With median of 11 years of follow-up now in hand, investigators from the landmark Women Health Initiative (WHI) confirm that estrogen-plus-progestin hormone therapy is associated with greater breast cancer incidence than placebo. In short, they now say that the effect is long-term.
The new follow-up data are published in the October 20 issue of the Journal of the American Medical Association.
The data also provide other insights ” that the cancers of combined hormone therapy users are more commonly node-positive than those of placebo users, and that breast cancer mortality seems to be increased with hormone therapy.
These data and others “dictate caution in the current approach to the use of hormone therapy,” according to an editorial by Peter Bach, MD, which accompanies the study. Dr. Bach is from the Memorial Sloan-Kettering Cancer Center in New York City.
Dr. Bach says that this current approach, which employs hormone therapy for “brief periods” to relieve menopausal symptoms, has not had its safety proven in “rigorous clinical trials.”
Clinicians cannot present patients with a risk/benefit analysis of short-term hormone therapy because no such data exist, he points out; the current WHI provides no information on short-term use.
Caution is especially advised for clinicians, says Dr. Bach, “because one of the lessons from the WHI is that physicians are ill-equipped to anticipate the effect of hormone therapy on long-term health.”
However, the WHI authors seem concerned about longer-term use of combined hormone therapy ” not short-term use.
They write that the “use of combined hormone therapy ” other than short-term therapy in women with climacteric symptoms not ameliorated by other therapies ” seems unwarranted.”
Pfizer, which bought Wyeth in 2009 and with it Prempro combination hormone therapy, issued a statement as the media embargo on the WHI data was lifted. “We stand behind the current, science-based guidance in Prempro’s label, which advises doctors to prescribe the medicine at the “lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman”,” the company stated.
In the WHI, 16,608 postmenopausal American women, 50 to 79 years of age, who had not undergone hysterectomy were randomly assigned to receive either combined conjugated equine estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day, or placebo.
After the original trial completion date, reconsent was required for continued follow-up for breast cancer incidence, and was obtained from 12,788 (83%) of the surviving participants, report the authors, led by Rowan T. Chlebowski, MD, PhD, from the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, California.
The WHI authors performed intention-to-treat analyses and found that combined estrogen-plus-progestin hormone therapy increased the incidence of invasive breast cancer, compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]).
They also found that significantly more women in the combined hormone therapy group had breast cancers with positive lymph nodes than in the placebo group (81 [23.7%] vs 43 [16.2%]).
The authors point out that this finding conflicts with observational studies. With some exceptions, observational studies “have associated combined hormone therapy use with an increase in breast cancers that have favorable characteristics” and are at a lower stage than breast cancers in women not receiving the therapy, write the study authors.
Observational studies have also found that women with breast cancer receiving combined hormone therapy survived longer than those not receiving therapy. This was not the case with the WHI’s latest data, report the authors.
In the WHI data, there were more deaths directly attributed to breast cancer among the hormone group than among the placebo group (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; hazard ratio, 1.96; 95% confidence interval, 1.00 – 4.04; P = .049).
These deaths represent 2.6 and 1.3 deaths per 10,000 women per year, respectively, the authors write.
Dr. Bach believes that the study authors downplayed their mortality findings because, in part, of the “marginally significant” P value. They circumspectly wrote that “breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.”
However, Dr. Bach believes that other evidence, including the fact that the mortality curves “appear to still be separating at the end of the current follow-up,” suggests that the effect might be worse with longer follow-up.
So why have observational studies found longer survival in women with breast cancer receiving combined hormone therapy”
The authors point to potential confounders. For instance, postmenopausal hormone therapy users have mammograms at more regular intervals than nonusers, write the authors.
Observational studies that are not able to control for mammography can be confounded by differences between screening-detected and nonscreening-detected breast cancers. “Screening more commonly identifies slow-growing, favorable-grade, hormone-receptor-positive breast cancers, and diagnosis is made at an earlier stage,” they point out.
The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services. Dr. Chlebowski reports receiving consulting fees from AstraZeneca, Novartis, and Pfizer; lecture fees from AstraZeneca and Novartis; and grant funding from Amgen. A number of other study authors report relationships with industry, as detailed in the paper.
JAMA. 2010;304:1684-1692, 1719-1720.0