Combined HRT breast cancer risk ‘may have been underestimated’

“Women who take a common form of HRT are nearly three times as likely to get breast cancer, a major study has found,” the Daily Mail reports.

Hormone replacement therapy (HRT) is a treatment used to relieve symptoms of the menopause, such as hot flushes. It replaces hormones that typically drop to a lower level during the menopause.

A landmark study in 2001 first linked HRT to an increased risk of breast cancer. But exactly how much of an increase has since been a matter of debate.

Some critics argue the risk was overstated, leading to a “‘wasted decade’ of suffering since the HRT scare”, as we discussed in 2012.

This study aimed to better quantify the size of the risk with the different HRT types by looking at questionnaire data from around 40,000 women in the UK.

Researchers found women taking combined HRT – both oestrogen and progestogen – had just over twice the risk of developing breast cancer compared with women who have never taken HRT.

Women who took the pill for 15 years or more had three times the risk – though this was only seven women in total, meaning the link may have been subject to chance.

Reassuringly, the risk returned to baseline around a year or two after a woman had stopped taking HRT.

Baroness Delyth Morgan, Chief Executive at Breast Cancer Now, advised: “Some women will feel HRT to be a necessity. But in order to minimise the risk of breast cancer … it is recommended that the lowest effective dose is used for the shortest possible time.”

Where did the story come from?

The study was carried out by researchers from the Institute of Cancer Research and the National Cancer Registration Service, Public Health England, both in the UK.

It was funded by Breast Cancer Now, the Institute of Cancer Research and the Royal Marsden/ICR NIHR Biomedical Research Centre.

The study was published in the peer-reviewed scientific journal British Journal of Cancer. It is available on an open access basis and is free to read online.

The authors declared no conflict of interest.

The UK media’s reporting was accurate, acknowledging that it is only the combined oestrogen and progesterone pill that has demonstrated these findings.

The Mail should be given credit for being one of the few sources that made an attempt to put the estimated rise in risk in context.

Headlines stating that the combined HRT “triples the risk of breast cancer”, as The Times put it, don’t actually provide much useful information unless you know what the initial risk is.

The Mail helpfully summarised the results, saying: “According to the new estimates, 34 women in 1,000 would get breast cancer on combined HRT, an extra 20 than among the group who does not take the drugs.”

What kind of research was this?

This was a prospective cohort study of 39,183 women taking part in the Breakthrough Generations Study, which has ascertained hormone replacement therapy use and menopausal status.

The link between HRT and breast cancer is already recognised. It has also already been observed that most cases have tended to occur in women taking combined HRT.

Women who still have a womb usually need to take oestrogen combined with a progestogen, as oestrogen alone may increase the risk of womb cancer.

Prospective cohort studies, particularly of this size and length, can be useful ways to demonstrate the link between drug use and risk on health outcomes.

However, observational studies cannot prove that one factor – in this case, the combined HRT pill – directly causes another – breast cancer – because other factors may be involved.

For example, obesity, family history and alcohol consumption are all known to be linked to breast cancer risk.

What did the research involve?

Researchers used data from a large questionnaire-based study that took place between 2003 and 2015. Assessments were made at recruitment, after 2.5 years and again at six years.

Breast and other cancers were identified from recruitment and follow-up questionnaires, and spontaneous reports to the centre. Diagnoses were confirmed by looking at cancer registries in the UK and accessing the women’s medical records.

Women were only included if they had no previous history of breast cancer. The researchers also excluded women who had had a hysterectomy.

Information on HRT use was obtained at recruitment and in follow-up questionnaires. Women were asked the ages they started and stopped use and the name of the drug.

Analysis of HRT use was from when women had been taking the pill for at least a year and continued for a year after they stopped taking it, as this was considered the time women were exposed to the drug.

The researchers took into account a range of confounding variables that may be associated with breast cancer risk.

These included:

  • family history of breast cancer in first-degree relatives
  • socioeconomic status
  • age at first pregnancy
  • number of children
  • alcohol consumption
  • duration of breastfeeding
  • pre- and post-menopausal body mass index (BMI)

What were the basic results?

Over the course of the six-year follow-up, 775 (2%) of the total 39,183 women in the study developed breast cancer.

Among current users of HRT, there were reported to be 52 cases among women taking combined HRT, 23 in women taking oestrogen only, and 15 among women taking other or unknown HRT.

This calculated to a more than doubled increased risk of breast cancer in women taking combined HRT for 5.4 years on average, compared with those with no previous HRT use (hazard ratio [HR] 2.74, 95% confidence interval [CI] 2.05 to 3.65).

For more than 15 years of combined HRT, the hazard ratio increased to 3.27 (95% CI 1.53 to 6.99) compared with no HRT use.

There was no increased risk for oestrogen-only HRT (HR 1.00, 95% CI 0.66 to 1.54). However, there was an increased risk for any type of HRT not specified by type (HR 1.95, 95% CI 1.55 to 2.46).

How did the researchers interpret the results?

The authors concluded that, “Our results show that risk of breast cancer increases with duration of use of combined MHT up to ≥15 years, and relative risks in most of the published literature are likely to be substantially underestimated.

“These results provide further information to allow women to make informed decisions about the potential risks and benefits.”


This study shows a link between the use of combined oestrogen and progesterone HRT and breast cancer risk, particularly among women who take the pill for a long period of time. But this is not the entire story.

The study included a large cohort of women. The risk increase for combined HRT is based on only 52 of the 39,183 women taking the combined pill who developed breast cancer.

Of these, only seven women had been taking the pill for more than 15 years. Therefore, the analysis was based on a very small number, which may mean the risk associations are not completely accurate.

Assessments were based on self-report questionnaires, so there is a possibility of recall bias. For example, some information about use of HRT pills was collected from women after their breast cancer diagnosis. As the combined HRT pill has been linked to breast cancer, women may have recalled their use differently from those who didn’t develop cancer.

Although the researchers took into account a wide range of factors, it’s possible that some unaccounted factors influenced the link. One of these factors the authors note is BMI, which should be taken into consideration, particularly when comparing results between studies.

These findings will be of concern to women taking combination HRT. But there are a few extra points to put this into perspective.

The baseline risk of developing breast cancer with combined HRT is still quite small. This research found no link with the oestrogen-only pill.

But we still can’t conclude with complete certainty that it’s only the combined pill that carries a breast cancer risk – particularly when the analyses combining all types of HRT found an increased risk. For now, it has to be considered that any type of HRT could carry a small increased risk of breast cancer.

HRT can also increase the risk of developing other types of cancer. Oestrogen-only HRT can increase the risk of womb cancer and is normally only used in women who’ve had a hysterectomy – women who were excluded from this study.

This means we cannot conclude that all women taking combined HRT should switch to oestrogen-only – they could be increasing their risk of another type of cancer.

Other potential risks of HRT include ovarian cancer and blood clots. Whether or not the benefits outweigh the risks therefore has to be considered on an individual basis.

The authors call for women to be provided with more information to make informed decisions about the potential risks and benefits of HRT overall, and by the specific type: combined or oestrogen-only.

There is no one-size-fits-all recommendation when it comes to whether a woman should take HRT. Your GP should be able to provide more detailed information about your own individual circumstances.