Increased Risk of Breast Cancer with Estrogen-Progestin Therapy
Increased Risk of Breast Cancer with Estrogen-Progestin Therapy
Abstract & Commentary
Synopsis: Postmenopausal estrogen-progestin therapy increased the risk of breast cancer in a population-based cohort in Sweden, and estrogen-only did not.
Source: Olsson HL, et al. San Antonio Breast Cancer Symposium, December 2002. Abstract 34. In press.
Olsson and colleagues from Lund Sweden reported about 2 years ago1 the incidence of breast cancer in a population-based cohort of 29,508 women. The women were recruited between 1990-1992, and followed for a median time of 7.6 years. There were 434 cases of breast cancer compared with 388 cases expected according to national statistics, which amounted to an increased risk of 1.92 with 4-10 years of postmenopausal estrogen-progestin use. There was no interaction with family history of breast cancer among first-degree relatives or previous use of oral contraceptives. That report was recently updated at the San Antonio Breast Cancer Symposium in December 2002. The number of breast cancers now totals 556 vs 508 expected. This produced a calculated overall increased risk of 1.09 that almost but not quite reached statistical significance. The risk for users of combined estrogen-progestin daily therapy for 4 years or more was calculated to be 3.68 (CI = 2.14-6.34). Sequential estrogen-progestin therapy had a risk of 2.81 (CI = 1.57-5.08). The use of estradiol without progestins was reported to have no increased risk.
Comment by Leon Speroff, MD
These results, highlighted in the media, are no different than those recently reported by the Women’s Health Initiative. One could argue that this Swedish study is more impressive because the size of the risks associated with estrogen-progestin therapy is much larger, but there are problems with the study that make such a conclusion a little shaky.
The strength of the study is in the size of the cohort and the prospective design. Added to that is the ability to accurately track individuals in Sweden through a comprehensive registry system. Nevertheless, there are several problems. The risk ratios are calculated by comparing the observed number of cases with an expected number based upon the reference data in the government registries. Therefore, hormone users were not compared to nonusers; both users and nonusers were compared to expected outcomes. This is not a bad technique, but it provides approximations not absolutely accurate determinations.
The study carefully adjusted for many factors that affect the risk of breast cancer, including age of menarche, age at menopause, age at first full-term pregnancy, parity, and age at diagnosis. However, there are at least 4 more critical influences that were unaccounted for: use of mammography, presence of benign breast disease (specifically with atypical hyperplasia), body size, and alcohol intake.
The specific estrogen and progestin drugs were not identified, but in Sweden we know that the most popular regimen is composed of estradiol and norethindrone. This at least is evidence that American reports based mainly on the use of conjugated equine estrogens and medroxyprogesterone acetate do not indicate results limited to one formulation.
As in the Women’s Health Initiative, the appearance of an increased risk by 4 years of use is relatively rapid. This is consistent with an effect on pre-existing tumors. Therefore, the recent data have not answered our most fundamental question: is there a slightly increased risk of breast cancer with combined estrogen-progestin postmenopausal therapy or are we seeing the results of earlier detection of tumors because of effects on pre-existing tumors? The now well-recognized better survival rates in postmenopausal women who develop breast cancer while on hormone therapy argues in favor of an effect on pre-existing tumors.
The good news is that the Swedish study reported no increase in risk associated with the use of estrogen alone. This is the reason that the estrogen-only arm of the Women’s Health Initiative has not been discontinued. Only time will tell if estrogen-only is a different story.
Dr. Speroff is Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, Ore.
Reference
1. Olsson H, et al. Br J Cancer. 2001;85:674-677.
Postmenopausal estrogen-progestin therapy increased the risk of breast cancer in a population-based cohort in Sweden, and estrogen-only did not.Subscribe Now for Access
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