Hormone Therapy Compromises Mammograms and Breast Biopsies

Roxanne Nelson

February 28, 2008

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February 28, 2008 — Combination hormone therapy might compromise the diagnostic performance of mammograms and breast biopsies, according to a report published in the February 25 issue of the Archives of Internal Medicine. Even after hormone therapy was discontinued, the higher frequency of mammograms with abnormalities continued for at least 12 months.

"Clinicians should be aware that breast cancer diagnosis is hindered by combined hormone therapy, and the problem persists for at least a year after stopping its use," said lead author Rowan T. Chlebowski, MD, PhD, an investigator at the Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, in Torrance, California. "The risk of an abnormal mammogram was significant up to 12 months, but problems still didn't completely clear until 2 years after hormone therapy was halted."

The Women's Health Initiative (WHI) previously reported that the combination of conjugated equine estrogens and medroxyprogesterone acetate was associated with an increased risk for invasive breast cancers in menopausal women. Results from this large randomized trial also show that combined hormonal therapy significantly increases the number of abnormal mammograms and breast cancers that are larger and diagnosed at a more advanced stage.

"We have already found that combined hormone therapy increases the incidence of breast cancer, and that these cancers are likely to be in a more advanced stage," Dr. Chlebowski said in an interview. "We started to think about mammograms, and if diagnosis was going to be hindered by hormone therapy. We had an idea that it might be a problem."

Observational studies that evaluated the effect of combined hormone therapy on breast cancer detection have yielded mixed results. In the current study, Dr. Chlebowski and colleagues examined the impact of combination hormone therapy on breast cancer detection in a cohort of 16,608 postmenopausal women who participated in the WHI clinical trial between 1993 and 1998.

The participants were randomized to either a treatment group (a combination of equine estrogens at 0.625 mg a day and medroxyprogesterone acetate at 2.5 mg a day) or a placebo group. The women received a mammogram and breast examination at baseline and then annually over the course of the study period. Biopsies were performed on the basis of clinical findings. The researchers evaluated the effects of combined hormone therapy for 5.6 years, using receiver operating characteristic analyses to evaluate mammography results.

They found that there was a significantly higher frequency of mammograms with abnormalities among women in the combination hormone-therapy group than among those in the placebo group (35.0% vs 23.0%; P < .001). Women using hormone therapy also had an approximately 4% greater risk of having an abnormal mammogram after 1 year; that number rose to approximately 11% after 5 years.

Although the specificity and the negative predictive value of mammograms were only slightly lower among women using hormones, the sensitivity and the positive predictive values were compromised by their use.

The number of breast cancers were significantly higher and they were diagnosed at more advanced stages in the hormone group, but biopsies that were performed in these women less frequently diagnosed breast cancer. A total of 1220 biopsies were performed in women using combined hormone therapy, and 180 (14.8%) yielded a diagnosis of breast cancer. In the placebo group, 672 biopsies were performed and breast cancer was diagnosed in 132 (19.6%).

"The women using hormones had more cancers, but they were missed more often than in the placebo group," Dr. Chlebowski told Medscape Oncology."This is a therapy that not only increases the risk of cancer, but makes it harder to find it."

Hormone therapy also increases breast density, although the biologic significance of these changes or their effect on mammographic interpretation has not been established. Some observational studies have suggested that a higher breast density is associated with delays in diagnosis. Breast density is not the only significant factor, Dr. Chlebowski explained; rather, it is just part of the puzzle.

Among women 50 to 59 years of age, the increase in mammogram abnormalities among those using hormones was the same as for the overall group. Compared with the placebo group, their time to first biopsy was significantly shorter, and the percentage undergoing a biopsy after 5 years was significantly higher. They also had a 3% higher risk for mammogram abnormalities after 1 year, and a 9% greater risk after 5 years.

"Women considering combined hormone therapy should be aware that they will have about a 1 in 10 and 1 in 25 chance of having an otherwise avoidable mammogram or breast biopsy, respectively," said Dr. Chlebowski.

Although other imaging techniques are available (such as magnetic resonance, ultrasound, and digital mammography, which is more accurate than regular mammography in women with dense breast tissue), it is unclear whether they are more effective than mammography in women using combination hormone therapy.

Dr. Chlebowski is a consultant for AstraZeneca, Novartis, Organon, and Eli Lilly & Co., and has received grant support from Eli Lilly & Co. Coauthor Robert D. Langer, MD, MPH, is an expert witness for Wyeth Pharmaceuticals. The WHI program is funded by the National Heart, Lung, and Blood Institute, US Department of Health and Human Services.

Arch Intern Med.
2008; 168:370-377. Abstract


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