To the Editor: In their Special Report on the decrease in theincidence of breast cancer in the United States in 2003, Ravdinet al. (April 19 issue)1 state that a 2002 report by the Women'sHealth Initiative (WHI)2 noted a significant increase in therisk of breast cancer associated with the use of estrogen–progestincombination therapy by postmenopausal women. However, the increasedrisk of breast cancer in the WHI study did not reach statisticalsignificance. The increased risk of breast cancer in the follow-upreport3 barely achieved statistical significance, and no increasedrisk was found among WHI study subjects taking estrogen alone,as compared with those who did not receive hormone-replacementtherapy.4
If the decreased incidence of breast cancer were due to a decreasein stimulation of subclinical estrogen-receptor–positivetumors, as proposed by Ravdin et al., the decreased incidenceshould have been confined to small, early breast cancers. Itwas not.
Moreover, the incidence of breast cancer increases with increasingage through menopause, and the majority of postmenopausal breastcancers are estrogen-receptor–positive. If the authors'postulate is correct, the incidence of breast cancer in thispopulation of women, most of whom do not receive hormone-replacementtherapy, should decrease with age. It does not.
Avrum Z. Bluming, M.D. University of Southern California Los Angeles, CA 90033 av{at}lafn.org
References
Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007;356:1670-1674. [Free Full Text]
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333. [Free Full Text]
Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 2003;289:3243-3253. [Free Full Text]
Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712. [Free Full Text]
To the Editor: Recognizing that breast cancer is sensitive toboth estrogen (stimulation) and antiestrogen (inhibition) agents,Ravdin and colleagues believe that the data "are most consistentwith a direct effect of hormone-replacement therapy on preclinicaldisease." However, several factors argue against this conclusion.First, the incidence of estrogen-receptor–positive breastcancer appeared to peak in 1999, and a downward trend appearedto begin in 2000, not in 2002. Second, from 2002 to 2003, therewas a 38% reduction in the use of hormone-replacement therapybut only a 15% reduction in the incidence of estrogen-receptor–positivebreast cancer among women between the ages of 50 and 69 years.Third, all the women who had estrogen-receptor–positivebreast cancer must have had occult disease before the cancerwas detected. The establishment of cause and effect with epidemiologicdata is difficult, at best. One might wonder whether hiddencovariables were responsible for the changes in incidence seenin data from the National Cancer Institute's Surveillance, Epidemiology,and End Results (SEER) registries.
Answers to three questions may be enlightening: What is theincidence of estrogen-receptor–positive breast cancerin women who never received hormone-replacement therapy, whatis the incidence in those who have discontinued hormone-replacementtherapy, and what is the incidence in those who continue toreceive hormone-replacement therapy?
Gerald J. Elfenbein, M.D. Boston University School of Medicine Boston, MA 02118 gerald.elfenbein{at}verizon.net
To the Editor: Ravdin et al. report that between 2002 and 2003there was a 6.7% decrease in the incidence of breast cancerin the United States. During the same period in Canada, prescriptionrates for hormone-replacement therapy decreased by 26.8%,1 andthe age-adjusted standardized incidence rate for breast cancerdecreased by 5.6%.2 In Canada, breast-cancer rates peaked in1999 and since then have been declining among women of all ages(Figure 1). However, the decline was significant only for women75 years of age or older; the annual change from 1999 to 2003for all women was –1.8% (P=0.06); for women 20 to 49 yearsold, –1.5% (P=0.19); for those 50 to 74 years old, –1.7%(P=0.13); and for those 75 years of age or older, –2.6%(P=0.01). These results suggest that the use of hormone-replacementtherapy may have had a role in the decrease in breast-cancerincidence rates. However, the fact that the rates for womenin all three age groups started to decline before 2002 suggeststhat other factors were also involved.
Figure 1. Breast-Cancer Incidence Rates among Canadian Women According to Age and Year of Diagnosis, 1992–2003.
Erich V. Kliewer, Ph.D. Alain A. Demers, Ph.D. Zoann J. Nugent, Ph.D. CancerCare Manitoba Winnipeg, MB R3E 0V9, Canada erich.kliewer{at}cancercare.mb.ca
To the Editor: In contrast to the results reported by Ravdinet al., from 2002 to 2005, breast-cancer incidence rates werestable in Norway1 and Sweden,2 despite a sharp decline in theuse of hormone-replacement therapy. Sales data for hormone-replacementtherapy and the incidence of cancer during this period amongwomen in four Norwegian counties who were between the ages of50 and 69 years are shown in Figure 1. In this population, thebreast-cancer incidence rate and the rate of mammographic screeninghave been stable since screening was introduced in 1996–1997.3From 2002 to 2004, the decrease in the number of women receivinghormone-replacement therapy per 100,000 postmenopausal womenwas similar to the decrease in the United States. Our resultsdo not support the suggestion by Ravdin et al. that a largereduction in the use of hormone-replacement therapy was associatedwith a rapid and large reduction in the breast-cancer incidencerate.
Figure 1. Hormone-Replacement Therapy (HRT) and Breast-Cancer Incidence among Women between the Ages of 50 and 69 Years in Four Norwegian Counties.
The population of the four counties represented in the graph constitutes 40% of the 4.6 million people living in Norway. The red curve indicates the average number of women receiving HRT per year, based on the sales of defined daily doses of HRT divided by 365 days. The black curve shows the breast-cancer incidence. Mammographic screening was introduced in 1996–1997 in this population.
Per-Henrik Zahl, M.D., Ph.D. Norwegian Institute of Public Health N-0403 Oslo, Norway per-henrik.zahl{at}fhi.no
Jan Mæhlen, M.D., Ph.D. Ullevål University Hospital N-0407 Oslo, Norway
References
Cancer in Norway 2005. Oslo: Cancer Registry of Norway (Kreftregisteret), 2006.
Cancer incidence in Sweden 2005. Stockholm: National Board of Health and Welfare (Socialstyrelsen), 2007.
Zahl P-H, Strand BH, Mæhlen J. Breast cancer incidence in Norway and Sweden during introduction of nationwide screening: prospective cohort study. BMJ 2004;328:921-924. [Free Full Text]
To the Editor: Another explanation for the results reportedby Ravdin et al. is surgical removal of preinvasive ductal carcinomain situ (DCIS). Mammographic screening accelerated after 1985,with frequent detection of DCIS; the removal of this lesionusually prevents invasive breast cancer. Since the decline inthe incidence of breast cancer began 15 years after mammographicscreening became widespread, such a drop fits well, in bothtiming and magnitude, with the presumed delay between the detectionof DCIS and the subsequent appearance of invasive cancer. Webelieve that most of the decline in the incidence of breastcancer is the result of screening.
Blake Cady, M.D. 24 Walnut Pl. Brookline, MA 02445 bcady123{at}comcast.net
Maureen A. Chung, M.D. Rhode Island Hospital Providence, RI 02903
James S. Michaelson, Ph.D. Massachusetts General Hospital Boston, MA 02114
To the Editor: Ravdin et al. did not examine whether regionalchanges in the incidence of breast cancer correlated with regionalchanges in the use of hormone-replacement therapy. If so, sucha finding would strengthen the causal hypothesis that the useof hormone-replacement therapy is associated with an increasedrisk of breast cancer. California differs from most populationsin that the population-based cancer incidence and data regardingrisk factors are collected for individual counties. We recentlyanalyzed data from all 58 counties in California to see whetherregional changes in the incidence of breast cancer between 2001and 2004 correlated with regional changes in the use of hormone-replacementtherapy.1
We obtained data on rates of invasive female breast cancer thatwere specific for age, race or ethnic group, and county fromthe population-based California Cancer Registry, and we obtainedpopulation estimates from the National Center for Health Statistics.Data on the use of hormone-replacement therapy were obtainedfrom the 2001 and 2003 California Health Interview Surveys.2We limited the study to non-Hispanic white women between theages of 45 and 74 years because the incidence of breast cancervaries widely according to race or ethnic group and becausethis age group had the highest prevalence of use of hormone-replacementtherapy. For all California counties, we obtained estimatesof the prevalence of the use of hormone-replacement therapyin 2001 and 2003 and the age-adjusted incidence of breast cancerper 100,000 women in 2001 and in 2004 (the most recent yearfor which data were available). To measure the correlation betweena change in breast-cancer incidence (I) and a change in theprevalence of the use of hormone-replacement therapy (P), weused weighted linear regression, with weights that were proportionalto the inverse of the variance of I.
Regression results suggested that each 1% decrease in the prevalenceof the use of hormone-replacement therapy was associated witha decrease in breast-cancer incidence of 3.1 cases per 100,000women (P<0.001). The correlation coefficient between P andI was 0.75, and it indicated that 57% of the variation in Iwas explained by variation in P.
Although other, unmeasured changes in the population may explainthe observed changes in the incidence of breast cancer, thesedata provide further evidence that population-level changesin the use of hormone-replacement therapy between 2001 and 2003,when media attention surrounding the WHI results was widespread,may be responsible for a substantial population-level declinein the incidence of breast cancer between 2001 and 2004.
Anthony S. Robbins, M.D., Ph.D. California Cancer Registry Sacramento, CA 95815 arobbins{at}ccr.ca.gov
Christina A. Clarke, Ph.D. Northern California Cancer Center Fremont, CA 94538
Dr. Clarke reports receiving consulting fees from attorneys preparing litigation regarding hormone therapy. No other potentialconflict of interest relevant to this letter was reported.
References
Robbins AS, Clarke CA. Regional changes in hormone therapy use and breast cancer incidence, California, 2001–2004. J Clin Oncol (in press).
To the Editor: Ravdin et al. do not mention that the recentdecrease in the incidence of breast cancer was not observedin black women. Between 2001 and 2004, the delay-adjusted breast-cancerincidence rate for women 50 years of age or older increasedfrom 313.8 to 327.0 per 100,000 person-years among black women,as compared with a decrease from 408.8 to 358.8 per 100,000person-years among white women. Among U.S. women who becamemenopausal between 1970 and 1992, 33% of black women and 51%of white women reported the use of hormone-replacement therapy;the duration of use was at least 10 years for 11% of black womenand 20% of white women.1 Among 14,468 black and 5793 white postmenopausalwomen enrolled in the Southern Community Cohort Study2 fromcommunity health centers from 2002 to 2007, 31% of blacks and51% of whites reported ever receiving hormone-replacement therapy;12% of blacks and 18% of whites reported current use. Similarreductions in the use of hormone-replacement therapy after July2002 were reported for both black women and white women.3,4The breast-cancer trend since 2001 among black women does notappear to support a role of reduced use of hormone-replacementtherapy in the recent decrease in breast cancer among womenin the United States.
Lisa B. Signorello, Sc.D. Robert E. Tarone, Ph.D. International Epidemiology Institute Rockville, MD 20850 bob{at}iei.ws
References
Brett KM, Madans JH. Use of postmenopausal hormone replacement therapy: estimates from a nationally representative cohort study. Am J Epidemiol 1997;145:536-545. [Free Full Text]
Signorello LB, Hargreaves MK, Steinwandel MD, et al. Southern Community Cohort Study: establishing a cohort to investigate health disparities. J Natl Med Assoc 2005;97:972-979. [Medline]
Wei F, Miglioretti DL, Connelly MT, et al. Changes in women's use of hormones after the Women's Health Initiative estrogen and progestin trial by race, education, and income. In: Vogt TM, Wagner EH, eds. Health care systems as research platforms: the cancer research network. Journal of the National Cancer Institute monographs. No. 35. Bethesda, MD: Oxford University Press, 2005:106-12.
Hillman JJ, Zuckerman IH, Lee E. The impact of the Women's Health Initiative on hormone replacement therapy in a Medicaid program. J Womens Health (Larchmt) 2004;13:986-992. [CrossRef][Medline]
The authors reply: Multiple factors affect the incidence ofbreast cancer: mammographic screening, demographic and lifestylechanges, and the use of exogenous hormones. Understanding theinterplay among these influences is a challenge. The WHI study1shows that even a single factor can be complex — for example,both the type of hormone-replacement therapy and its durationof use are important. Given this complexity, various trendsin the incidence of breast cancer within population subgroupsis not surprising. These differences — essentially naturalexperiments — may provide insights into how to use hormone-replacementtherapy in the safest and most beneficial fashion.
Recent data such as those from California (reported by Robbinsand Clarke2), Canada (noted by Kliewer et al.), and Germany(reported by Katalinic and Rawal3) provide additional supportfor our hypothesized connection between the use of hormone-replacementtherapy and the incidence of breast cancer. Modeling of intracountychanges in breast-cancer incidence and the prevalence of theuse of hormone-replacement therapy in California suggest that57% of the variation in incidence is explained by variationin the use of hormone-replacement therapy. This analysis providesan answer to Elfenbein's statement about nonproportionalitybetween the use of hormone-replacement therapy and the incidenceof breast cancer.
We are not surprised by the absence of an effect on breast-cancerincidence among black women, an issue raised by Signorello andTarone, since the prevalence of use of hormone-replacement therapyin this group was lower than that among white women. Moreover,the statistical power to identify an effect is lower among blacksbecause they are a subgroup of the population. Bluming suggeststhat older postmenopausal women are less likely to receive hormone-replacementtherapy than are younger postmenopausal women and that its discontinuationin older women might therefore be expected to have less of aneffect. On the other hand, since these women have received hormone-replacementtherapy for a longer period than have younger women, the effectof discontinuation could still be substantial.
We cannot fully explain the absence of a change in breast-cancerincidence in Norway. One possibility is that there are only170,000 women between the ages of 50 and 69 years in the Norwegiandatabase, so statistical power is an issue. Also, in Norway,the major forms of hormone-replacement therapy are based onestradiol rather than conjugated estrogens. The effects on breastcancer and the effect of the discontinuation of hormone-replacementtherapy may well differ for these preparations.
Several writers mention that the decrease in the incidence ofbreast cancer began in 1999. Cady et al. propose that earlydetection of DCIS may eventually lower the overall incidence,thus explaining at least part of the decrease, and that thisdecrease may have started in 1999. In a similar vein, Jemalet al.4 propose that the modest decrease beginning in 1999 isconsistent with saturation of mammographic screening. However,neither of these factors accounts for the sharp drop withina single year. Although there is no conclusive proof of a causallink between coincident sharp declines in the use of hormone-replacementtherapy and the incidence of estrogen-receptor–positivebreast cancer, we have yet to see a credible alternative explanation.
Peter M. Ravdin, M.D., Ph.D. M.D. Anderson Cancer Center Houston, TX 77030
Kathleen A. Cronin, Ph.D. National Cancer Institute Bethesda, MD 20892
Rowan T. Chlebowski, M.D., Ph.D. Harbor–UCLA Medical Center Los Angeles, CA 90502
References
Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 2003;289:3243-3253. [Free Full Text]
Robbins AS, Clarke CA. Regional changes in hormone therapy use and breast cancer incidence, California, 2001–2004. J Clin Oncol (in press).
Katalinic A, Rawal R. Decline in breast cancer incidence after decrease in utilization of hormone replacement therapy. Breast Cancer Res Treat (in press).
Jemal A, Ward E, Thun MJ. Recent trends in breast cancer incidence rates by age and tumor characteristics among U.S. women. Breast Cancer Res 2007;9:R28-R28. [CrossRef][Medline]
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[Abstract][Full Text]
Banks, E., Canfell, K.
(2009). Invited Commentary: Hormone Therapy Risks and Benefits--The Women's Health Initiative Findings and the Postmenopausal Estrogen Timing Hypothesis. Am J Epidemiol
170: 24-28
[Abstract][Full Text]
Clarke, C. A., Robbins, A. S.
(2007). In Reply. JCO
25: 5039-5040
[Full Text]
I) and a change in the prevalence of the use of hormone-replacement therapy (
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