This week the Journal of the American Medical Association (JAMA) published results of a large study with significant implications for women who consider taking hormone replacement therapy (HRT). The new findings are based on careful examination over 16,000 individuals, part of the larger Women’s Health Initiative, who were randomly assigned to take either a placebo, or Prempro – a combination pill that includes estrogen, extracted from equine (horse) urine, and medroxyprogesterone acetate, a synthetic progesterone compound.

The extended data confirm that women who take hormone replacement therapy are more likely to develop breast cancer than those who don’t take it. But this finding has been seen previously, and was one of the reasons why the randomization was halted earlier on –

What’s new is that the breast cancers in women who took hormone replacement therapy are more invasive, with greater extension to the lymph nodes, and more deadly. Women ages of 50 to 79 years who take hormones are roughly twice as likely to die from breast cancer as those who don’t take hormones, and are more likely to die earlier, of any cause.*

In 2002, JAMA published a landmark report on an earlier analysis of the same trial, which was halted because of the evident toxicity, then, of hormone replacement therapy. Before that time, the treatment was thought – on theoretical grounds – to reduce the risk of heart disease.

The drugs were marketed heavily throughout the 1990s, particularly through gynecologists and primary care physicians, and later to women directly – an “ask your doctor” kind of thing. In tangible ways, these drugs tend to make women feel younger and suppler, with fewer hot flashes. Many women I knew were eager to try these hormone supplements.

My perspective is that of an oncologist. Knowing that most breast cancer cells have receptors on their surfaces for estrogen and progesterone – steroid hormones that stimulate growth of normal mammary (breast) tissue cells in healthy women – the findings seem entirely plausible. . Besides that the hormones can bind receptors on cancer cells’ surfaces and trigger growth pathways, there may be other effects. The authors of the new JAMA article suggest, for example, that the hormones can enhance the blood vessels that “feed” breast tumors, and so might make them worse.

Denise Grady provides a thorough report in the Times on this topic. As she points out, approximately 3 million women in the U.S. still take hormone replacement therapy. Before the 2002 report, as many as 6 million postmenopausal American women were prescribed this kind of medication. The incidence of breast cancer in North America has declined since 2002, and most oncologists and epidemiologists ascribe much of that improvement to reduced use hormone replacement therapy.

Still, many doctors still prescribe hormone replacement therapy. There’s a huge potential market for these drugs, and so a lot of money’s at stake, besides women’s health. Based on U.S. census data from 2000, the number of women between the ages of 50 and 79 approached 40 million and, today, is likely larger still.

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*The absolute numbers run like this:

Among the 8506 women randomized to take hormone replacement therapy (HRT), there were 385 BC cases detected; among the 8102 assigned to placebo, there were 293 cases identified. (This was a statistically significant difference.) These numbers can be whittled down, then, to a total of 678 BC cases – out of 16,000 women on the trial – who developed BC. The pathology was similar between the two groups, in terms of molecular subtypes. But the invasiveness – in terms of lymph node involvement – was higher in the HRT group, as was the mortality: 25 women died from BC in the HRT group; 12 women died from BC in the placebo group. (This was also significant, but with a p value of just 0.049).

One caveat, or limitation, to the study is that the authors didn’t have access to detailed information on the women’s treatments, which may or may not have differed between the groups. A strength of the study is the relatively long follow-up, of 11 years on average.

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