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Research table: Menopausal hormone therapy and breast cancer risk

This summary table contains detailed information about research studies. Summary tables are a useful way to look at the science behind many breast cancer guidelines and recommendations. However, to get the most out of the tables, it’s important to understand some key concepts. Learn how to read a research table.

Introduction: Menopausal hormone therapy (MHT) is FDA-approved for the short-term relief of menopausal symptoms. MHT is also called postmenopausal hormone therapy or hormone replacement therapy (HRT).

The main types of MHT are:

  • Estrogen plus progestin
  • Estrogen alone

Estrogen alone raises the risk of uterine cancer, so it’s only used by women who no longer have a uterus (those who’ve had a hysterectomy). Women who still have a uterus most often use estrogen plus progestin.

Estrogen plus progestin

Results from the Women’s Health Initiative (a large randomized clinical trial) confirmed long-term use of MHT containing estrogen plus progestin increases the risk of breast cancer [1-2].

Estrogen alone

Findings on MHT containing estrogen alone are mixed. The Women’s Health Initiative found a slight decrease in risk of breast cancer after short-term use [3]. 

However, large cohort studies and pooled analyses (listed below) have found the use of MHT containing estrogen alone is linked to an increased risk of breast cancer. The Nurses’ Health Study found an increased risk only after 20 or more years of use [4]. 

Learn more about menopausal hormone therapy and breast cancer risk.

Learn about the strengths and weaknesses of different types of studies.

See how this risk factor compares with other risk factors for breast cancer.

Study selection criteria: Randomized clinical trials, prospective cohort studies, pooled analyses and meta-analyses with at least 300 breast cancer cases.

Table note: Relative risk above 1 indicates increased risk. Relative risk below 1 indicates decreased risk.

Study

Study Population
(number of participants)

Menopausal Hormone Therapy
(MHT)

Relative Risk of Breast Cancer in Women Who Used MHT Compared to Women who Never Used MHT,
RR (95% CI)

Current, Recent, Past or Ever Use

Duration
of Use

Estrogen Alone*

Estrogen plus Progestin

Randomized clinical trials

Women’s Health Initiative [2]

16,608
(1,031 cases)

Past use

6 years

 

1.28
(1.13-1.45)

 

10,739
(534 cases)

Past use

7 years

0.78
(0.65-0.93)

 

Cohort studies

Million Women Study [4]

828,923
(9,364 cases)

Current use

Any

1.3
(1.21-1.40)

2.0
(1.88-2.12)

NIH-AARP cohort [5]

118,760
(8,333 cases†)

Current use

Any

1.05
(0.95-1.16)

1.67
(1.56-1.79)

Norwegian Breast Cancer Screening Program [6]

449,717
(4,597 cases)

Recent use

1-2 years

1.03
(0.85-1.25)

2.06
(1.90-2.24)

EPIC [7]

133,744
(4,312 cases)

Current use

Any

1.42
(1.23-1.64)

1.77
(1.40-2.24)

   

1 year or less

1.01
(0.70-1.46)

1.44
(1.09-1.89)

   

1-3 years

1.39
(1.07-1.81)

1.73
(1.44-2.08)

   

3-5 years

1.40
(1.01-1.93)

1.81
(1.44-2.29)

   

5-10 years

1.63
(1.26-2.09)

1.93
(1.58-2.35)

   

More than 10 years

1.72
(1.15-2.57)

1.98
(1.12-3.50)

Breast Cancer Detection Demonstration Project [8]

46,355
(2,082 cases)

Current or recent use (within the past 4 years)

10 years for estrogen alone

4 years for estrogen plus progestin

1.2
(1.0-1.4)

1.4
(1.1-1.8)

Nurses’ Health Study [3,9]

58,520
(1,761 cases)

Current use

10 years

 

1.7
(1.2-2.4)

 

28,835*
(934 cases)

Current use

Less than 5 years

0.96
(0.75-1.22)

 
   

5-10 years

0.90
(0.73-1.12)

 
   

10-15 years

1.06
(0.86-1.30)

 
   

15-20 years

1.18
(0.95-1.48)

 
   

20 or more years

1.42
(1.13-1.77)

 

Danish Cancer Registry [10]

48,812
(869 cases)

Ever use

Any

1.35
(1.01-1.80)

1.52
(1.21-1.93)

UK Breakthrough Generations Study [11]

39,183
(590 cases)

Current use

Any

1.00
(0.66-1.54)

2.74
(2.05-3.65)

Icelandic Cancer Detection Clinic cohort [12]

16,928
(654 cases)

Ever use

At least 5 years

1.24
(0.86-1.78)

2.58
(1.88-3.56)

  

Current use

Any

1.20
(0.84-1.71)

2.48
(1.88-3.27)

  

Past use

Any

1.04
(0.69-1.55)

1.91
(1.28-2.87)

Olsson et al. [13]

29,508
(556 cases)

Ever use

At least 4 years

0.58
(0.22-1.55)

3.13
(1.70-5.75)

French E3N Cohort [14]

78,353
(543 cases)

Current use

Any
(average 5 years)

1.17
(0.99-1.38)

 
  

Past use

Any
(average 2 years)

1.06
(0.95-1.19)

 

Cancer Prevention Study II-Nutrition Cohort [15]

67,754
 (471 cases)

Current use

10-19 years for estrogen alone

At least 10 years for estrogen plus progestin

Ductal breast cancer:
0.95
(0.77-1.17)

Lobular breast cancer:
1.59
(1.07-2.35)

Ductal breast cancer:
2.07
(1.70-2.52)

Lobular breast cancer:
2.19
(1.50-3.22)

  

Past use

At least 5 years

Ductal breast cancer:
0.94
(0.75-1.18)

Lobular breast cancer:
0.86
(0.54-1.37)

Ductal breast cancer:
1.53
(1.14-2.06)

Lobular breast cancer:
1.06
(0.52-2.17)

Women’s Health Study [16-17]

17,835
(411 cases)

Current use

5 or more years

 

1.76
(1.29-2.39)

 

12,718
(305 cases)

Current use

8 or more years

1.35
(0.90-2.02)

 

Pooled and meta-analyses

CGHFBC [18]

24 studies
(108,647 cases)

Current use

1-4 years

1.17
(1.10-1.26)

1.60
(1.52-1.69)

 

 

Current use

5-14 years

1.33
(1.28-1.37)‡

2.08
(2.02-2.15)

Collins et al. [19]

 

Current or recent use (past 1-4 years)

5 or more years

1.24
(1.07-1.44)

1.89
(1.54-2.31)

Munsell et al. [20]

21 studies

Ever use

  

1.34
(1.24-1.46)

 

13 studies

Current use

  

1.72
(1.55-1.92)

 

* Results for oral estrogen alone MHT (pills) only (does not include vaginal estrogen use).

† Included cases of invasive breast cancer and cases of ductal carcinoma in situ (DCIS), a non-invasive breast cancer.

‡ For women who currently used vaginal estrogen for 5-14 years, there was no increased risk of breast cancer. Relative risk was 1.09 (0.97-1.23).

References

  1. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 288(3):321-33, 2002.
  2. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 324(4):369-380, 2020.
  3. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and risk of invasive breast cancer. Arch Intern Med. 166(9):1027-1032, 2006.
  4. Beral V for the Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 362:419-27, 2003.
  5. Wang SM, Pfeiffer RM, Gierach GL, Falk RT. Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort. Breast Cancer Res. 22(1):129, 2020.
  6. Suhrke P, Zahl PH. Breast cancer incidence and menopausal hormone therapy in Norway from 2004 to 2009: a register-based cohort study. Cancer Med. 4(8):1303-8, 2015.
  7. Bakken K, Fournier A, Lund E, et al. Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 128(1):144-56, 2011.
  8. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 283(4):485-491, 2000.
  9. Colditz GA and Rosner B. Cumulative risk of breast cancer to age 70 according to risk factor status: data from the Nurses’ Health Study. Am J Epidemiol. 152(10):950-64, 2000.
  10. Ewertz M, Mellemkjaer L, Poulsen AH, et al. Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study. Br J Cancer. 92(7):1293-7, 2005.
  11. Jones ME, Schoemaker MJ, Wright L, et al. Menopausal hormone therapy and breast cancer: what is the true size of the increased risk? Br J Cancer. 115(5):607-15, 2016.
  12. Thorbjarnardottir T, Olafsdottir EJ, Valdimarsdottir UA, Olafsson O, Tryggvadottir L. Oral contraceptives, hormone replacement therapy and breast cancer risk: a cohort study of 16 928 women 48 years and older. Acta Oncol. 53(6):752-8, 2014.
  13. Olsson HL, Ingvar C, Bladstrom A. Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer. 97(6):1387-92, 2003.
  14. Fournier A, Mesrine S, Dossus L, Boutron-Ruault MC, Clavel-Chapelon F, Chabbert-Buffet N. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat. 145(2):535-43, 2014.
  15. Calle EE, Feigelson HS, Hildebrand JS, Teras LR, Thun MJ, Rodriguez C. Postmenopausal hormone use and breast cancer associations differ by hormone regimen and histologic subtype. Cancer. 115(5):936-45, 2009.
  16. Porch JV, Lee IM, Cook NR, Rexrode KM, Burin JE. Estrogen-progestin replacement therapy and breast cancer risk: the Women’s Health Study (United States). Cancer Causes Control. 13(9):847-54, 2002.
  17. Zhang SM, Manson JE, Rexrode KM, Cook NR, Buring JE, Lee IM. Use of oral conjugated estrogen alone and risk of breast cancer. Am J Epidemiol. 165(5):524-9, 2007.
  18. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 394(10204):1159-1168, 2019.
  19. Collins JA, Blake JM, Crosignani PG. Breast cancer risk with postmenopausal hormonal treatment. Hum Reprod Update. 11(6):545-60, 2005.
  20. Munsell MF, Sprague BL, Berry DA, Chisholm G, Trentham-Dietz A. Body mass index and breast cancer risk according to postmenopausal estrogen-progestin use and hormone receptor status. Epidemiol Rev. 36(1):114-36, 2014.

Updated 10/15/21

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