Researchers from the National Cancer Institute (NCI) in Bethesda, Md., have found that combined estrogen-progestin replacement therapy is associated with a greater risk of breast cancer than estrogen alone. Both groups had a higher risk than non-users. The study appears in the Jan. 26 issue of the Journal of the American Medical Association (JAMA).*

 Using follow-up data from 46,000 women who participated in the Breast Cancer Detection Demonstration Project (BCDDP), a nationwide breastcancer screening program conducted between 1973 and 1980, the scientistsfound that compared to non-users, the relative risk for breast cancer increasedby 8 percent per year for the estrogen-progestin therapy compared to 1percent for estrogen therapy alone in women who had used hormones duringthe previous four years.  There was no increase in risk among womenwho had stopped either therapy for more than four years.  (Relativerisk calculates the risk of developing breast cancer in the group of womentaking hormones compared to that of women not on therapy.)  For women who had used hormones during the previous four years, the averagelength of use was 3.6 years for the estrogen-progestin therapy comparedto 10.3 years for estrogen alone.

 When the scientists looked at subgroups of women, they found increasesin risk associated with hormone replacement therapy among lean women, butnot heavy women.  Compared to non-users, among lean women the rateof breast cancer increased by 12 percent for each year of estrogen-progestinuse compared to 3 percent for estrogen alone.  (Leanness was measuredby body mass index, BMI, which takes into account both height and weight. See http://www.nci.nih.gov/ClinicalTrials/digest-postmenopausal-hormone-use. The women at increased risk in this study had a BMI of 24.4. or less.) 

 For lean women, the researchers also found that the longer a womanused the hormones, the more likely she was to develop breast cancer. In contrast, short-term use was not associated with increased risks. 

 These results, as well as those from other studies, suggest thatwomen who take hormones for two to three years for relief of menopausalsymptoms are not at increased risk of breast cancer, said Catherine Schairer,Ph.D., first author of the study from NCIs Division of Cancer Epidemiologyand Genetics, Bethesda, Md.

 The data for the current study was collected between 1980-1995by follow-up telephone interviews and questionnaires of participants inthe original BCDDP.  The study focused on women who took hormone pills;those reporting hormone use in the form of shots, creams, or patches wereexcluded.  Eighty-six percent of the participants were white, 5 percentblack, 2 percent Hispanic, and 5 percent Asian-Americans.  The increasedrisk was largely limited to lean women who had taken the combined therapyfor longer periods of time, including the last four years of the study. Those who had stopped hormone use more than four years prior to the diagnosisof breast cancer had about the same risk as non-users.

 Estrogen therapy became available for menopausal women in the1940s, and was administered then in high doses without progestin. In the l970s, however, it became clear that women who received estrogenalone had a six to eight times higher risk of developing cancer of theendometrium (the lining of the uterus) than non-users.  Since then,researchers have found that the addition of progestin to estrogen reducesthe risk of endometrial cancer.  As a result, it has become increasinglycommon to prescribe estrogen-progestin replacement therapy for women whohave not had a hysterectomy (surgery to remove the uterus). 

 Reliable data on the effects of estrogen-progestin therapy onbreast cancer risk are only recently available.  Three studies thepooled analysis of more than 90 percent of the worlds epidemiologicaldata that appeared in 1997, a preliminary updated report in1998 from theNurses Health Study, and an updated analysis from a Swedish study suggestthat the estrogen-progestin regimen is associated with greater increasesin breast cancer risk than estrogen alone, consistent with the currentstudy. 

 The current study, however, differs in certain aspects from others. The authors found that hormone replacement therapy among lean women wasassociated with increases in both early and later stage invasive diseasewhereas in the 1997 pooled analysis increases in risk were greater forlocalized rather than distant or later-stage disease.  However, the1997 report did not look at the extent of disease in lean women.

 In addition, Schairer et al found increased risk of invasiveductal and lobular cancers whereas a report last year in JAMA found thathormone replacement therapy did not increase the occurrence of invasiveductal or lobular cancers. 

 Although several studies have reported beneficial effects of hormonereplacement therapy on the bone and heart, Schairers study as well asother data suggest possible risks and uncertainties.

 An individual womans decision to take hormone replacement therapydepends on a analysis of the risks versus the benefits which do not easilylend themselves to simple formulas, said Schairer.  The potentialincreased risk of breast cancer with hormone replacement therapy has tobe weighed against the reduced risks of bone fractures and possible coronaryheart disease.  However, it does seem clear that if a decision ismade to use hormones, that estrogen alone is recommended for women withouta uterus and that hormone use for two to three years is not likely to substantiallyincrease the risk of breast cancer.

 Several other issues are expected to be addressed in future studies. For example, it is not clear whether continuous progestin use carries thesame risks as the use of progestins for 15 or fewer days per month, themost common regimen in this study.  Additional studies are also neededto define the risks associated with long-term use of combined therapy.

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* The study is titled, Menopausal Estrogen and Estrogen-Progestin ReplacementTherapy and Breast Cancer Risk.  The authors are Catherine Schairer,Jay Lubin, Rebecca Troisi, Susan Sturgeon, Louise Brinton, and Robert Hoover. JAMA, Jan. 26, 2000, Vol. 283, No.4.

1. Breast Cancer and Hormone Replacement Therapy.  The authorsare Collaborative Group on Hormonal Factors in Breast Cancer.  Lancet,1997; 350: 1047-1059.

2. Use of Estogen Plus Progestin is Associated with Greater Increasein Breast Cancer Risk than Estrogen Alone.  The authors are GrahamColditz and B. Rosner for the Nurses Health Study Research Group.  American  Journal of Epidemiology 1998: 147(suppl):84S.

3. Hormone Replacement Therapy and the Risk of Breast Cancer with aFavorable Histology.  The authors are Susan M. Gapstur, Monica Morrow,and Thomas A. Sellers.  JAMA. 1999;281:2091-2097.

4. Risks of Breast and Endometrial Cancer After Estrogen and Estrogen-ProgestinReplacement.  The authors are I. Persson, E. Weiderpass, L. Bergvist,R. Bergstrom, C. Schairer. 1999 Cancer Causes Control 1999: 10(4):253260.

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