen replacement therapy in patients with early breast cancer. American journal of obstetrics and gynecology. 2002; 187:289-95.
64. Natrajan PK, Soumakis K, Gambrell Jr RD. Estrogen replacement therapy in women with previous breast cancer. American journal of obstetrics and gynecology. 1999; 181:288-95.
65. Urši?-Vrš?aj M, Bebar S. A case-control study of hormone replacement therapy after primary surgical breast cancer treatment. European Journal of Surgical Oncology (EJSO). 1999; 25:146-51.
66. DiSaia PJ, Brewster WR, Ziogas A, Anton-Culver H. Breast cancer survival and hormone replacement therapy: a cohort analysis. American journal of clinical oncology. 2000; 23:541-5.
67. Eden JA, Bush T, Nand S, Wren BG. A case-control study of combined continuous estrogen—progestin replacement therapy among women with a personal history of breast cancer. Menopause. 1995; 2:67-72.
68. Disaia PJ, Grosen EA, Odicino F, Cowan B, Pecorelli S, Wile AG, et al. Replacement therapy for breast cancer survivors. A pilot study. Cancer. 1995; 76:2075-8.
69. Wang Y, Lewin N, Qaoud Y, Rajaee AN, Scheer AS. The oncologic impact of hormone replacement therapy in premenopausal breast cancer survivors: A systematic review. The Breast. 2018; 40:123-30.
70. Col NF, Hirota LK, Orr RK, Erban JK, Wong JB, Lau J. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. Journal of Clinical Oncology. 2001; 19:2357-63.
71. Sarri G, Davies M, Lumsden MA. Diagnosis and management of menopause: summary of NICE guidance. Bmj. 2015; 351:h5746.
72. Pritchard KI, Khan H, Levine M, Care SCoCPGft, Cancer ToB. Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer. Cmaj. 2002; 166:1017-22.
73. Sellers TA, Mink PJ, Cerhan JR, Zheng W, Anderson KE, Kushi LH, et al. The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Annals of internal medicine. 1997; 127:973-80.
74. Evans DG, Graham J, O’Connell S, Arnold S, Fitzsimmons D. Familial breast cancer: summary of updated NICE guidance. Bmj. 2013; 346:f3829.
75. Marchetti C, De Felice F, Boccia S, Sassu C, Di Donato V, Perniola G, et al. Hormone replacement therapy after prophylactic risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: A meta-analysis. Critical reviews in oncology/hematology. 2018; 132:111-5.
76. Kotsopoulos J, Gronwald J, Karlan BY, Huzarski T, Tung N, Moller P, et al. Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA1 mutation carriers. JAMA oncology. 2018; 4:1059-65.