Hormone Replacement Therapy and Breast Cancer Risk

Hormone Replacement Therapy (HRT) increases the risk of breast cancer, with the risk varying by formulation type and duration of use. 1

Evidence on HRT and Breast Cancer Risk

The Women's Health Initiative (WHI) study was terminated early due to a 26% increased incidence of breast cancer (HR, 1.26; 95% CI, 1.00-1.59) in women using combined estrogen-progestin therapy 1
Breast cancers were more advanced in the treatment group compared to the placebo group, although the increased risk declined rapidly after cessation of HRT 1
Similar increases in breast cancer incidence were observed in the Heart and Estrogen/Progestin Replacement Study (HERS) with an RH of 1.27 (95% CI, 0.84-1.94) over 6.8 years of follow-up 1
Recent long-term users of combined HRT have a 79% increased risk of breast cancer (adjusted odds ratio 1.79; 95% CI, 1.73 to 1.85) 2

The WHI study of women who had undergone hysterectomies and were receiving unopposed estrogen did not show a significant increase in breast cancer risk 1
Long-term follow-up (mean 7.1 years) of the WHI estrogen-only arm showed no significant difference in breast cancer incidence between treatment and placebo groups (HR, 0.80; 95% CI, 0.62-1.04; P = .09) 1
However, observational studies contradict these findings:
- The Million Women Study showed an association between current use of estrogen-only HRT and increased risk of breast cancer (relative risk, 1.30; 95% CI, 1.21-1.40; P < .0001) 1
- The Nurses' Health Study demonstrated significantly increased breast cancer risk after long-term use (≥20 years) of estrogen alone (relative risk, 1.42; 95% CI, 1.13-1.77) 1
- Recent long-term users of estrogen-only therapy have a 15% increased risk of breast cancer (adjusted odds ratio 1.15; 95% CI, 1.09 to 1.21) 2

The risk increases with longer duration of HRT use 1, 3, 2
For each year of HRT use, the relative risk of breast cancer increases by a factor of 1.023 (95% CI, 1.011-1.036) 4
Women using HRT for 5 years or longer have a relative risk of 1.35 (95% CI, 1.21-1.49) 4

The increased risk of breast cancer declines after cessation of HRT 1, 4
Five or more years after stopping HRT, there is no significant excess risk of breast cancer overall 4
However, past long-term users of estrogen-progestogen combinations still have a 16% increased risk (1.16,95% CI, 1.11 to 1.21) 2

Different progestogens carry different levels of risk:
- Highest risk with norethisterone (OR 1.88,95% CI, 1.79 to 1.99)
- Lowest risk with dydrogesterone (OR 1.24,95% CI, 1.03 to 1.48) 2

HRT use is particularly associated with lobular breast cancer:
- Longer use of HRT (OR 3.07 for 57 months or more; 95% CI, 1.55-6.06)
- Current use of combination therapy (OR 3.91; 95% CI, 2.05-7.44) 5
Long-term HRT use is also associated with a 50% increase in non-lobular cancer (OR 1.52 for 57 months or more; 95% CI, 1.01-2.29) 5

In North America and Europe, the cumulative incidence of breast cancer between ages 50-70 in never-users of HRT is about 45 per 1000 women 4
The estimated excess cases of breast cancer per 1000 women who begin HRT at age 50:
- 5 years of use: 2 extra cases (95% CI, 1-3)
- 10 years of use: 6 extra cases (95% CI, 3-9)
- 15 years of use: 12 extra cases (95% CI, 5-20) 4
Recent research suggests:
- For estrogen-only users: 3-8 extra cases per 10,000 women-years
- For estrogen-progestogen users: 9-36 extra cases per 10,000 women-years
- For past estrogen-progestogen users: 2-8 extra cases per 10,000 women-years 2

The National Comprehensive Cancer Network (NCCN) recommends against the use of HRT for women taking tamoxifen or raloxifene outside of a clinical trial 1
The U.S. Preventive Services Task Force (USPSTF) concluded there is fair to good evidence that HRT increases the incidence of breast cancer, particularly with estrogen plus progestin 1

Differences in study populations between randomized trials and observational studies:
- Women in the WHI trials often started HRT years after menopause
- Women in observational studies typically initiated HRT at menopause and used it for longer periods 1
One hypothesis suggests that short-term estrogen use after estrogen deprivation may decrease breast cancer risk by inducing apoptosis of occult tumors, while long-term use may promote new tumor growth 1
Effects of HRT on breast tissue may interfere with mammography's ability to detect new breast cancers 1