The authors of a study showing that hormone replacement therapy (HRT) increases the risk of breast cancer have defended their findings, following criticism from a team of experts linked to pharmaceutical companies that make the treatment.

The Million Women Study, part-funded by Cancer Research UK, began recruiting women in 1996. In 2003, it found that using HRT that combines oestrogen and progesterone increases a woman's risk of developing breast cancer. Several subsequent analyses including a follow-up paper in 2011 found similar results, including a "rapid fall in risk" after HRT is stopped.

Although more than 20 further independent studies have also found an increased risk of breast cancer in women who use HRT, especially the combined form, such a link has proved controversial, with some suggesting that the findings have been exaggerated.

In the latest critique, the original research has been analysed by a team led by Professor Samuel Shapiro of the University of Cape Town Medical School, and published in the Journal of Family Planning and Reproductive Health Care.

The researchers claim that the Million Women Study does not in itself establish HRT as linked to breast cancer. But they don't rule out the possibility that HRT may indeed increase risk of the disease.

The critique's authors, from South Africa, Germany and the UK, admitted that they had all acted (or continue to act) as consultants for pharmaceutical companies that make HRT.

Prof Shapiro's team wrote: "HRT may or may not increase the risk of breast cancer, but the Million Women Study did not establish that it does."

His team examined criteria applied to scientific research to show a causal link, and identified several flaws it claims would have skewed the findings.

Researchers said that cancers detected within a few months of the study's start would have already been present when the women were enrolled in the research, but these women were not excluded from the analysis.

And they said inviting women to join the study would, in itself, have increased the number who were already aware of breast lumps or pre-cancerous changes, leading to higher numbers of cancers being detected.

This claim is borne out by a higher rate of cancers among the study participants than in the general population, irrespective of whether or not they used HRT, they said.

And they point out that crucial data was often missing, and in the third report from the Million Women Study they said follow-up data on HRT use was not available for at least 57 per cent of participants.

Prof Shapiro's group added: "The validity of any study is dependent on the quality of its design, execution, analysis and interpretation. Size alone does not guarantee that the findings are reliable."

The Million Women Study was an observational study and "if the evidence was unreliable, the only effect of its massive size would have been to confer spurious statistical authority to doubtful findings," they said, adding that the study evidence "was indeed unreliable."

Defending the findings, Cancer Research UK's Professor Dame Valerie Beral (pictured), head of the Cancer Epidemiology Unit at the University of Oxford, said the paper was a re-statement of previously refuted views from "many consultants to HRT manufacturers, as these authors are, attempting to dispute evidence" about its adverse effects.

"The authors omit to say that Million Women Study findings, of an increased risk of breast cancer in users of HRT, especially of oestrogen-progestagen combinations, have been replicated in over 20 other studies. The totality of the worldwide evidence is now overwhelming."

Professor Beral's colleague Professor Sir Richard Peto added that although the report raises valid criticisms of certain aspects of the Million Women Study, it fails to challenge its central finding: that HRT is a major cause of breast cancer, and that women can reduce their risk by stopping taking it.

Sir Richard, Professor of Medical Statistics and Epidemiology at the University of Oxford, said the results were biologically valid.

"Ordinary breast cells can be stimulated to divide by the female hormone, oestrogen. Even when one cell from the breast has gone wrong and has turned into the seed of a growing cancer, that cancer can still be dependent on the continued stimulation by the body's own oestrogen.

"Hormone-sensitive breast cancers can, however, be shrunk (and sometimes cured completely) by drugs such as tamoxifen, which block the action of oestrogen on the breast cancer cells.

"In women who have had a hormone-sensitive breast cancer apparently completely removed from their breast, invisibly small deposits of cancer cells may remain either nearby or in distant parts of the body". These, he said, could cause the cancer to return.

"In the Million Women Study participants were recruited just before they attended a breast screening clinic, at which some cancers were detected.

"But, even if attention is restricted to cancers that were detected only later, hormone-sensitive cancers are still three times as common in HRT users as in non-users or ex-users. Thus, the Million Women Study provides strong, biologically plausible evidence of causality.

Sir Richard concluded that there is clearly an increased chance of getting breast cancer among otherwise similar women and a rapid decrease after they stop.

Hazel Nunn, head of health information at Cancer Research UK, said that women shouldn't be unduly worried by the new criticisms.

"HRT can be an effective short-term treatment for menopausal symptoms - women taking it should try and use the lowest dose possible for as short a time as they need it.

"If you are considering starting or stopping HRT, or using it for a long time, you should discuss it with your doctor. The issues are different for every woman and your doctor will be able to help you weigh up the benefits and risks of different types of HRT and make the right choice based on your own circumstances.

"In the UK, HRT use has been falling since the start of the Millennium. Studies suggest that in 2005 there were 1,400 fewer cases of breast cancer in the UK among women aged 50-59 than would have been if there had been no drop in HRT use," she added.

Source: CRUK