July 20, 2022

expert reaction to study looking at menopausal hormone therapy after early-stage breast cancer, and breast cancer recurrence

An observational study published in the Journal of the National Cancer Institute looks at the use of hormone therapy after early breast cancer.

Prof Stephen Duffy, Professor of Cancer Screening, Queen Mary University of London, said:

“These results are interesting, although there are some caveats.  The study compares cancer recurrence rates in women with oestrogen receptor positive cancer by whether they received hormonal treatment for menopausal symptoms.  The main findings seem to be that the hormone treatments if anything were associated with improved survival.  There is a finding of an increased risk of cancer recurrence with the hormonal treatment in those women whose cancers were treated with aromatase inhibitors.

“I do have some worries about the reliability of the observed improved survival with hormone therapy for menopausal symptoms, as the patients who received these therapies by and large had less advanced and aggressive cancers than those who did not.  Although the authors have quite correctly adjusted for the pathological features of the tumours in their analysis, there may be further unobserved differences between the populations given and not given hormone replacement therapy.”

Dr Melanie Davies, Consultant Obstetrician and Gynaecologist, UCLH, said:

“Women are advised against using systemic HRT after a breast cancer diagnosis for sound reasons: most breast cancers are hormone sensitive, anti-oestrogen therapy has been shown to significantly reduce the risk of recurrence, and randomised trials of HRT after breast cancer showed increased risk of recurrence.  The randomised trials are not recent, but are scientifically more reliable than observational studies.  This is an observational study and although it has the advantage of being a national cohort, Denmark is not a large country and there were only 133 women who took HRT for 5 years after breast cancer.  Also, we don’t know if they may be a selected group of women with a good prognosis, or how long ago they had cancer.  So I don’t think this is enough to change advice.

“Vaginal oestrogen is very different from HRT because the amount absorbed through the vagina is very small and so it is much less likely to have an effect on the breast.  Vaginal oestrogen is probably safe with Tamoxifen, which blocks oestrogen receptors so it might counteract the effect of any oestrogen that does get absorbed.  However aromatase inhibitors work differently (they reduce production of oestrogen in the body but don’t block its effects) so even using vaginal oestrogen is usually considered unwise.”

Prof Paul Pharoah, Professor of Cancer Epidemiology, University of Cambridge, said:

“This is a large, observational study (that is it is not a randomised controlled trial) investigating the potential association between vaginal estrogen therapy or menopausal hormone therapy use in women with early breast cancer and recurrence of the breast cancer.  All the women with cancer had been treated with some form of anti-estrogen therapy that can be associated with symptoms of the menopause.  Most of the women who had some form of treatment for menopausal symptoms used vaginal estrogen therapy (1,222) and only 117 had used menopausal hormone therapy in the form of patches or tablets.

“The numbers of women using menopausal hormone therapy in the form of patches or tablets was too small to make any meaningful inferences about the effects on recurrence.

“The main findings were that vaginal estrogen therapy was not associated with an increased risk of disease recurrence.  However there was some evidence that the subgroup of women whose breast cancer was treated with an aromatase inhibitor are at a slightly increased risk of recurrence.

“The data on which the study is based are of a high quality and the analyses appear to be sound.  These results are reassuring for women who get menopausal symptoms as a result of treatment of their breast cancer with tamoxifen, but they cannot definitively rule out a small increase in risk as all observational studies are prone to some forms of bias and the interpretation of the results can be difficult.

“[An example of why the results may not be as straightforward as they seem.  Subtle but could be important:-  For example, women who use vaginal estrogen therapy or menopausal hormone therapy are likely to have more severe symptoms.  Such symptoms may indicate that the breast cancer therapy they are taking is more effective and so these women might be expected to have better outcomes rather than the similar outcomes observed in this study.  This is conjecture, but the truth cannot be known outside a randomised controlled trial.  A fundamental problem with observational studies is small risks v hard to rule in or out.]”

Dr Channa Jayasena, Consultant Reproductive Endocrinologist, Imperial College London, said:

“Breast cancer treatment often involves blocking actions of the female hormone, oestrogen.  This is because oestrogen can ‘feed’ the growth of breast tumours.  Unfortunately, women surviving breast cancer may feel symptoms of low oestrogen like vaginal dryness, low mood or hot flushes.  The authors have conducted a huge study of over 8000 women treated for breast cancer in Denmark.  It has been analysed appropriately, and their results look credible.

“20% of these women also took vaginal creams containing oestrogen; very little of this cream escapes to the rest of body.  2% of women with breast cancer took HRT tablets containing oestogen, which would certainly raise oestogen levels in the whole body.  Overall, their results have failed to demonstrate risk associated with giving HRT tablets.  However this was an observational study.  It is therefore possible that doctors gave HRT tablets to those women who they were most confident would not have breast cancer coming back (because the tumour was very small and not aggressive).  So, it seems premature to recommend HRT to women after breast cancer based on just this study.  However, the results suggest that future trials looking at the safety of HRT are warranted.”

Dr Annice Mukherjee, Consultant Endocrinologist, Spire Manchester Hospital, said:

“It should be emphasised that this study includes women with early-stage breast cancer who did not receive chemotherapy.  They are therefore a highly selected group with a lower risk of recurrence than women with more advanced disease at presentation who are treated with chemotherapy.

“The data are very reassuring for the use of vaginal oestrogen therapy and this is consistent with previous data.  The long follow-up times are also extremely helpful and reassuring, although there remains some question about women who are treated with aromatase inhibitors.

“The numbers in the systemic menopausal hormone therapy (MHT) groups are far too small to make any new conclusions about safety of systemic MHT.  Also, as with all the previous observational studies there is effectively a “healthy user bias”, because women who were prescribed MHT had smaller tumours and other parameters suggesting they were at the lowest overall risk of recurrence than non-users of MHT or those excluded from the analysis with more advanced disease at presentation.

“The study supports an individualised approach to managing menopause symptoms in women who have had breast cancer and the nuances mean that decisions should be made by specialists involved in the multidisciplinary care of breast cancer survivors.” 

‘Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study’ by Søren Cold et al. was published in the Journal of the National Cancer Institute at 05:01 UK time on Wednesday 20 July 2022.

DOI: 10.1093/jnci/djac112

Declared interests

Prof Stephen Duffy: “No conflict.”

Dr Melanie Davies: “I run a ‘late effects’ service in the NHS seeing women with menopause problems after cancer.  I have a research grant to study non-hormonal treatments for menopause awarded by NIHR but the contract has not started.”

Prof Paul Pharoah: “I have no conflicts of interest to declare.”

Dr Channa Jayasena: “No conflicts.”

Dr Annice Mukherjee: “No declarations other than being a Society for Endocrinology member.”