Link found between MHT and breast cancer risk

An international collaboration, using data from more than 100,000 women with breast cancer from 58 epidemiological studies worldwide, has found that using menopausal hormone therapy (MHT) is associated with an increased risk of breast cancer, and that some increased risk persists for more than a decade after use stops.

Published in The Lancet, the findings suggest that all types of MHT, except topical vaginal oestrogens, are associated with increased risks of breast cancer, and that the risks are greater for users of oestrogen-progestagen hormone therapy than for oestrogen-only hormone therapy. For oestrogen-progestagen therapy, the risks were greater if the progestagen was included daily rather than intermittently.

Women tend to begin MHT at around the time of menopause, when ovarian function ceases, causing oestrogen levels to fall substantially, progesterone levels to fall to near zero and some women to experience serious hot flushes and discomfort that can be alleviated by MHT. Although regulatory bodies in Europe and the USA recommend MHT be used for the shortest time that is needed, some clinical guidelines recommended less restrictive prescribing. About five years of use is now common, whereas about 10 years of use used to be common.

A previous meta-analysis of the worldwide evidence found that current and recent users of MHT were at an increased risk of breast cancer, but insufficient information was available about the effects of different types of MHT or about long-term risks after MHT use had ceased. In the new study, the authors brought together and re-analysed centrally all the eligible prospective studies from 1992–2018 that had recorded MHT use and then monitored breast cancer incidence, with 108,647 women subsequently developing breast cancer at an average age of 65 years. They looked at the type of MHT last used, duration of use and time since last use in these women.

Among women who developed breast cancer in the prospective studies, half had used MHT, the average age at menopause was 50 years and the average age at starting MHT was also 50 years. The average duration of use of MHT use was 10 years in current users and seven years in past users.

For women of average weight in Western countries who have never used MHT, the average risk of developing breast cancer over the 20 years from ages 50 to 69 inclusive is about 6.3 per 100 women. The authors estimate that for women with five years’ use of the three main types of MHT, starting at age 50, the 20-year breast cancer risks from ages 50 to 69 inclusive would increase from 6.3 per 100 in never-users to:

• 8.3 per 100 in users of oestrogen plus daily progestagen)
• 7.7 per 100 in users of oestrogen plus intermittent progestagen
• 6.8 per 100 in users of oestrogen-only
   

The increases in the 20-year risk include the increased risks both during the five years when MHT is being used and during the 15 years after use had stopped. Increases in breast cancer risk would be about twice as great for women who use MHT for 10 years rather than five years. There was little excess risk after using any form of MHT for less than a year, or from topical use of vaginal oestrogens that are applied locally as creams or pessaries and are not intended to reach the bloodstream.

“Our new findings indicate that some increased risk persists even after stopping use of menopausal hormone therapy,” said study co-author Professor Valerie Beral, from the University of Oxford. “Previous estimates of risks associated with use of menopausal hormone therapy are approximately doubled by the inclusion of the persistent risk after use of the hormones ceases.”

Overall, MHT use was much more strongly associated with oestrogen-receptor-positive (ER+) breast cancer than with other types of breast cancer (as hormonal factors mainly affect ER+ breast cancer). The increased risk of developing ER+ breast cancer accounted for most of the excess breast cancer risk associated with MHT.

As menopause usually occurs in women’s 40s and 50s, almost all the evidence was for women who had had their menopause and started MHT in this age range. The proportional increases in risk were similar for women starting MHT at ages 40–44, 45–49, 50–54 and 55–59. The risks appeared, however, to be somewhat attenuated among the few who had started using MHT after age 60 years. The risks were also attenuated by adiposity (particularly for oestrogen-only MHT, which had little effect in obese women).

The authors claimed that the findings were robust to variations in the analytical methodology used and did not differ by family history of breast cancer, nor by any characteristics of the women (other than obesity). They did acknowledge, however, that there is still not enough information on women who had used MHT for long periods and had stopped more than 15 years ago. In addition, they did not collect information on breast cancer mortality, although evidence is cited that the results for breast cancer mortality would parallel the results for incidence.

So does this mean menopausal women should stop taking MHT? According to the Australian and New Zealand scientists who have commented on the story, that depends.

Cindy Farquhar, Professor of Obstetrics and Gynaecology at the University of Auckland, recommended that women who are taking MHT should talk to their doctors about any other risk factors for breast cancer, and to make sure they are up to date with their mammograms. She also suggested patients briefly stop MHT and see if they still have a need for it, as hot flushes usually resolve over time.

Gino Pecoraro, Associate Professor of Obstetrics and Gynaecology at the University of Queensland, Federal Councillor for the National Association of Specialist Obstetricians and Gynaecologists (NASOG) and federal member of the Australian Medical Association (AMA) Board, agreed that doctors and patients should discuss all available treatment options as well as their risks and benefits, with non-hormonal treatment for menopausal symptoms both available now and continuing to be researched. He noted that advantages of MHT, including a 50% decrease in hip fracture, were not addressed in the study and these are among the effects that should be considered.

Professor Susan Davis, Director of the Women’s Health Research Program at Monash University and President of the International Menopause Society, emphasised the fact that MHT can be particularly beneficial for young postmenopausal women, restoring their breast cancer risk to approximately what it would have been if they had not gone through an early menopause.

“This is extremely important as menopause before the age of 45 years is associated with a greater risk of premature death from all causes and premature death from cardiovascular disease, as well as substantially greater risk of osteoporosis and fragility fracture in later life,” Prof Davis said. “Therefore, early/premature menopause is a relative hormone deficiency state and MHT is restorative therapy.”

She added that the paper does not inform readers of the impact of current recommended prescribing practices on breast cancer risk, stating that “virtually all of the included information pertains to MHT formulations and doses known to have adverse breast effects, that are no longer recommended”.

But while such formulations may not be recommended, Martha Hickey, Professor of Obstetrics and Gynaecology at the University of Melbourne and Head of Menopause Services at The Women’s Hospital Victoria, said the study will nevertheless provide better evidence to inform women and their healthcare providers about whether to take MHT and for how long.

“We do not yet have national clinical guidelines for managing menopause in Australia,” Prof Hickey noted. “Now would be a good time to develop these guidelines to better support women to make informed decisions about safe and effective options for managing troublesome menopausal symptoms.”

Image credit: ©stock.adobe.com/au/missty

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