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June 23, 2003 — Relatively short-term use of combined estrogen plus progestin hormone therapy (CHT) is associated with an increased risk of breast cancer, diagnosis at a more advanced stage of breast cancer, and more abnormal mammograms, according to an article in the June 25 issue of The Journal of the American Medical Association.
According to the article, on July 9, 2002, the Women's Health Initiative (WHI), a randomized, controlled trial of 16,608 postmenopausal women comparing the effects of CHT with placebo, was stopped early when the overall health risks associated with CHT, including breast cancer, exceeded the benefits. The women underwent clinical breast examinations and mammographies at the beginning of the study, and each year afterward. The overall results of the WHI study were reported in 2002.
In the current study, Rowan T. Chlebowski, M.D., Ph.D., of Harbor-UCLA Research and Education Institute, Torrance, Calif., and colleagues analyzed data collected during the WHI trial to determine the relationship between CHT, breast cancer characteristics and mammography. The researchers found that CHT increased total breast cancers (245 cases vs. 185 cases) and invasive breast cancer (199 cases vs. 150 cases) compared with placebo. Invasive breast cancers among women in the CHT group were larger and were diagnosed at a more advanced stage compared with those diagnosed in the placebo group. The researchers also found that after one year, the percentage of women with abnormal mammograms was substantially greater in the CHT group (716 [9.4 percent] of 7,656) compared with the placebo group (398 [5.4 percent] of 7,310), a pattern that continued throughout the study.
"The breast cancers diagnosed in women in the hormone therapy group had similar histology and grade (clinical characteristics) but were more likely to have advanced stage vs. women in the placebo group," the researchers write. "These results suggest that invasive breast cancers developing in women receiving estrogen plus progestin therapy may have an unfavorable prognosis."
"The absolute increase in abnormal mammograms of about 4 percent per year in women receiving estrogen plus progestin translates into approximately 120,000 otherwise avoidable abnormal mammograms annually for the estimated three million U.S. postmenopausal women currently using this hormone regimen," write the authors. "Consideration for use of estrogen plus progestin for any duration by postmenopausal women should incorporate the current findings into established and emerging risks and benefits of these agents," they conclude.
Related Article: Combined Estrogen and Progestin Therapy Linked With Increased Breast Cancer Risk Regardless of Use Patterns
An analysis of 51 studies found that current users of CHT or progestin alone for five years or longer had a 53 percent increase in risk of breast cancer. However, few studies have looked at the effects of long durations of CHT use on breast cancer risk, or the effects of continuous vs. sequential use of the progestin component.
Christopher I. Li, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center, Seattle, and colleagues investigated the effects of long term CHT use (both continuous and sequential) and estrogen therapy (ET, estrogen alone) in 975 women, 65-79 years old who were diagnosed with invasive breast cancer (between April 1, 1997 through May 31, 1999) and in 1,007 women without breast cancer.
The researchers found that women using estrogen hormone therapy for 25 years or longer had no significant increase in risk of breast cancer. Women who used CHT (and may have also used estrogen therapy at some point) had a 1.7-fold increased risk of breast cancer, including a 2.7-fold increased risk of invasive lobular carcinoma (a specific type of breast cancer), a 1.5-fold increased risk of invasive ductal carcinoma (another type of breast cancer), and two-fold increase in breast cancers sensitive to the effects of either estrogen or progestin, (known as ER-positive or PR-positive tumors).
The researchers also found that the increased risk of breast cancer was greatest in women using CHT for longer lengths of time: users for five to 14.9 years and users for 15 or more years had a 1.5-fold increased risk and a 1.6-fold increased risk for invasive ductal carcinoma, respectively, and a 3.7-fold and 2.6-fold increase in risk for invasive lobular carcinoma, respectively). Similar risk patterns were noted in women who took CHT continuously and sequentially.
They write: "Evidence is mounting regarding the adverse impact on breast cancer risk of adding progestin to HRT. This adverse impact appears to be manifest within several years of initiating use of CHRT, and to be similar in magnitude irrespective of the pattern of CHRT use (continuous or sequential)," write the authors. "At least for the forms of CHRT used most commonly by U.S. women in the latter part of the 20th century, including both sequential CHRT and continuous CHRT, an increased incidence of breast cancer must be tallied as a possible consequence."
Editorial: Combined Hormone Therapy and Breast Cancer — A Single-Edged Sword
In an accompanying editorial, Peter H. Gann. M.D., Sc.D., and Monica Morrow, M.D., of The Feinberg School of Medicine, Northwestern University, Chicago, comment on the papers by Chlebowski et al and Li et al. Gann and Morrow note, "The study (WHI trial) demonstrates that alteration of a woman's basic hormonal physiology over decades in the interest of long-term disease prevention is fraught with hazard." "The ability of combined hormone therapy to decrease mammographic sensitivity creates an almost unique situation in which an agent increases the risk of developing a disease while simultaneously delaying its detection," write the authors regarding the research by Chlebowski et al. They further suggest, "The expanded report from the WHI trial is significant because it strongly suggests that the breast cancers related to estrogen plus progestin use are not 'good' ones, that they occur earlier than expected based on some previous studies, that there are no easily identified subgroups at higher risk, and that, to top it off, women using estrogen plus progestin experience a much higher rate of mammographic abnormalities leading to anxiety and further costly workups."
According to the editorialists, "Experienced observers hesitate to label any biomedical research study as 'definitive,' especially in an area as historically controversial as the study of menopausal hormone therapy. Nevertheless, the WHI trial of estrogen plus progestin therapy is as close to definitive as can be expected," write the authors. "The effort and commitment of the investigators, funding agency, and participants were prodigious. Although the results are clear enough to discourage any future attempt at replication, further research certainly is necessary."
"In the meantime, the message for physicians caring for menopausal patients is clear. The increased risk of breast cancer and the mammographic abnormalities among women in the WHI study provide further compelling evidence against the use of combination estrogen plus progestin hormone therapy," they conclude.