Caveats and Concerns With New Study on Hormone Therapy and Breast Cancer

From Medscape Medical News

Janis C. Kelly

August 12, 2010 — The use of postmenopausal hormone therapy (HT) dropped from about 40% of eligible women to about 20% after the 2002 report from the Women's Health Initiative (WHI) clinical trial that found an elevated risk for breast cancer associated with HT, but about 30 million women per year still use HT in the United States.

New data from the California Teachers Study might renew concern about this link.

In a report published online August 10 in Cancer Epidemiology, Biomarkers & Prevention, Tanmai Saxena, an MD/PhD student at the Keck School of Medicine at the University of Southern California, in Los Angeles, and colleagues found that women who used estrogen therapy (ET) for more than 15 years had a 19% greater risk of developing breast cancer than women who had never used ET.

The authors also found that breast cancer risk was higher for women who took postmenopausal hormones for longer periods, and highest for those using combined estrogen plus progestin (EPT).

Current use of either ET or EPT was associated with higher risk than past use of the same regimen, and risk increased with the number of days per month of progestin in a current EPT regimen.

Notably, the results suggest that there is also an increased risk for tumors that are HER2-positive. The study is one of the first to include data on HER2 status.

Caveats

The researchers analyzed HT use and the subsequent development of breast cancer in 56,867 perimenopausal and postmenopausal women, 2,857 of whom (5%) were subsequently diagnosed with pathologically confirmed invasive breast cancer. Mean follow-up was 9.8 years. The analysis included type, pattern, and recency of HT use.

Breast cancer expert Rowan T. Chlebowski, MD, PhD, from the University of California, Los Angeles, told Medscape Medical News that clinicians should consider several points when interpreting data from this observational study.

First, Dr. Chlebowski, who was lead author of the WHI study of EPT (JAMA. 2003:289:3243-3253), noted that the significant increase in breast cancer risk in the California Teachers Study was associated with the use of estrogen alone for 15 years or more, but that in real-world settings, few women take any type of ET or EPT for more than a few years. "The patient who is continuing to take ET or EPT after 15 years might also be different from a typical patient in other ways," he said. Also, in the WHI randomized trial, there was a strong trend toward lower breast cancer risk with ET.

Dr. Chlebowski pointed out that the California Teachers Study investigators controlled for differences in mammography use only in the last 2 years of the 9.8-year follow-up. He said that because women taking HT are known to have more mammograms, the data might partly reflect differences between screened and unscreened populations. "We know that with screening we find more, smaller, lower-grade, and [estrogen-receptor]-positive tumors," he said.

Data on HER2 and BMI

The California Teachers Study produced some surprises, senior author Giske Ursin, MD, PhD, told Medscape Medical News.

There may be some increased risk for tumors that are HER2-positive.
Dr. Ursin, who is from Institute of Basic Medical Sciences at the University of Oslo, Norway, said that they "expected that hormone therapy would only increase the risk of the most benign breast cancer subtype (i.e. the type with estrogen and progesterone receptors, but which do not have HER2 receptors). Although overall our findings are consistent with this —the hormone users tend to get relatively small and less lethal tumors — our findings on HER2 are not conclusive and suggest that there may be some increased risk for tumors that are HER2-positive as well."

Dr. Ursin said that an increased risk for HER2-positive cancers would be "worrisome," but that further study is needed on the matter.

"We know that there are large differences in survival, depending on which molecular subtype of breast cancer women develop. We need to understand which subtype hormone users develop," she said.

Women who used EPT for 15 or more years had an 83% greater risk than those who did not use HT. Breast cancer risk was highest among women who used the combination regimen.

The data also showed that HT-associated breast cancer risk was highest for women with a body mass index (BMI) below 25 kg/m2. In contrast, obese women (i.e., a BMI of 30 kg/m2 or more) had no further increase in risk associated with EPT.

The authors suggest that this might just mean that in obese women, the additional risk associated with HT fades to insignificance against the background of circulating estrogens produced by peripheral aromatase activity in fat tissue.

Finally, the risk for breast cancer was confined to tumors that were positive for both estrogen and progestin receptors. The risk was somewhat weaker for HER2-negative tumors.

Limit Postmenopausal HT to Brief Duration

HT is "prescribed for the treatment of menopausal symptoms around the time of menopause, and we currently recommend a relatively short duration of treatment," Dr. Ursin said.

It is the estrogen component of EPT "that is useful to treat menopausal symptoms. The [progesterone] component is added because, in women with a uterus, [estrogen] treatment alone increases the risk of endometrial cancer greatly. However, while [estrogen] alone does little to the breast, EPT increases the risk of breast cancer. In general, women with a uterus should be prescribed EPT, and women without a uterus can manage with [estrogen] treatment alone," she advised.

Clinicians vary in their approaches to HT, said Dr. Ursin. "Certain gynecologists are very careful with finding the right dose for each woman, and some even prescribe [estrogen] alone for women who have a uterus, but then monitor the uterus carefully. Please keep in mind that the risk of breast cancer associated with EPT is relatively moderate. The risk of endometrial cancer with [estrogen] alone is much higher — a more than 4-fold increase in risk in this same population of California teachers," she said.

Dr. Ursin and Dr. Chlebowski have disclosed no relevant financial relationships.

Cancer Epidemiol Biomarkers Prev. Published online August 10, 2010. Abstract