The increased risk of breast cancer seen with combination hormone replacement therapy (HRT) persists at about the same level for nearly three years after women come off treatment, indicates a follow-up to the original US trial whose outcomes dealt a severe blow to sales of HRT products.

In the follow-up to the pivotal trial of combined oestrogen and progestin conducted as part of the Women’s Health Initiative (WHI), women tracked for an average of 2.4 years after discontinuing combination HRT had a 27% higher risk of developing invasive breast cancer than those in the original placebo group.

In 2002, the WHI study was stopped early due to a 26% increase in the risk of breast cancer in women who had taken combination HRT for an average of 5.6 years, as well as evidence that overall health risks (including coronary heart disease, stroke and pulmonary embolism) outweighed any benefits of therapy.

The latest results were published in the 5 March issue of the Journal of the American Medical Association,/i> (JAMA). The researchers followed up 15,730 of the 16,608 postmenopausal women with an intact uterus who had participated in the WHI trial. Age at enrollment ranged from 50 to 79 years, with an average age of 63 years. The follow-up study began in July 2002, after the WHI trial participants were instructed to stop taking combination HRT, and continued through to March 2005.

During the follow-up period, 79 of the women who had taken oestrogen plus progestin, or 0.42% of the total, were diagnosed with breast cancer compared with 60 (0.33%) of the women from the placebo group. Moreover, the risk of developing any kind of cancer was 24% higher, with 281 women (1.56% of the total) in the post-treatment group diagnosed with malignancies versus 218 (1.26%) of the women on placebo.

On the other hand, there were no significant differences in the number of heart attacks, strokes and blood clots seen during follow-up in the HRT and placebo groups. A total of 343 cardiovascular events (an annualised rate of 1.97%) were recorded in the post-treatment group compared with 323 (1.91%) in the placebo group. All-cause mortality was elevated in patients who had taken HRT – 233 (1.20%) of whom died during follow-up versus 196 women (1.06%) on placebo – but this was not regarded as statistically significant.

Other observed effects of combination HRT, such as decreased risks of colorectal cancer and hip fractures, were essentially eliminated when therapy ceased. Largely due to the increased incidence of cancer during follow-up, the global risk index – which measured a variety of outcomes, including death – was 12% higher in those women who had been randomly assigned oestrogen plus progestin.

Only if needed
“We continue to encourage women to use hormones only if needed for menopausal symptoms, and for the shortest time possible, and to adopt and maintain a healthy lifestyle, that is, engage in regular physical activity, maintain a healthy body weight, consume a diet low in saturated fat, and to not smoke, to reduce their risks of cardiovascular and other chronic diseases,” said Dr Marcia Stefanick, professor of medicine at Stanford University in California, co-author of the JAMA paper and chair of the WHI Steering Committee.

But she acknowledged that “we can’t really define what ‘short’ means” in this context, adding: “Clearly, taking oestrogen and progestin for 5.6 years is too long because the risk of breast cancer continued to be elevated after the women stopped taking the hormones and remained significant, compared to placebo, after stopping the hormones for 2.4 years.”

Dr Michael Lauer, director of the NHLBI Division of Prevention and Population Sciences – the US National Heart, Lung, and Blood Institute (NHLBI) sponsors the WHI along with the National Institutes of Health – commented: “While it is reassuring that the heart attack risk decreased and that the risks for strokes and blood clots did not grow after the women stopped taking hormones, this study provides further evidence that five years of combination hormone therapy is harmful. All the accumulated risks do not simply disappear.”

While media coverage of the WHI follow-up study largely focused on the cancer findings – with the Daily Telegraph declaring, startlingly, that “Stopping HRT ‘increases cancer risk’” – some observers downplayed their significance, particularly in relation to the relatively advanced age of the participants. As the study outcomes were not broken down by age, there was no way of determining whether or to what extent the higher cancer risk was age-related.

Another uncertainty was whether the persistently higher risk of breast cancer derived from new malignancies or cancers that had not been detected during the original WHI trial. A recent analysis of the trial in the Archives of Internal Medicine found that the women on combination HRT were more susceptible to abnormal mammograms and these were less sensitive to breast cancer.

Take-home message
Writing on the WHI follow-up in Journal Watch Women’s Health, deputy editor Dr Andrew Kaunitz commented: “In contrast to findings at the time study medication was discontinued, no increased risk for thrombosis, CHD [coronary heart disease] or stroke was observed during the subsequent three years in women who had received HT [hormone therapy]; furthermore, neither a statistically significant increased risk for invasive breast cancer nor reduced risk for fractures or colorectal malignancies was seen.”

The observation that “increased risks for adverse cardiovascular outcomes or invasive breast cancer and prevention of fractures and colorectal cancer all did not persist after women discontinued HT represents a notable take-home message from this follow-up analysis of WHI participants”, he contended.

Noting that recent WHI reports have suggested HRT, particularly oestrogen-only therapy, “might be associated with a lower risk for CHD in recently menopausal women and menopausal women in their 50s”, Kaunitz said that “we await with interest the age-specific follow-up analyses of both the oestrogen-plus-progestin and the oestrogen-alone WHI clinical trials focusing on cardiovascular outcomes. At the same time, the overall increase in risk for malignancies calls for continued surveillance after oestrogen-plus-progestin HT is stopped”.

Wyeth, which markets the hormone replacement therapies Prempro and Premarin, argued that the new data from the WHI trial “provide little new insight into the appropriate use of hormone therapy when it is prescribed to symptomatic, newly menopausal women”.

Both women and healthcare professionals “should be cautious about drawing generalised conclusions with regard to the benefits and risks of hormone therapy based upon an observational follow-up of the WHI”, the company stated.

The women who participated in the WHI study “were predominantly non-symptomatic and were on average 63 years of age, which is more than a decade past the average onset of menopause”, it pointed out. “In recent years, re-analysis of WHI findings has repeatedly shown that the risks associated with hormone therapy use in this older study population were not consistently shared across all outcomes by the younger subset of women who are more representative of a newly menopausal, hormone therapy user.”

“Selectively releasing information contained in the WHI database, without providing the full context of the data assessed, is not in the best interest of menopausal women and their healthcare professionals and may needlessly cause confusion,” commented Dr Gary Stiles, executive vice president and chief medical officer, Wyeth Pharmaceuticals.

Clinical guidance as outlined in product labelling and patient information for HRT recommends using the lowest effective dose for the shortest duration of time, Wyeth noted.