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Long Durations and Different Regimens of Hormone Therapy and Risk of Breast Cancer
Abstract & Commentary
Synopsis: The data in this case-control study of combined estrogen plus progestin therapy revealed an increased risk of breast cancer, particularly invasive lobular tumor, regardless of whether the progestin component was taken sequentially or continuously. There was no increased risk of breast cancer in those exposed postmenopausally to estrogen only.
Source: Li CI, et al. JAMA. 2003;289:3254-3263.
The aim of this study was to investigate the role of progestin use in the risk of postmenopausal breast cancer. Li and colleagues conducted a thorough case-control study in which hormone use was carefully ascertained. The subject population was women living in 3 counties in the Seattle-Puget Sound metropolitan area. There were 1007 control women and 975 cases of breast cancer. More than 95% of all incident cancer cases were entered into a registry. Control women were culled from the same population using HFCA records. The designation of ERT use was restricted to women who were exclusive users of ERT. The 2 groups were comparable in almost all regards except that those with breast cancer were more likely to have a family history of breast cancer and higher levels of alcohol consumption. Those diagnosed with invasive ductal breast carcinoma were more likely to have never used oral contraceptives, while those diagnosed with invasive lobular breast cancer were more likely to have used oral contraceptive for greater than 5 years.
Compared to ERT-only users, exclusive users of combined HRT (CHRT) had a 1.8-fold (CI, 1.3-2.2) increased risk of breast cancer of all types. When examined by histologic type, ever users of CHRT had an increased risk of both invasive ductal (OR, 1.5; CI, 1.1-2.0) and invasive lobular carcinoma (OR, 2.7; CI, 1.7-4.3). The increases were greatest for those using CHRT the longest. The increased risk associated with ever and current use of CHRT differed little by progestin regimen (continuous vs sequential). In contrast, the OR for current use of only ERT was 1.0 (CI, 0.7-1.3) and in those using ERT > 25 years (101 cases), the OR was 1.0 (CI, 0.7-1.5).
Comment by Sarah L. Berga, MD
This study complements other WHI data1 and buttresses the notion that the progestin component of menopausal hormone therapy may explain the excess risk of breast cancer seen in the CEE+MPA arm of the WHI. If the data from these 2 studies are true, then they suggest that we ought to be doing all that we can to minimize progestin exposure in women who take hormone therapy after menopause. If there is an increased risk of dementia as was purportedly observed in the WHI in the CEE+MPA arm, it may also be attributed to the progestin component abrogating the neuroprotective effects of estrogen or via direct effects of progestins on neurons or glia. As far as I know, there are no known benefits associated with progestin use other than protection of the endometrium from hyperplasia and cancer. Progestins cause many symptoms, including dysphoria in some and bleeding in others.
What can we do to minimize progestin exposure in postmenopausal women who want to take estrogen? For years, there were some practitioners who advocated estrogen-only use even when the uterus was intact. However, the PEPI trial demonstrated high rates of hyperplasia in women given the standard dose of CEE of 0.625 mg. This led some to suggest the use of much lower estrogen doses, in the hope that this approach would confer benefits but avoid the risk of overstimulating the endometrium. In select individuals who consent to monitoring, this plan may have merit. The use of a progestin-containing intrauterine device also has merit, although some have raised concerns that even the small amount of progestin in the circulation that results from this approach may increase the risk of breast cancer. It is also possible that not all progestin preparations carry the same risk. The study by Li et al did not specify the type of progestin used by the cases, although medroxyprogesterone acetate is by far the most commonly used progestin. With regard to the vascular bed, it appears that synthetic progestins induce vasospasm while progesterone does not. Can we expect differential tissue responses to progestins in the breast and brain as well? Only ongoing research on this topic will tell us. In summary, taken together, these 2 studies strongly link the progestin component of CHRT to the increased risk of invasive breast cancer. One could also counter that, taken together, these 2 studies exonerate estrogens, but this latter statement is more controversial. In the meantime, it is abundantly clear that we need to explore the notion that not all progestins are the same while we simultaneously explore methods to give unopposed estrogen. The concept of "chemoamelioration" of aging has merit, but we must continue to refine the approaches with an eye toward safety and enhanced efficacy.
Dr. Berga is James Robert McCord Professor and Chair, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Ga.
1. Chlebowski RT, et al. JAMA. 2003;289:3243-3253.