While women with breast cancer who have used hormone-replacement therapy are known to have better survival odds than those who have never taken hormones, the advantage is likely due to more-frequent mammography screening rather than the effect of the hormones on tumor biology, according to researchers in the Public Health Sciences Division.
"Most of the good prognostic factors that have been ascribed to HRT-such as smaller tumor size and earlier cancer stage at diagnosis-may simply be an artifact of screening," said Dr. Janet Daling, lead author of the study, which appears in the November issue of Cancer Epidemiology, Biomarkers and Prevention.
"In many cases the HRT itself is probably doing nothing other than getting women to the doctor once a year for a prescription renewal and a mammogram."
Daling, PHS colleagues Dr. Kathi Malone, David Doody and Dr. Lynda Voigt, and co-authors from five study sites nationwide reported that 90 percent of women who used combination estrogen/progestin HRT had undergone a screening mammogram within two years of breast-cancer diagnosis. In contrast, only 65 percent of women with breast cancer who had never used HRT had undergone a mammogram during that time period.
The difference in tumor size between the two groups was significant. Sixty-seven percent of the women screened within two years of diagnosis had tumors smaller than 2 centimeters (about the size of a pea), whereas only about 34 percent of the unscreened women had tumors that small.
"I was floored when I saw this data," Daling said, "because tumor size is one of the most important prognostic factors in breast cancer. The difference in the size of the tumors between the two groups was staggering. If that isn't a good advertisement for mammography screening, then I don't know what is."
Women's CARE study
The findings were based on data from the Women's CARE (Contraceptive and Reproductive Experience) Study, the first project of its kind to collect detailed information about mammography screening in an attempt to assess markers of breast-cancer prognosis in relation to HRT use, said Daling, the study's principal investigator.
"Previous studies have shown a link between HRT and improved breast-cancer prognosis, but this is the first to account for screening history as verified by medical records, not just based on the women's recall," she said.
The federally funded, multicenter study, which was designed to assess hormonal influences on breast-cancer risk, was based on the analysis of tumors and medical records, as well as in-person interviews, with 2,346 women in Atlanta, Detroit, Los Angeles, Philadelphia and Seattle who were diagnosed with breast cancer between the ages of 50 and 64. About 1,400 of the women had used some form of HRT for six months or more, while the rest had no history of hormone use.
In addition to tumor size, the researchers evaluated the effects of HRT on other markers of prognosis such as tumor stage (how far the cancer has spread), the hormonal sensitivity of the breast tumors (estrogen- and progesterone-receptor status) and tumor histology, or cellular type (ductal versus lobular carcinoma).
"Our goal was to determine whether hormone therapy directly influenced the development of such tumor characteristics at the biological level or whether they were the result of confounding factors such as cancer screening, age and race," said Daling, also a professor of epidemiology at the University of Washington School of Public Health and Community Medicine.
After adjusting for screening history and other factors that can influence breast-cancer outcome, the researchers found several compelling links between HRT use and improved prognosis that did suggest a true impact on tumor biology.
Among women with a history of continuous-combined HRT, who received estrogen and progestin daily, 73 percent developed estrogen-receptor-positive (ER+) and progesterone-receptor-positive (PR+) breast cancer as compared to 54 percent of women who'd never used HRT. Such hormonally sensitive tumors respond well to estrogen-blocking drugs such as tamoxifen.
About 20 percent of the women on continuous-combined HRT also developed lobular breast cancer, which tends to be hormonally sensitive, as compared to 12 percent of women who had never used hormones. Such cancer involves the lobules, or chambers in the breast that contain milk-producing glands. While lobular carcinoma accounts for only 10 percent to 15 percent of all breast-cancer cases, it is more treatable than the more common ductal variety, which arises in the ducts that carry milk from the lobules to the nipple. Daling and colleagues earlier this year reported that the incidence of lobular cancer has risen 65 percent during the past decade, a trend that may be due to the increased use of combined HRT.
After adjusting for screening history, the researchers also found a statistically significant link between the use of unopposed estrogen (estrogen-only therapy) and reduced diagnosis of more-advanced disease. Women taking estrogen only had 70 percent less-frequent diagnosis of advanced breast cancer than did women who never used hormone therapy.
The National Institute of Child Health and Human Development and the National Cancer Institute funded the study. A national cancer registry operated by the National Cancer Institute, Surveillance, Epidemiology and End Results (SEER) program identified women for the study. The Centers for Disease Control and Prevention served as the study's data-coordinating center. Study sites were located at the CDC (Atlanta), Wayne State University (Detroit), University of Southern California (Los Angeles), University of Pennsylvania (Philadelphia) and Fred Hutchinson.