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EXPERT REACTION: HRT soon after menopause may increase breast cancer risk

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An international study that brought together data from 58 studies, including more than 100,000 women with breast cancer, found that all forms of hormone replacement therapy (HRT), except vaginally administered oestrogens, were associated with an increased risk of breast cancer. Incidence of breast cancer was 6.3 per cent in women who had never used HRT, rising to 8.3 per cent in those who had used combination HRT (oestrogen and progestogen) for five years. That translates to one additional case of cancer for every 50 women using combination HRT. Using oestrogen with intermittent progestogen lead to one additional cancer per 70 women treated, and using oestrogen alone led to one additional cancer per 200 women. The researchers also say women who have stopped using HRT had an elevated risk of breast cancer for 10 years after therapy stopped, although their risk was lower than women who were still using HRT.

Journal/conference: The Lancet

DOI: 10.1016/ S0140-6736(19)31709-X

Organisation/s:

Funder: Cancer Research UK and UK Medical Research Council.

Media Release

From: The Lancet

The Lancet: New analyses of the worldwide epidemiological evidence demonstrate link between different forms of menopausal hormone therapy and breast cancer incidence, and find that some risk persists for many years

  • For women of average weight in Western countries, five years of menopausal hormone therapy (MHT), starting at age 50 years, would increase breast cancer incidence from age 50 to 69 years by about one additional case in every 50 users of oestrogen plus daily progestogen MHT, one in every 70 users of oestrogen plus intermittent progestogen MHT, and one in every 200 users of oestrogen-only MHT.
  • After ceasing MHT, some excess risk persists for more than 10 years – the size of this risk depended on the duration of previous use. If a woman had used MHT for less than a year, however, there was little excess risk thereafter.

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

The findings, published in The Lancet, 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 (eg, for 10-14 days per month).

Women tend to begin MHT at around the time of the 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.

In Western countries, MHT use increased rapidly during the 1990s, halved abruptly in the early 2000s, then stabilised during the 2010s. Currently, there are about 12 million users in Western countries – about six million in North America and six million in Europe (including one million in the UK). [1] Although some are short-term users, 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.

Co-author Professor Valerie Beral from the University of Oxford, UK, says: “Our new findings indicate that some increased risk persists even after stopping use of menopausal hormone therapy. 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.” [2]

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 [3]. 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 (ie, about 63 in every 1,000 women who never use MHT develop breast cancer during the 20 years from ages 50 to 69).

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 (ie, 83 in every 1,000 users would develop breast cancer) – an absolute increase of 2 per 100 users (one in every 50 users);
  • 7.7 per 100 in users of oestrogen plus intermittent progestagen (ie, 77 in every 1,000) – an absolute increase of 1.4 per 100 users (one in every 70 users);
  • 6.8 per 100 in users of oestrogen-only (ie, 68 in every 1,000 users) – an absolute increase of 0.5 per 100 users (one in every 200 users).

Increases in breast cancer risk would be about twice as great for women who use MHT for 10 years rather than 5 years (see Figure 7).

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. The excess risks during and after MHT use depended on how long MHT had been used for (see Figures 2 and 7 – for MHT taken for five years, about half of the excess risk would be during the five years of current use, and the other half would be during the following 15 years after a woman stopped taking MHT). There was little excess risk after using any form of MHT for less than a year.

Co-author Professor Gillian Reeves from the University of Oxford, UK, says: “Use of menopausal hormone therapy for 10 years results in about twice the excess breast cancer risk associated with 5 years of use. But, there appears to be little risk from use of menopausal hormone therapy for less than one year, or from topical use of vaginal oestrogens that are applied locally as creams or pessaries and are not intended to reach the bloodstream.” [2]

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 (see Figure 5).

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 (see Figure 3). The risks were also attenuated by adiposity (particularly for oestrogen-only MHT, which had little effect in obese women: figures 6-7).

The findings were robust to variations in the analytical methodology used. Nor did they differ by family history of breast cancer, or by any characteristics of the women (other than obesity).

The authors note that a limitation of the currently available epidemiological evidence is 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 [4].

Writing in a linked Comment, Dr Joanne Kotsopoulos, Women’s College Hospital, Canada, notes that it is important to estimate accurately the increased risks of breast cancer from MHT. She says: “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. This might be dependent on severity of the symptoms, contraindications for MHT […], and BMI, and could take into account patient preference.”

[1] Oestrogen-only menopausal hormone therapy is generally used by women who have had a hysterectomy, while oestrogen plus progestagen hormone therapy is generally used by women who have not had a hysterectomy (progestagens are synthetic hormones that mimic the actions of natural progesterone).
[2] Quote direct from author and cannot be found in the text of the Article.
[3] The authors also reviewed retrospective studies which were, in aggregate, considered to be less reliable and they review such studies only in the accompanying online appendix.

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Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Professor Martha Hickey is Professor of Obstetrics and Gynaecology, University of Melbourne and Head of Menopause Services, The Women’s Hospital Victoria

This important publication in The Lancet, one of the leading medical journals, brings together data from 58 large international studies to provide new evidence about the association between use of menopausal hormone therapy (MHT) and risk of breast cancer. Based on over 100,000 women who developed breast cancer, half of whom had used MHT, the authors found that all types of MHT except vaginal oestrogen increased the risk of breast cancer. As previously reported in randomised controlled trials, combined MHT (oestrogen plus progestogen) was associated with a greater breast cancer risk than oestrogen alone. A new finding is that even women who took MHT for less than five years also had an increased risk of breast cancer, though the risk was greater for women using MHT for longer durations.

This risk translates into around one additional breast cancer for every 50-70 women taking combined MHT and one additional breast cancer for every 200 women taking oestrogen-only MHT for up to five years. Less than one year of MHT showed little increase in breast cancer risk, and use of topical vaginal preparations did not appear to affect risk. Although the breast cancer risks reduced after stopping MHT, some increased risk persisted for more than 10 years after stopping MHT. Another novel observation was that breast cancer risk was increased in younger women (from 40-45 years) taking MHT. However, the number of younger women included in these studies was relatively small and because MHT may provide additional benefits to younger menopausal women, such as prevention of osteoporosis and fracture, decisions about MHT use should be made on an individualised basis.

Accompanying results from a large observational UK study (The UK Million Women Study) show that women taking MHT are at an increased risk of dying from breast cancer, compared to women who have never taken MHT. Women using oestrogen-only MHT for five years or more had a 35 per cent relative increased risk of dying from breast cancer and those taking combined (oestrogen and progestogen MHT) had a 64 per cent relative increased risk of dying from breast cancer.

This new information will 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. 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.

Last updated: 29 Aug 2019 2:49pm
Declared conflicts of interest:
None declared.
Professor Susan Davis is a Professor of Women's Health and NHMRC Senior Principal Research Fellow and Director of the Women's Health Research Program at Monash University, and President of the International Menopause Society

The overall information regarding breast cancer risk and MHT reported in this paper is not new.

This paper provides an important public health message about obesity and breast cancer risk.

The reported the effects of MHT for women who go through early menopause (before the age of 45 years) must be be seen in the context of what is 'normal' for women of this age.

The paper reports slightly larger risks for oestrogen+progestogen therapy in their analyses of observational studies, compared with the randomised clinical trials they have listed in their paper.

A small, but significant, risk of breast cancer is also reported for oestrogen-only use, whereas the randomised trials did not demonstrate an increase in breast cancer risk with oestrogen-only therapy.

It is extremely important to note that this paper does not inform us of the impact of current recommended prescribing practices on breast cancer risk as virtually all of the included information pertains to MHT formulations and doses known to have adverse breast effects, that are no longer recommended.

A take home message of this paper should be that obesity is an important breast cancer risk, with a risk similar to that of taking MHT.

The most significant potential adverse public health consequence of this paper pertains to the application of the analysis to women who commenced MHT before the age of 45 years.

In the current paper the authors report that young postmenopausal women who use MHT have an increase in breast cancer risk compared with young post-menopausal non-users.

But what they fail to highlight is that, for young women, MHT restores 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.

Therefore early/premature menopause is a relative hormone deficiency state, and MHT is restorative therapy.

Last updated: 29 Aug 2019 11:45am
Declared conflicts of interest:
None declared.
Professor Andrew Shelling, Associate Dean of Research, Faculty of Medical and Health Sciences, University of Auckland

This large study describes that current and recent users of menopausal hormone therapy (MHT) are at an increased risk of breast cancer. While this known risk is small, the increase is significant. Balancing the amount of increased risk of breast cancer (and other disease risk), compared to the benefits to women with menopausal symptoms, is a difficult and important conversation.

What this new study provides us, that looks at over 100,000 postmenopausal women with breast cancer, is the impact of different types of MHT and the length of treatment. It shows that the risks of breast cancer are higher for combination therapy (estrogen and progestogen) than estrogen-only therapy. Most importantly, the study describes that outcomes for women are related to the amount of time they were taking MHT. The study clearly shows that there is little increased risk of breast cancer if MHT is used for less than a year, but risk significantly increases with the duration of treatment.

This new information will benefit discussions around the use of MHT in women with menopausal symptoms. While MHT remains an appropriate treatment for women with moderate to severe menopausal symptoms, it must now be considered that it is best to provide an appropriate MHT, for the shortest period of time necessary to control symptoms.

Last updated: 29 Aug 2019 11:29am
Declared conflicts of interest:
None.
Professor Cindy Farquhar, Professor of Obstetrics and Gynaecology, University of Auckland

We already knew that MHT using estrogen and progesterone HT was associated with increased risk of breast cancer and that the risk was greater for > 5 years use. Estrogen alone was thought to be safer with little or no change in the risk of breast cancer. And moderate term use up to 4-5 years was also thought to be relatively safe.  

We also knew that mortality from breast cancer was not increased among postmenopausal women in the Women’s Health Initiative study (the largest randomised study in this new analysis) who took combination MHT for a median of 5.6 years. Taking estrogen alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. 

There is no increased risk of breast cancer with MHT use only if women use it for less than one year. While this is reassuring - as MHT can be used for short term management of menopausal hot flushes - it does mean that treatments longer than one year need to be considered carefully.

The study also provides some details about risks for different ages and risks persisting after stopping. Starting MHT after the age of 60 appears to be safer but only for those women taking estrogen only.  

The study also reports that, in Western countries, there have been 20 million breast cancers diagnosed since 1990, of which 1 million would have been caused by MHT use. This means that 5 per cent of breast cancers could have been avoided.

Women on MHT should talk to their doctors about their risks of breast cancer (other risk factors are high BMI, increased alcohol intake, family history). Making sure that they are up-to-date with their mammogram (every two years) would be one step. A second step would be to assess their need for MHT by stopping and seeing if they still have a need for it – hot flushes usually resolve over time. It is safe to use MHT short term if hot flushes make you miserable but don’t use if for long (one year in this case).

Last updated: 29 Aug 2019 11:28am
Declared conflicts of interest:
None.
Dr Samantha Oakes is head of the Cancer Cell Survival group at the Garvan Institute of Medical Research.

This manuscript comes from a large worldwide collaboration that began in 1992, with the team performing a meta-analysis (an investigation of a 58 separate studies) containing approximately 150,000 cases of breast cancer and approximately 350,000 controls. The largest of its kind.

While not the main purpose of the study, the team found (like what has been reported before) that oral and topical MHT was associated with an increased risk of developing breast cancer and that use of combined oestrogen and progestogen produces a greater risk than MHT containing oestrogen alone. It is unclear from this study whether the increased number of cases resulted in a similar increase in mortality.

The team found that this increased breast cancer risk was associated with the duration and frequency of use (e.g. an oestrogen and progestogen combination producing an increased risk of 2.3-fold if used between five to fourteen years, compared to only a 1.6-fold risk if used only for one to four years). For reference, smoking results in more than a 20-fold increased risk.

Interestingly preparations that were administered vaginally, which are likely to have less systemic effects, showed no increased risk of breast cancer incidence. Also interesting in this study was that obesity was again linked to increased risk of developing breast cancer and the use of MHT did not further increase the risk of developing breast cancer in this population.

Overall, the study suggests that MHT, which is a very effective treatment for the symptoms of menopause, should be prescribed carefully and with regard to an individual patient's situation, taking into account the benefits and risks of such a therapy. Certainly the study suggests that MHT should be limited to five years of use or shorter if the symptoms of menopause subside.

Last updated: 29 Aug 2019 11:25am
Declared conflicts of interest:
None declared.
Associate Professor Marina Reeves is Deputy Associate Dean (Researcher Development) and Associate Professor (Nutrition) in the School of Public Health, University of Queensland

This new meta-analysis provides important evidence for women in terms of understanding the increased breast cancer risk from hormone replacement therapy used to manage menopausal symptoms.

This study adds more specific information than we knew previously about the risk associated with different types of HRT. The biggest risk factors for breast cancer are being female followed by getting older – two things we unfortunately can’t change.

The World Cancer Research Fund (WCRF) regularly reviews the evidence around modifiable ‘lifestyle’ risk factors and cancer risk. The 2018 WCRF report confirmed that excess body weight, increased alcohol consumption and physical inactivity increase the risk of postmenopausal breast cancer.

An important contribution of this new study is the analysis of the association between types of MHT and breast cancer risk across subgroups of women.

This analysis suggests that low alcohol intake and a healthy body weight do not provide any ‘protection’ over the increase in breast cancer risk attributed to MHT use.

Unfortunately subgroup analysis by physical activity level was not conducted in this meta-analysis.

Menopausal symptoms can be extremely severe impacting on women’s quality of life, so menopausal hormone therapy is often used as a means of managing daily symptoms.

This study highlights the need for more evidence on effective interventions for managing menopausal symptoms that do not adversely increase risk of other health conditions such as breast cancer.

Last updated: 29 Aug 2019 10:49am
Declared conflicts of interest:
None declared.
Gino Pecoraro is Associate Professor of Obstetrics and Gynaecology at the University of Queensland, a Federal Councillor for the National Association of Specialist Obstetricians and Gynaecologists (NASOG) and a Federal member of the Australian Medical Association (AMA) Board. He is also a practising obstetrician and gynaecologist in private practice in Brisbane.

Menopause is a rite of passage that every woman will pass through. For most women the most pressing symptoms associated with declining ovarian function are hot flushes, vaginal dryness, irritability, sleep disturbance and mood swings. 

Menopausal hormone therapy (previously referred to as HRT) is currently the most effective treatment available for these symptoms and also protects against other health consequences of menopause such as osteoporosis. In addition, MHT decreases the risk of bowel cancer.

With these advantages, however, come the disadvantages of an increased risk of breast cancer and thrombosis.

The rate of bowel cancer prevention is about the same as the increased risk of breast cancer meaning the net cancer effect of hormone treatment is close to nil.

From a high in the late 80s and 90s, the number of women taking hormone treatments for menopausal symptoms fell rapidly after the Women’s Health Initiative study reported in 2002 that breast cancer cases were increased in women taking combination (oestrogen plus progesterone) preparations. Although WHI  reported that oestrogen only treatment had no increased risk, it is important to remember that all women with an intact uterus must have progesterone as well as oestrogen to protect against endometrial cancer.

Published in the prestigious The Lancet medical journal today is a prospective study that began in 1992 and has looked at the results of over 58 previous studies involving nearly 600,000 women,  143,000 of whom developed invasive breast cancer.

The results confirm previous studies suggesting that women taking oestrogen-containing menopausal treatment, are at a higher risk of developing breast cancer than women who have not used hormonal treatment.

An increased risk was found in all types of hormonal treatment except for vaginal-only oestrogen. The risk increase was greatest for women taking combined hormones, especially if the progestogen was given daily rather than for one week out of every four. Among women taking continuous combined hormone treatment from the age of 50 for 5 years, we can expect an extra two breast cancers per 100 women or a 2 per cent increase. While the rate of cancer diagnosis is increased, this does not necessarily equate to premature death.

The only real differences found by this group of researchers are that even oestrogen-only use  (unless it is administered vaginally) is associated with a small increased risk of 0.5 per cent or one extra case per 200 women, that the increased risk is seen even among short term (one- to four-year) users, and that the risk persists for more than a decade after hormonal treatments are stopped.

This should not be seen as alarming, but rather a confirmation of previous research with some added detail. As always, before starting any treatment a discussion between doctor and patient of available treatment options as well as their risks and benefits should be undertaken.

Other advantages of menopausal hormone treatment such as the 50 per cent decrease in the risk of hip fracture is not addressed in this paper and it is important to consider all effects (positive and negative) before making a decision on whether to take hormones or not.

Finally, it is important that research into effective menopausal treatments (which all but stopped after the WHI report) continue and that women be made aware that nonhormonal treatment for menopausal symptoms is both available now and continuing to be researched.

Last updated: 29 Aug 2019 10:28am
Declared conflicts of interest:
None declared.

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