Menopausal Hormone Therapy and Breast Cancer Link Confirmed

Roxanne Nelson, RN, BSN

August 29, 2019

All types of menopausal hormone therapy (MHT), with the exception of vaginally-inserted estrogen, are associated with an increased risk of developing breast cancer, concludes a large meta-analysis.

Even after MHT was stopped, some excess risk could persist for a decade, with the size of risk dependent on the duration of use, note the authors, who form the Collaborative Group on Hormonal Factors in Breast Cancer.

"Use of menopausal hormone therapy for 10 years results in about twice the excess breast cancer risk associated with 5 years of use," said coauthor Gillian Reeves, PhD, from the University of Oxford, United Kingdom, in a statement. "But there appears to be little risk from use of menopausal hormone therapy for less than 1 year, or from topical use of vaginal estrogens that are applied locally as creams or pessaries and are not intended to reach the bloodstream."

The risk was somewhat attenuated among the small number of women who had started therapy after the age of 60, and by weight. Obese women had a lower risk of breast cancer with MHT use as compared with those who were lean or overweight, the team reports.

The risk for breast cancer was higher for products containing estrogen-progestagen combinations vs those with estrogen alone, especially if progestagen was given daily as opposed to intermittently.

The researchers estimate that — if this association is largely causal — then the use of MHT in western nations since 1990 has already led to approximately 1 million cases of breast cancer, out of a total of 20 million.

Five years of MHT use beginning at age 50 would increase the incidence of breast cancer by about 1 additional case in every 50 users of estrogen plus daily progestagen; by 1 additional case in every 70 users of estrogen plus intermittent progestagen; and by 1 additional case in every 200 users of estrogen used alone.

The study was published online today in The Lancet.

This new study confirms the findings of an association between MHT and breast cancer reported in a previous meta-analysis (Lancet. 1997;350:1047-1059), but also adds new information on the duration of the risk, and how the risk varies with different types of products.  

In an accompanying editorial, Joanne Kotsopoulos, PhD,  a scientist at the Women's College Research Institute and associate professor, Dalla Lana School of Public Health, University of Toronto, Canada, notes that it is important to accurately estimate the increased risks of breast cancer from MHT, which is also known as hormone replacement therapy.

"Clinicians must heed the message of this study but also to take a rational and comprehensive approach to the management of menopausal symptoms, with careful consideration of the risks and benefits of initiating MHT for each woman," she writes.

"The take-home message is that this large, comprehensive study has demonstrated that MHT is indeed a risk factor for breast cancer," Kotsopoulos told Medscape Medical News.  "Importantly, the risks were higher for women who used combined therapy vs estrogen alone and with increasing duration of use," she added.

Given the consistency in the evidence and the dose-response that was reported, she emphasized the importance of clinicians and patients having serious/frank discussions about the risk and benefits associated with the initiation of MHT use.

"That being said, short-term use was associated with a lower and even no risk if used for less than a year," she said. "For estrogen alone, the risk dissipated within 5 years of stopping. Taking into account these facts, along with the severity of menopausal symptoms and personal history of other conditions, clinician and patient will be able to decide on the ideal candidates for MHT use."

Risk Linked to Type and Duration

For their study, the Collaborative Group on Hormonal Factors in Breast Cancer reviewed 58 studies conducted between 1992 and 2018 and found a total of 108,647 postmenopausal women who developed breast cancer, at a mean age of 65 years.

About half of these women (n = 55,575, 51%) had used MHT. The average age at menopause and at starting MHT was 50 years.

Women who were current users (who were using MHT when they were diagnosed with breast cancer) had been taking the products for an average of 10 years, while past users had been taking the products for an average of 7 years.

The team calculated that, for women of average weight who had never used MHT, the average risk of developing breast cancer from ages 50 to 69 was about 6.3 per 100 women.

The authors estimate that 5-year use of MHT products containing estrogen plus daily progestagen, beginning at age 50, would increase the 20-year risk from 6.3% to 8.3%, for an absolute increase of 2.0 per 100 women.

For MHT products containing estrogen plus intermittent progestagen, the increase would be from 6.3% to 7.7%, an absolute increase of 1.4 per 100 women; for 5 years use of estrogen-only products, the 20-year risk would increase from 6.3% to 6.8%, an absolute increase of 0.5 per 100 women.

Benefits of Hormone Therapy for Menopause

Reactions to the new study were issued by two UK medical societies, both of which emphasized that hormonal therapy benefits many women who suffer through menopause.   

In a statement, Janice Rymer, MD, consultant gynecologist and vice president of the Royal College of Obstetricians and Gynecologists, said, "Women must be informed of the small increase in risk of breast cancer so they can weigh these up against the benefits that they may have from taking HRT. 

"Every woman experiences the menopause differently and symptoms vary. These can be extremely debilitating and have a significant impact on a woman's physical and psychological health, career, social life, and relationships," she said. "Unfortunately, many women are still suffering in silence and are reluctant to seek advice and support due to concerns around the risks of breast cancer associated with HRT.

"The findings from this research should be helpful to both women and doctors, particularly when considering whether to start hormone therapy, for how long, and which preparation they could take — whether it includes estrogen and progestagen combined, or estrogen alone. These findings should not put women off taking HRT if the benefits — such as protection of bones and decrease in cardiovascular risk — outweigh the risks.

"To put the risk into context, a woman has greater risk of developing breast cancer if she is overweight or obese compared to taking HRT," she said. "Women must be aware of the effect of obesity and alcohol, which increase the risk of breast cancer and modifies the additional risk of HRT."

Haitham Hamoda, MD, chair of the British Menopause Society, said in a statement:  "We welcome this further data on the incidence of breast cancer, which will help us counsel our patients and women in general better. This paper provides further data…and includes some new information on different types of progestagen that surprisingly were found to not vary as much as had been thought.

"Women must be informed of the data on breast cancer risk with HRT to help them make an informed decision," he continued. "However, this should be considered in comparison to the risk of breast cancer with other lifestyle factors such as alcohol intake and obesity, which have been shown to be associated with a higher risk compared to that with HRT.

"This should also be taken in the context of the overall benefits obtained from using HRT, including symptom control and improving quality of life as well as considering the bone and cardiovascular benefits associated with HRT use."

This study was funded by Cancer Research UK and the Medical Research Council. It was conducted by researchers from the Collaborative Group on Hormonal Factors in Breast Cancer. The members of the writing committee and Kotsopoulos have disclosed no relevant financial relationships.

The Lancet. Published online August 29, 2019. Full text

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