http://bmj.com/cgi/content/full/327/7405/9

BMJ  2003;327:9 (5 July)
 

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Collections under which this article appears: Menopause (incl HRT)

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Long term use of combined HRT doubles cancer risk

David Spurgeon

Quebec

Women over the age of 65 who take combined oestrogen and progestogen hormone replacement therapy (HRT) for five to 15 years or more face a 100% increase in the risk of developing breast cancer, regardless of their pattern of progestogen use, says a new study ( JAMA 2003;289: 3254-63[Abstract/Free Full Text]).

Although it had been shown previously—with the early closing of an arm of the Women's Health Initiative study—that women taking the combined therapy have an increased risk of breast cancer ( BMJ 2002;325: 61[Free Full Text]), data on the long term use of the therapy and on the risks associated with patterns of use have been lacking.

The new study was undertaken to fill that gap. It involved 975 women aged 65 to 79 who had been given a diagnosis of invasive breast cancer between 1 April 1997 and 31 May 1999 in three counties in western Washington state.

Dr Christopher Li, the lead author and an assistant member of the public health sciences division of the Fred Hutchinson Cancer Research Center, Seattle, said, "We found that long term use of combined oestrogen and progestin hormone replacement therapy not only doubles cancer risk but that the magnitude of this risk increases with duration of use.

"Few studies have assessed whether sequential progestin use is related to breast cancer risk, although some studies have suggested that continuous use of progestin is more strongly associated with breast cancer risk than sequential use. In this study we found that both regimens were associated with similar increases in breast cancer risk. There does not seem to be any advantage to sequential progestin use compared to continuous progestin use with respect to reducing this risk."

The researchers assessed the effect of combined hormone replacement therapy on the risk of specific types of breast cancer. Among their findings was that the risk of invasive lobular breast cancer increased by 170%. This is the second most common histological type of breast cancer, affecting the lobes in the breast that contain milk producing glands. Lobular cancer accounts for 10% to 15% of cancer cases, and its incidence has increased by 65% in the United States during the last 12 years, which Dr Li says may be partly accounted for by greater use of combined hormone replacement therapy. The risk of ductal breast cancer increased by 50%. This type, involving the ducts that carry milk from the lobules to the nipple, accounts for about 80% of all cases of breast cancer. Women who took the combined therapy had twice the risk of hormone receptor positive breast cancer, which requires oestrogen or progesterone to grow. About two thirds of all breast cancers are either oestrogen receptor positive or progesterone receptor positive.

Dr Li said that the study's finding that combined hormone replacement therapy increased only the risk of hormonally positive tumours shows the importance of progesterone in the development of breast cancer.

"It appears that hormone replacement therapy must contain progesterone to promote breast cancer growth and that it may act through stimulation of both oestrogen and progesterone receptors, not just one or the other," he said.

A potential clinical implication is the need for development of chemotherapeutic agents that target progesterone receptors—similar to the way that tamoxifen is used to treat oestrogen receptor positive tumours by blocking the oestrogen pathway.

© 2003 BMJ Publishing Group Ltd