Menopausal Hormone Therapy and the risk of Breast Cancer?

Studies clarify menopausal HT’s impact on breast cancer risk

One of the greatest concerns of women who are considering Menopausal Hormone Therapy (MHT) is the relationship between hormone use and breast cancer. Data from the The Women’s Health Initiative (WHI) suggest an increase in risk with combined estrogen-progestin therapy, but a reduction in risk with short-term unopposed estrogen therapy.

The WHI represents the largest and longest-term randomized trial assessing the health impacts of systemic Hormone Therapy (HT). In an issue of JAMA, WHI investigators analyzed longer-term data (cumulative median follow-up >20 years), which allowed assessment of whether breast cancer incidence persisted and if they led to changes in mortality from breast cancer.

WHI data on breast cancer risk trends in Estrogen Therapy (ET) vs Estrogen-Progestin Therapy (EPT) users

In the ET trial, 10,739 women with prior hysterectomy, 238 versus 296 new cases of breast cancer were diagnosed in women in the ET versus placebo groups, respectively (annualized incidence, 0.30% [ET] vs 0.37% [placebo]. ET also was associated with significantly lower mortality from breast cancer: 30 versus 46 deaths (annualized mortality, 0.031% [ET] vs 0.046% [placebo].

In the EPT trial, which included 16,608 participants with an intact uterus, EPT compared with placebo was associated with significantly elevated risk for incident breast cancer: 584 versus 447 new cases, respectively (annualized incidence, 0.45% [EPT] vs 0.36% [placebo]. However, mortality from breast cancer was similar in the EPT and placebo groups: 71 and 53 deaths (annualized mortality, 0.045% [EPT] and 0.035% [placebo].

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What is the association of estrogen plus progestin or estrogen alone with breast cancer incidence and breast cancer mortality?

In this long-term follow-up study of randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of Conjugated Equine Estrogens (CEE) plus Medroxyprogesterone acetate (MPA), compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

Authors consider the initiation of menopausal hormone therapy (MHT) to be a safe option for healthy, symptomatic women who are within 10 years of menopause or younger than age 60 years and who do not have contraindications to MHT (such as a history of breast cancer, coronary heart disease [CHD], a previous venous thromboembolic event or stroke, or active liver disease).

Long-term use of MHT for prevention of disease is not currently recommended.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

In clinical practice, for women with an intact uterus who are considering the use of EPT for treatment of bothersome menopausal symptoms, clinicians should counsel that long-term use of HT slightly elevates the risk for breast cancer.

Combination HRT increases breast cancer risk by about 75%, even when used for only a short time.

By contrast, they should advise post-hysterectomy women with bothersome menopausal symptoms that ET does not appear to increase the risk for breast cancer.

Estrogen-only HRT increases the risk of breast cancer, but only when used for more than 10 years.

Conclusions

The objective of this study was to report updated findings regarding breast cancer incidence and breast cancer mortality over 20 years of follow-up of the randomized trials that evaluated Conjugated Equine Estrogens (CEE) plus Medroxyprogesterone acetate (MPA) in postmenopausal women with an intact uterus and Conjugated Equine Estrogens (CEE) alone in postmenopausal women with prior hysterectomy.

In conclusion, clinicians have to put the risk of breast cancer associated with MHT into clinical context:

The risk associated with long-term estrogen use is much lower than the risk conferred by obesity, inactivity and alcohol use. Furthermore, the findings of this study are not relevant to women with Primary ovarian insufficiency (POI), in whom risks are calculated in comparison to women with regular menstruation.

In general, tailoring hormone therapy to the needs of the individual woman ensures its long-term safety.

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Abstract

Importance: The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials.

Objective: To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials.

Design, setting, and participants: Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017.

Interventions: In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration.

Main outcomes and measures: The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer.

Results: Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37% and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%.

In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%).

Conclusions and relevance: In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

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