What is the risk of cancer associated with estrogen replacement therapy (ERT)?

From the Guidelines

Estrogen replacement therapy is associated with a small but significant increased risk of certain cancers, particularly breast cancer and endometrial cancer, as evidenced by the most recent and highest quality study 1. The risk of cancer associated with estrogen replacement therapy (ERT) is a critical consideration for women undergoing menopause.

Key Points to Consider

• The risk of breast cancer is increased with combined estrogen-progesterone therapy, with a 75% increase after 5-10 years of use, while estrogen-only therapy carries a lower risk increase of about 30% 1.
• Endometrial cancer risk is substantially elevated with estrogen-only therapy but can be mitigated by adding progesterone for women who still have a uterus 1.
• The risk varies based on the specific formulation, dosage, duration of use, and individual risk factors 1.

Recommendations

• Women considering hormone therapy should use the lowest effective dose for the shortest duration necessary to manage symptoms 1.
• Those with a personal history of breast cancer, endometrial cancer, or blood clots should generally avoid estrogen therapy 1.
• Alternative non-hormonal options for managing menopausal symptoms include SSRIs like paroxetine (7.5-25mg daily), venlafaxine (37.5-150mg daily), gabapentin (300-900mg daily), or clonidine (0.1-0.2mg daily) 1.

Important Considerations

• The cancer risk must be weighed against the benefits of symptom relief and potential protection against osteoporosis and cardiovascular disease in early menopause 1.
• Clinicians should develop a shared decision-making approach to preventing chronic diseases in perimenopausal and postmenopausal women, considering individual risk factors and preferences in selecting effective interventions 1.

From the FDA Drug Label

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0. 80) The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5. 6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA.

The risk of cancer associated with estrogen replacement therapy (ERT) includes:

• Endometrial cancer: increased risk with unopposed estrogen therapy, 2 to 12 times greater than in non-users, dependent on duration and dose of treatment 2
• Breast cancer:
  • Estrogen-alone therapy: no increased risk of invasive breast cancer, relative risk 0.80 2
  • Estrogen plus progestin therapy: increased risk of invasive breast cancer, relative risk 1.24, absolute risk 41 versus 33 cases per 10,000 women-years 2

From the Research

Risk of Cancer Associated with Estrogen Replacement Therapy (ERT)

• The risk of endometrial cancer is increased with estrogen replacement therapy (ERT) without progestins 3, 4, 5, 6.
• The addition of progestins to ERT can reduce the risk of endometrial cancer, with continuous progestin use being more effective than cyclic use 4, 5, 6.
• The risk of breast cancer with ERT is still a topic of debate, with some studies suggesting an increased risk with combined estrogen-progestin therapy 4, 7, 6, while others find no significant increase in risk with estrogen alone 3, 7.
• The biological roles of estrogen and progestin in tumorigenesis are different between the endometrium and breast, which may explain the varying effects of ERT on cancer risk 7.
• Factors such as body-mass index and duration of ERT use can also influence the risk of endometrial and breast cancer 4, 5, 6.

Specific Cancer Risks

• Endometrial cancer: increased risk with ERT without progestins, reduced risk with continuous progestin use 4, 5, 6.
• Breast cancer: possible increased risk with combined estrogen-progestin therapy, no significant increase in risk with estrogen alone 3, 4, 7, 6.

Study Findings

• A study of 716,738 postmenopausal women found that ERT with estrogen alone increased the risk of endometrial cancer, while combined estrogen-progestin therapy reduced the risk 4.
• A case-control study of 709 postmenopausal women with endometrial cancer found that ERT with estrogens alone increased the risk of endometrial cancer, while combined estrogen-progestin therapy had a weaker association 5.
• A review of recent studies found that the biological roles of estrogen and progestin in tumorigenesis are different between the endometrium and breast, which may explain the varying effects of ERT on cancer risk 7.
• A cohort study of 11,231 Swedish women found that long-term use of estrogen-progestin combined replacement therapy may increase the risk of breast cancer, while exposure to estrogen alone substantially elevates the risk of endometrial cancer 6.