Published: Mar 29, 2013
By Nancy Walsh , Staff Writer, MedPage Today

Full Story:  http://www.medpagetoday.com/OBGYN/HRT/38162

Action Points

• Note that this observational cohort study demonstrated an increased risk of invasive breast cancers among women taking estrogen-plus-progestin hormone replacement therapy (HRT) after menopause.
• Be aware that the overall incidence of breast cancer in users of HRT was relatively low: 0.75% per year.

The use of combined estrogen plus progestin among postmenopausal women was associated with an increased risk of breast cancer, a longer-term analysis of data from the observational Women’s Health Initiative (WHI) suggested.

With mean follow-up of 11.3 years, the annualized rate of breast cancer among hormone users was 0.60% compared with 0.42% for women not taking the hormone replacement therapy (HRT), giving a hazard ratio of 1.55 (95% CI 1.41 to 1.70,P<0.001), according to Rowan T. Chlebowski, MD, PhD, of Harbor-UCLA Medical Center in Torrance, Calif., and colleagues.

Particularly high risks were seen for women who began using the hormones at the time of menopause (HR 1.68, 95% CI 1.52 to 1.86), the researchers reported online in the Journal of the National Cancer Institute.

In addition, “because prognosis after a breast cancer diagnosis is similar for combined hormone therapy users and non-users, increased breast cancer mortality on a population basis can be expected,” Chlebowski and colleagues stated.

The Women’s Health Initiative included several randomized clinical trials and also an observational study that enrolled 93,000 women who were not eligible or were not willing to participate in the trials.

The current analysis focused on 41,449 women from the observational study who had had a negative mammogram within 2 years of entry. A total of 16,121 were users of estrogen plus progestin, while 25,328 were nonusers.

Characteristics of hormone users included younger age, lower risk scores, BMI below 25, and alcohol consumption.

This analysis adjusted for ongoing mammography, time from onset of menopause to initiation of hormone use, and use of hormones before enrollment.

During follow-up, there were 2,236 invasive breast cancers.

In a sensitivity analysis, the association between combined hormone therapy and breast cancer was stronger among women with ongoing use, with an annual rate of 0.75% compared with 0.41% in the overall population (HR 1.99, 95% CI 1.68 to 2.37, P<0.001).

The risk for breast cancer among hormone users also related to body mass index, being 1.70 (95% CI 1.48 to 1.95) in women with BMI below 25 and 1.34 (95% CI 1.11 to 1.62) for those whose BMI was 30 or higher (P=0.03 for interaction).

For each 5-year interval between onset of menopause and the beginning of-hormone use, the risk fell by a factor of 0.87 (95% CI 0.80 to 0.94, P<0.001), the researchers reported.

They also analyzed tumor characteristics, and found that overall, hormone users had tumors that were more likely to be well differentiated and hormone receptor positive, but less commonly triple negative.

But in women who initiated hormone therapy after study entry, the tumors were more likely to be poorly differentiated, hormone receptor negative, and triple negative.

Survival after the diagnosis of breast cancer was comparable in users and nonusers (HR 1.03, 95% CI 0.79 to 1.35).

Mortality risk specifically from breast cancer was increased among hormone users, though not to a statistically significant extent (HR 1.32, 95% CI 0.90 to 1.93, P=0.15). However, all-cause mortality was higher among hormone users (HR 1.65, 95% CI 1.29 to 2.12, P<0.001).

When the analysis included adjustment for adherence to mammography screening, hormone users had a nonsignificant hazard ratio for death from breast cancer of 1.31 (95% CI 0.81 to 2.11, P=0.27).

In contrast, after adjustment for mammography, women using the hormones had a “substantially greater” hazard ratio of 1.87 (95% CI 1.37 to 2.54, P<0.001) for all-cause mortality, the researchers reported.

“The current analyses now place findings in the WHI Observational Study in parallel to the WHI randomized trial, where the hazard ratio was 1.25 (95% CI 1.07 to 1.46) for the estrogen plus progestin influence on invasive breast cancer incidence,” Chlebowski and colleagues wrote.

They noted that challenges remain in how to present these findings to clinicians and their patients, assuming that there may be a “substantial breast cancer mortality risk” associated with the use of combined hormone therapy.

“From a public health perspective, there should be reasonable caution in recommending a therapy for less than limiting climacteric symptoms,” they stated.

In an editorial accompanying the study, Catherine Schairer, PhD, and Louise A. Brinton, PhD, of the National Cancer Institute in Rockville, Md., commented that “lingering questions” remain.

In particular, they noted that neither the WHI randomized trials nor this observational study considered the possible influence of duration of hormone therapy or current use at the time of diagnosis on the type or prognosis of the tumors.

They also suggested analyzing outcomes for the women excluded from this analysis because of not having had a recent negative mammogram.

“It might be informative to include these women in a future analysis to further determine the potential impact of screening on breast cancer survival and mortality associated with estrogen plus progestin use,” wrote Schairer and Brinton.

An additional limitation of the analysis was the unavailability of information on breast cancer treatments used.