Breast cancer decline linked to HT cessation (New WHI data affirm hormonal link)

Two new statistical analyses of Women’s Health Initiative data persuasively indicate that the recent abrupt decline in breast cancer incidence in the United States is attributable to a dramatic drop in the use of estrogen-plus-progestin menopausal hormone therapy, and not  as skeptics have argued  to less utilization of mammography.

Academic fencing over causality aside, the practical take-home message from the latest Women’s Health Initiative (WHI) data analyses is that the breast cancer risk imparted by hormone therapy rises sooner and more steeply than previously recognized, and it swiftly declines after HT is discontinued, said at the San Antonio Breast Cancer Symposium.

“The good news for women here is that the risk rapidly dissipated in just a year or year and a half,” a medical oncologist at the Los Angeles Biomedical Research Institute in Torrance, California said.

The WHI was a very large National Institutes of Health-sponsored study on the prevention of cardiovascular disease and other chronic diseases. The HT clinical trial portion was halted prematurely in July 2002 upon detection of an increased breast cancer rate in its treatment arm.

In response to this announcement, the annual number of prescription for menopausal HT in the United States plunged from 60 million in 2001 to 25 million in 2003. This development was temporarily related to sudden 8.6 percent decrease in the national annual age-adjusted incidence of breast cancer (20,000 fewer cases per year) beginning in 2003. The reduction has mostly affected the 50- to 69-year-old age group, and mostly has involved fewer estrogen receptor-positive tumors.

Critics argued that this decline in breast cancer might be an artifact resulting from women getting fewer mammographies after they stopped talking HT. But in San Antonio, two new analyses were presented — involving a total of nearly 57,000 WHI participants — that ruled out a change in mammography utilization as a significant causal factor.

One analysis involved 15,387 participants in the WHI randomized clinical trial who were assigned to 0.625 mg/day of conjugated equine estrogens plus 2.5 mg/day of medroxyprogesterone acetate, or to placebo. The breast cancer risk was 26 percent greater in the HT group and 0.36 percent in the control group.

Tellingly, there was no virtually no difference in the proportion of patients in the two study arms who had a mammogram in the year before the study was halted, nor in the beginning two years before, within one year after, or two years after.

The second analysis involved 25,328 women who were not using menopausal HT at entry into the nonrandomized WHI observational study and 16,121 others who were taking estrogen plus progestin at entry.

During 2001, the HT users had a highly significant 79 percent increased risk of being diagnosed with breast cancer, compared with HT nonusers, after adjustment for age, BMI, ethnicity, family history of breast cancer, and other potential confounders. During 2002, the HT users had a 65 percent increased risk.

However, during 2003 — after all WHI participants had been instructed to stop taking HT — women who were HT users at entry into the study had a nonsignificant 18 percent increased breast cancer risk, compared with HT nonusers at entry. In 2004, those who had been on HT at entry had a 20 percent increased incidence of breast cancer, again statistically nonsignificant.

In each arm of the observational study, the percentage of patients who had a mammogram remained unchanged every year during 2001-2004.

Among nearly 2,000 WHI observational study participants who were diagnosed with invasive breast cancer, the five-year mortality was roughly four percent regardless of whether they had been taking estrogen plus progestin or were HT nonusers. This finding stands in marked contrast to a report from the California Teachers Study (also presented during the San Antonio conference), which concluded that breast cancer patients who had been on HT had a significantly better prognosis than did HT never-users.

“One part of the story is that the risk is greater than we thought with longer-duration therapy. We can see the incidence curve going up starting in year two of the observational study . . . So there’s now a strong incentive for women to take HT for shorter intervals.”

Dr. Susan Love commented that she found the latest findings persuasive.

“When women stopped taking HT and the incidence of breast cancer went down the next year, everybody said: ‘Let’s see if it lasts. We won’t believe it unless it lasts.’ Today, the WHI people presented the data showing that the incidence is still down; it hasn’t gone back up. ‘They’re just not getting mammograms,’ but today they presented data showing the women are getting mammograms. So all the excuses are gone, and indeed it’s undoubtedly the HT,” the University of California, Los Angeles said.