Swedes break the HABITS

Two HRT trials axed after breast cancer recurrence in some subjects. Some intriguing questions left half-answered

By S H Cyr

Once again, a hormone replacement therapy (HRT) trial has been stopped early by researchers after preliminary findings suggested a link between HRT and breast cancer.

The Swedish HABITS (hormonal replacement therapy after breast cancer -- is it safe?) study was intended to follow women previously treated successfully for breast cancer. It was stopped on December 17, just two years into its planned five-year course. Preliminary findings were published in the February 7 issue of The Lancet.

However, some cancer experts in Britain have weighed in, accusing The Lancet of publishing the results too early. Dr Richard Sullivan, head of clinical programs for Cancer Research UK, says researchers often feel legally obliged to stop trials when there's evidence that the health of patients is compromised. "But these studies were set up to get important answers. At the end of the day, half an answer is no answer at all. Many women experience significant morbidity after treatment for breast cancer, and we know HRT can relieve those symptoms. Women need to be able to judge the risks and benefits of HRT accurately."

Breast cancer events
By the time the HABITS trial was stopped, 26 subjects had developed breast cancer out of 174 women assigned to HRT with at least one follow-up. Eight women in the 171-strong control group suffered a new breast cancer event. This suggested that the treatment group was 3.3 times more likely to develop breast cancer than women with a similar medical history who were not taking hormones.

The study's lead investigator, Dr Lars Holmberg, from the University Hospital in Uppsala, Sweden, said: "The trial was terminated because women with a history of breast cancer allocated to receive HRT for menopausal symptoms experienced an unacceptably high risk of breast cancer compared with breast cancer survivors allocated to best symptomatic treatment without hormones." Women on active treatment have been advised to discontinue.

Strong evidence of a link between HRT and breast cancer first emerged in 2002, when the Women's Health Initiative (WHI) study, an American investigation involving 16,000 women, was stopped three years early after running for five years. Preliminary results from the WHI study suggested that taking a combined estrogen and progestin pill increased the risk of breast cancer by 26%, heart attack by 29% and stroke by 41%.

Since there is no clear indication as to what happens when progestin is not part of the HRT, the estrogen-only arm of the WHI trial will continue until 2005. Currently, experts anticipate that prolonged use of estrogen-only therapy will bring no more than a slight increase in breast cancer risk.

The controversy rages on
The results of the WHI trial led governments around the world to re-examine their advice on HRT. Health Canada has since taken the position that HRT is not approved for women who have an existing cardiovascular disorder as its protective properties have been disproved. The combined pill is not recommended for long-term use in postmenopausal women under normal circumstances.

The HABITS trial was supposed to run in tandem with another Swedish trial, known as the Stockholm study, which was also examining HRT and the risk of recurrent breast cancer. Both groups had agreed they would stop if at any stage the relative hazard to their combined treatment groups were found to pass a predefined limit of 1.36 times greater than the control groups. That has now happened.

There are questions raised, however, by wide disparities in the findings of the two trials. Relative risk of a breast cancer event in the Stockholm HRT treatment group was actually lower than average (0.82) when the trial was stopped.

The HABITS study suggested a protective effect of tamoxifen, but not enough of the participants were taking the drug to allow meaningful analysis. It's unknown how many of the Stockholm subjects were taking tamoxifen and the results of that study are now unlikely to be published.