Study suggests HRT carries higher risk of breast cancer than thought

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A meta-analysis finds that many women who take hormone therapy during menopause are more likely to develop breast cancer than previously thought – and remain at higher risk of cancer for more than a decade after they stop taking the drugs. Stat News reports that the study looked at data from dozens of studies, including long-term data on more than 100,000 women who developed breast cancer after menopause. The increased riks equivalent to 20 extra cases per 1,000 women in those who took combined oestrogen, daily progestogen HRT

Half of those women had used what’s known as menopausal hormone therapy, or MHT. The longer women took the medicine, the more likely they were to develop breast cancer. Experts say the findings could shape how women and their health care providers decide how to manage symptoms of menopause. “This is a consensus of many researchers and many studies all around the world. These are important new results,” said Valerie Beral, a cancer epidemiologist at the University of Oxford and one of the lead authors of the new study.

Women have long been prescribed synthetic versions to replace the hormones that decline during menopause. The medications – usually delivered in a pill, but sometimes in a patch, gel, or injection – provide women either oestrogen or a combination of oestrogen and progesterone. For many women, they help to tamp down symptoms of menopause, including osteoporosis.

For years, research has suggested a potential link between MHT and an increased risk of breast cancer. In 2002 and 2004, the Women’s Health Initiative released reports that showed women who used combination MHT were more likely to develop breast cancer. MHT use fell after the reports received widespread coverage. That was followed by a decline in breast cancer rates.

But there wasn’t much information on whether that risk persisted, or how it differed based on the type of MHT a woman took. So, an international group of researchers pulled together data from dozens of studies – published and unpublished – to examine the issue more closely. They took a woman’s age at first use of MHT, how long she used the medication, and the time elapsed since she last used it into account. The mean age of women starting menopause was 50, which was also the mean age at which women started using MHT.

The researchers found that compared with women who never used MHT, women who did had a significantly higher risk of developing invasive breast cancer. They estimated that 6.3% of women who never used MHT developed breast cancer, compared to 8.3% of women who used the combination drug continually for five years. That’s roughly one extra cancer diagnosis for every 50 users.

The longer women used MHT, the greater their risk of breast cancer. Women who were no longer using MHT had a lower relative risk than women who were currently using it – but they remained at an elevated risk for more than a decade after they stopped taking the drug. The level of risk was dependent on how long a woman took MHT. The study also found that women who took the combination drug were more likely to develop cancer than women who took the oestrogen-only drug.

“The findings are significant,” said Joanne Kotsopoulos, a breast cancer researcher at Women’s College Research Institute in Toronto. “The longer you use it, the higher the risk,” added Kotsopoulos, who wasn’t involved in the research but wrote a commentary on the study.

The new analysis doesn’t show that MHT directly causes breast cancer. But researchers suspect the association has to do with the hormonal changes of menopause. The level of hormones produced by the ovaries dramatically drops during menopause. Going into menopause early is thought to lower the risk of breast cancer. But using MHT might keep women in something like a pre-menopausal state, keeping them from getting the protective benefits of menopause on cancer risk.

“Oestrogens stimulate activity in the breast and increase the risk of breast cancer. (MHT) is just putting that stimulus, which had gone after menopause, back,” said Beral.

The caveat: The findings, broadly speaking, apply to women of average weight in developed countries. The researchers found that MHT didn’t have a significant adverse effect on women who were obese, though obesity is also a risk factor for breast cancer after menopause.

For now, experts say patients and providers should carefully consider when the potential benefit of using MHT outweighs the risks. Alternatives to MHT – Like taking vitamin D and calcium supplements or keeping rooms cooler – should be a part of that conversation, experts said. It’s also critical for doctors to check in with women on MHT about whether the medication is actually easing their symptoms – and if it isn’t, clinicians should consider taking them off the drugs.

“It’s a balance. Every woman is different,” said Kotsopoulos. “But the risk is high for breast cancer, so they need to take a very serious approach.”

Abstract
Background: Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.
Methods: Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.
Findings: During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.
Interpretation: If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

Authors
Collaborative Group on Hormonal Factors in Breast Cancer

 

But doctors in the UK are encouraging women to keep taking HRT, says a Weekend Argus report. Doctors claim the “irresponsible” research may cause women to abandon HRT treatment, reducing their overall health and increasing their risk of developing other life-threatening illnesses. According to experts, the benefits of HRT in relieving debilitating symptoms, including night sweats, depression and hot flushes, outweigh the risks.

Professor Michael Baum, a breast cancer specialist from University College London, led the backlash, saying he wanted to reassure HRT users. He claimed the research was “appalling” as it did not take into account the benefits of HRT in preventing other illnesses including dementia and osteoporosis. “Some of the diseases that can be prevented by HRT carry a greater risk for women of dying than breast cancer. If you deny women HRT, they are more likely to die of problems like osteoporosis, fractures, heart disease, dementia,” Baum said. He added it was “totally inappropriate” of the Oxford team to publish the study without referring to the number of deaths from breast cancer caused by HRT, and the number of deaths that could be prevented by HRT.

Beral said: “We are concerned many GPs say it’s not something you need to worry about. We want GPs to quote the reliable figures.” Dr Julie Sharp of Cancer Research UK, which funded the study, said: “Women have to know the risks of which type of HRT they take and how long they take it for to decide what’s right for them.”

The NHS assessment notes that link between breast cancer and HRT has always been known, but this valuable research, based on a large volume of data, gives a better idea of how great those risks might be. But HRT still has an important place in care. Menopausal symptoms can significantly affect the daily life and wellbeing of some women, and HRT is highly effective at relieving these symptoms.

It writes that doctors need to assess the risks and benefits of HRT for each woman on an individual basis.There are some risk factors, like having a history of breast cancer or cardiovascular disease, that prevent its use altogether. If treatment is given, the type of HRT preparation used depends on a woman’s symptoms, preferences and other risk factors.

This study found vaginal oestrogen creams were the only form of HRT not linked to breast cancer risk. But creams can only help with symptoms like vaginal dryness. They do not help with other symptoms, like hot flushes and night sweats.

Stat News report
The Lancet abstract
Weekend Argus report (subscription needed)
NHS Briefing


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