Warning of risk to breast cancer patients from vaginal oestrogen
Research shows it may stop new breast cancer drugs working say UK specialists
Breast cancer specialists from one of the UKs leading cancer centres cautioned doctors (Thursday 26 January) of the risks in prescribing vaginal oestrogen to breast cancer patients being treated with the new aromatase inhibiting drugs, anastrozole, letrozole and exemestane.
Their concerns follow findings from the first study to examine the impact of vaginal oestrogen in women receiving aromatase inhibitors (AIs) for breast cancer, published on-line today in Annals of Oncology, by a team from the Royal Marsden NHS Foundation Trust in London.
AIs work by inhibiting the enzyme aromatase, which promotes the conversion of androgens to oestrogens in postmenopausal women. Breast cancer feeds off oestrogen, so reducing the circulating levels of the hormone as much as possible lessens the chance of the cancer recurring. The new AIs reduce circulating oestradiol by over 97%.
Around a fifth of patients on adjuvant AIs suffer from atrophic vaginitis – a distressing skin condition of the genitals caused by lack of oestrogen. Many ask if they can use topical oestrogen to alleviate the symptoms as conventional HRT is not recommended.
Senior author Professor Ian Smith, Head of the Breast Unit at the Royal Marsden, said: "Using this vaginal form of oestrogen which, we found, increases systemic oestradiol levels, will counteract AI treatment. With long term use, women may be risking the chance that their cancer may return, although this is probably not an issue if oestrogen rises for only one to two months."
Using a sensitive radioimmunoassay that they developed to quantify even extremely low levels, the researchers measured serum oestradiol in six women on adjuvant AI therapy who had actively asked to use the vaginal oestradiol tablet Vagifem for severe symptoms of atrophic vaginitis. They also monitored a seventh patient with metastatic breast cancer who was using Premarin oestradiol cream. Measurements were taken at baseline, then at 2, 4, 7-10 weeks and over 12 weeks from starting Vagifem.
Lead Researcher Dr Anne Kendall, Clinical Research Fellow at the Academic Department of Biochemistry at the Royal Marsden, said: "Our results showed a significant rise in serum oestradiol levels two weeks after starting Vagifem in six of the seven women (five of those on Vagifem and the one on Premarin). Typically, they fell after one month, but with a return to pre-Vagifem levels in only two women after seven and 12 weeks respectively. Two women who continued using Vagifem showed further increases between weeks seven and 10."
Dr Kendall said that in the UK and the USA there was currently uncertainty among cancer specialists and other doctors, including gynaecologists, about the safety of preparations such as Vagifem for women receiving AIs, and they are widely used. Some doctors do measure serum oestradiol, but most assays are not sensitive enough to detect changes in the low levels seen in women on AIs.
Although Vagifem is supposed to be used for a maximum of three months at a time, recurrence of symptoms often means repeat courses are prescribed. The manufacturers  patient information sheet does state that Vagifem should not be used in women with a history of breast cancer, but it also states that although there are reports of increased risk of breast cancer in women on HRT, Vagifem is not expected to pose an increased risk.
Professor Smith said: "Although the study is small, the magnitude of the effect in such a high proportion of the women strongly indicates it would be reproduced in a larger study population. It is particularly important that doctors are aware of the new findings, as increasing uptake of AI therapy means that it is likely that around 15,000 new women a year in the UK would be receiving AIs, a total of 100,000 at any one time."
The women in the study had been warned at the outset that they would be recommended to stop using the topical preparation at an early stage if there were concerns. One patient continued to use a low dose with regular monitoring. One elected to stop AI treatment and continue with Vagifem because of her poor quality of life. The others have stopped.
Dr Kendall said: "Our results raise concerns over the appropriateness of the combination of AI treatment and Vagifem, since the efficacy of aromatase inhibition depends on near total suppression of oestrogenic stimulation. The third generation AIs that inhibit aromatase by over 97% are more effective in controlling breast cancer than earlier agents, which achieved only 90%; this suggests that even a small increase in systemic oestrogen may be detrimental."
She added: "Our view is that the combination of AIs and Vagifem is contraindicated, apart from exceptional circumstances where regular monitoring of plasma oestradiol with specialist assays is available. Other non-hormonal vaginal moisturising gels or creams should be used in most cases." She said it was impossible to generalise about all vaginal oestrogens. However, given that a similar effect was seen with Premarin cream, caution was needed with all topical oestrogens.
Professor Smith concluded: "It is important that women discuss this with their doctor. Some complications related to atrophic vaginitis, such as recurrent urinary tract infection, may need treatment to be completed before stopping Vagifem. One option in those cases would be to switch from AIs to tamoxifen, which appears not to allow as much oestrogen to enter the system."
 Anastrozole (Arimidex); Letrozole (Femara); Exemestane (Aromasin)
 Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Annals of Oncology. doi:10.1093/annonc/mdj127.
 The baseline oestradiol serum levels for all the women (except the one on exemestane, a drug that can interfere with the assay used to measure oestradiol) were under or around 5pmol/l [picomoles per litre]. By 14 days they had risen from a median of 3 to 72pmol/l (range 3-232 pmol/l). By 28 days there was a drop in the majority to less than 35 pmol/l, but in two women who continued on Vagifem there was a further increase to 219 and 137 pmol/l respectively between 7 and 10 weeks.
 Vagifem is manufactured by Novo Nordisk. It comes in the form of a tablet that is inserted in the vagina via an applicator.
Margaret Willson | EurekAlert!