CORRESPONDENCE

RESPONSE: Re: Effect of Hormone Replacement Therapy on Breast Cancer Risk: Estrogen Versus Estrogen Plus Progestin

Malcolm C. Pike, Ronald K. Ross

Affiliation of authors: University of Southern California/Norris Comprehensive Cancer Center, Los Angeles.

Correspondence to: Ronald K. Ross, M.D., University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Ave., Rm. 8308B, Los Angeles, CA 90089–9181 (e-mail: ross_r{at}ccnt.hsc.usc.edu).

As Archer et al. state, in our study of HRT and breast cancer risk, we did exclude women (case patients and control subjects) who had had a simple hysterectomy before menopause. However, we do not simply "claim that including these persons would bias the risk estimates," but we have demonstrated previously that they do [reference (14) in our report (1)]. The belief of Archer et al. that excluding such women could bias the risk estimates is without foundation; a prospective cohort study of breast cancer that excluded (i.e., never recruited) women with a simple hysterectomy would provide perfectly valid estimates of risk associated with HRT. What we did in our analysis is the case–control equivalent of such a study.

"Simultaneous adjustment" has not been unusual in epidemiologic studies since the publication of the classic paper on multivariate logistic analysis by Cox (2) and the textbook of Breslow and Day (3) that made it readily available to epidemiologists. Presumably, if our risk estimates were "overadjusted," then the true risks would be even higher, but there is no basis for this fear, and our risk estimates can be used clinically in just the same way as the other such estimates are used. We believe that providing confidence intervals around every estimate of risk for each period of hormone use is not a sensible approach. Because of limited data, one would expect the individual estimates (and their confidence intervals) to vary quite considerably around the true risks, while the underlying true effect is much more likely to be a steady change with duration of use, which is best estimated in the manner we used.

Archer et al. have misread part of Table 2 in our report (1). Our estimate of the increase in breast cancer risk from 5 years of use of estrogen–progestin replacement therapy, which we termed "combination hormone replacement therapy (CHRT)," is 24%, not 10%. When we subdivided CHRT into sequential estrogen–progestin replacement therapy (SEPRT) and continuous combined replacement therapy (CCRT), our estimates of the increase in risk were 38% and 9%, respectively. These latter figures were not statistically significantly different from each other, possibly because of the relatively small number of long-term CCRT users in our study. These data are not totally reassuring with regard to CCRT, inasmuch as there are other data showing that CCRT has a large effect on breast cell proliferation (4) and on mammographic density (5), both being markers of increased risk of breast cancer. In fact, in the randomized trial described in (5), SEPRT and CCRT had similar effects. At present, it would appear most appropriate to use the 24% increase in breast cancer risk per 5 years of use as the figure from this study to include in any risk–benefit analysis of CHRT. This 24% increase in breast cancer risk per 5 years of CHRT use is in addition to any increase with age; it is not at all reassuring, but a true cause for concern.

The rather intransigent attitude of Dr. Archer and colleagues regarding their patients is especially unfortunate. To choose not to inform patients of the mounting, and now considerable, evidence that CHRT causes a large increase in breast cancer risk (evidence that a woman will want to take into account in her decision on using CHRT), is a real disservice. Less frequent use of progestins should be one option discussed and should be made available to any patient considering HRT use (6).

Instead of engaging in the type of nonscientific bickering that followed the early studies proving that ERT causes endometrial cancer, we should be addressing the considerable challenge of how to administer progestins to the endometrium without increasing breast cancer risk above that of ERT, so as to maximize the benefit to risk equation for CHRT.

REFERENCES

1 Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328–32.[Abstract/Free Full Text]

2 Cox DR. Regression models and life table. J R Stat Soc B 1972;34:187–220.

3 Breslow NE, Day NE. Statistical methods in cancer research. Volume 1—The analysis of case–control studies. IARC Sci Publ 1980;32:5–338.[Medline]

4 Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA, Haslam SZ. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab 1999;84:4559–65.[Abstract/Free Full Text]

5 Greendale GA, Reboussin BA, Sie A, Singh HR, Olson LK, Gatewood O, et al. Effects of estrogen and estrogen–progestin on mammographic parenchymal density. Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators. Ann Intern Med 1999;130:262–9.

6 Ettinger B, Selby J, Citron JT, Vangessel A, Ettinger VM, Hendrickson MR. Cyclic hormone replacement therapy using quarterly progestin. Obstet Gynecol 1994;83:693– 700.[Abstract]


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