Cancer Risk with Hormone Replacement Therapy: Latest Evidence
Hormone replacement therapy (HRT) increases the risk of several types of cancer, with the risk varying by cancer type, HRT formulation, and duration of use. Based on the latest evidence, specific cancer risks must be carefully considered when prescribing HRT.
Breast Cancer Risk
- Combined estrogen-progestin HRT increases the risk of invasive breast cancer (relative risk 1.26,95% CI 1.00-1.59) according to the Women's Health Initiative (WHI) study 1
- The absolute risk for combined HRT is 41 versus 33 cases per 10,000 women-years compared with placebo 2
- Risk increases with duration of use and is higher in women with prior hormone therapy use (relative risk 1.86) 2
- Breast cancers in HRT users tend to be larger, more likely node-positive, and diagnosed at more advanced stages 2
- Estrogen-alone therapy carries a smaller risk than combined therapy but still shows increased risk after several years of use 2
- The increased risk persists for up to 10 years after discontinuation of therapy 2
- Risk appears to be higher in women who initiate HRT immediately after menopause 3
Endometrial Cancer Risk
- Unopposed estrogen therapy significantly increases endometrial cancer risk (relative risk 2.3,95% CI 2.1-2.5) 4, 1
- Risk increases dramatically with duration of use, reaching a relative risk of 9.5 for 10 years of use 4
- The elevated risk remains for at least 5 years after discontinuation of unopposed estrogen therapy 4
- Combined estrogen-progestin therapy shows mixed results: cohort studies indicate decreased risk (RR 0.4,95% CI 0.2-0.6) while case-control studies show increased risk (OR 1.8,95% CI 1.1-3.1) 4
- The WHI and HERS trials found no significant increase in endometrial cancer with combined therapy 4
Ovarian Cancer Risk
- The WHI estrogen-progestin substudy found a non-significant increased risk of ovarian cancer (relative risk 1.58,95% CI 0.77-3.24) 2
- A comprehensive meta-analysis of 52 epidemiological studies found increased ovarian cancer risk with HRT use (relative risk 1.41,95% CI 1.32-1.50) 2
- Long-term HRT use (10+ years) is associated with increased risks of ovarian cancer mortality (RR 1.8-2.2) 4
- The elevated risk applies to both estrogen-alone and combined estrogen-progestin products 2
- The exact duration of HRT use associated with increased ovarian cancer risk remains unknown 2
Other Cancer Considerations
- HRT appears to reduce the risk of colorectal cancer, though this benefit must be weighed against other risks 4
- Some evidence suggests HRT may increase the risk of certain favorable-histology breast cancers more than aggressive types 5
- The risk profile differs between transdermal and oral administration routes, with transdermal routes showing lower thrombotic risk (odds ratio 0.9 vs 4.2 for oral) 1, 6
Clinical Implications and Risk Management
- For women with an intact uterus, progestogen must be used in combination with estrogen to protect against endometrial hyperplasia and cancer 1
- Transdermal estradiol is preferred over oral formulations, particularly for women with hypertension or elevated thrombotic risk 1, 6
- 17β-estradiol is preferred to ethinylestradiol or conjugated equine estrogens for estrogen replacement 1
- Annual clinical reviews with mammography are recommended for women using HRT 1
- The risk-benefit profile differs for women with premature ovarian insufficiency compared to those with natural menopause 7
Risk Reduction Strategies
- Limit duration of HRT use to the shortest period needed for symptom control 4
- Consider transdermal rather than oral administration to reduce thrombotic risk 1, 6
- After cessation of HRT, the increased breast cancer risk dissipates within approximately 2 years 3
- Women with BRCA gene mutations should be particularly cautious about HRT use due to potential breast cancer risk 1
The decision to use HRT should carefully weigh these cancer risks against potential benefits for menopausal symptom relief, with consideration of individual risk factors and alternative treatments.