Journal of the National Cancer Institute Advance Access originally published online on November 27, 2007
JNCI Journal of the National Cancer Institute 2007 99(23):1815-1816; doi:10.1093/jnci/djm210
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© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Re: Declines in Invasive Breast Cancer and Use of Postmenopausal Hormone Therapy in a Screening Mammography Population
Affiliations of author: Department of Surgery, University of Washington, Seattle, WA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
Correspondence to: Benjamin O. Anderson, MD, Department of Surgery, Section of Surgical Oncology, Box 356410, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195 (e-mail: banderso{at}u.washington.edu).
Kerlikowske et al. (1) suggest that decreased use of hormone replacement therapy (HRT) led to decreased breast cancer incidence in a mammographically screened study population. Using sophisticated modeling techniques, the authors were able to show statistical significance in changing HRT and breast cancer diagnosis rates. However, the clinical conclusions reached by the authors are poorly justified if not contradicted by their findings.
As the authors note, HRT use plummeted in the study group population between 2002 and 2004, presumably due to the public announcement of the Women's Health Initiative results in 2002 (2). Visual inspection of the study data (see their fig. 1, A and B) shows that this dramatic drop in HRT use occurred concomitantly with a drop in breast cancer incidence so small that it is virtually imperceptible to the naked eye. Although the rate of HRT use dropped from 50% in 2000 to less than 20% at the end of 2003, the actual rate of invasive breast cancer (solid triangles) hovered virtually unchanged at approximately 4 cases per 1000 mammograms between 1997 and 2004 (see their fig. 1, A). Had the dashed lines tracing the linear logistic regression model not been provided, the reader would be hard pressed to conclude that there was any relationship at all between the use of HRT and breast cancer incidence—the differences are simply too subtle and variable over time.
The data on estrogen receptor (ER)–positive invasive cancers are similarly problematic (see their fig. 1, B). The raw data (solid triangles) hover around 3 cases per 1000 mammograms during the entire study period, i.e., between 1997 and 2004. Although the authors describe a 13% decline in ER-positive cancers between 2001 and 2003 based on their model, visual inspection shows that this finding hinges on two high data points early in 2001 and a single low data point at the beginning of 2003 and is undermined by a subsequent rise in incidence later in 2003. The 13% rate would be lower and possibly statistically insignificant had a later time cutoff ("knot") been chosen. Although no difference in the incidence of ER-negative invasive cancers was found during this same period, ER-negative cancers represented less than 25% of the invasive breast cancers in the study population (<1 ER-negative case per 1000 mammograms). The number of ER-negative cases was therefore too small to show a change in incidence, even with sophisticated statistical modeling techniques.
Mammographically detected ER-positive cancers in postmenopausal women are, on average, clinically favorable cancers that change slowly over time, taking years to develop. The idea that a preexisting ER-positive cancer would rapidly disappear within a year of HRT discontinuation is biologically implausible. Were discontinuation of HRT to affect preexisting hormone-sensitive cancers, one would expect a corresponding change in incidence to take years to become demonstrable. Because no lag was observed between decreased HRT use and decreased breast cancer incidence in this study, other mechanisms to explain the findings should be considered.
If HRT causes hormone-sensitive cancers to "light up" and be more easily detected on mammograms, then discontinuation of HRT would reduce breast cancer detection at least for a period of time. This pattern is precisely what the authors observed. Did decreased HRT use simply delay the diagnoses of existing breast cancers in this mammographically screened population? Further follow-up needs to be performed. Until then, we should be cautious and circumspect before making sweeping clinical generalizations based on complex epidemiologic results that may be of negligible importance when considered at the level of the individual patient. Elimination of HRT would barely dent the current breast cancer epidemic but could have substantial adverse effects for women whose quality of life can really benefit from HRT.
NOTES
B. O. Anderson has served as a consultant and expert witness on behalf of Wyeth Pharmaceuticals in hormone therapy litigation.
REFERENCES
(1) Kerlikowske K, Miglioretti DL, Buist DS, Walker R, Carney PA. Declines in invasive breast cancer and use of postmenopausal hormone therapy in a screening mammography population. J Natl Cancer Inst (2007).
(2) Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, 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) 288:321–33.
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J Natl Cancer Inst 2007 99: 1816-1817.
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