Correspondence
Mammographic Breast Density
N Engl J Med 2007; 356:1885-1887May 3, 2007
- Article
To the Editor:
Boyd and colleagues (Jan. 18 issue)1 report a case–control study, nested within data derived from previous cohort studies, that strongly supports breast density as a risk factor for breast cancer. However, using only 1 matched control for the analysis, in spite of the identification of 10 potential controls for each case, limited the statistical conclusions. In addition, it is not clear how the breast cancers were ultimately discovered. If the majority of the cancers were eventually diagnosed on mammography, then despite the delay in diagnosis, annual mammography remains a valuable screening tool even in women with dense breast tissue.
1 ReferencesVani Dandolu, M.D.
Enrique Hernandez, M.D.
Temple University Hospital, Philadelphia, PA 191401
Boyd NF ,Guo H ,Martin LJ , et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med 2007;356:227-236
Full Text | Web of Science | Medline
To the Editor:
There is probably some relationship between the density of breast tissue and the risk of breast cancer, but the methods used by Boyd and colleagues preclude the emphasis that they and others place on this relationship, for several reasons. First, three-dimensional tissue-volume ratios cannot be quantitatively derived from two-dimensional mammographic images in the absence of values for the compressed thickness of the breast and half-value layers. Second, radiologists cannot determine true volume ratios. Third, computer algorithms allow reproducible segmentation of two-dimensional pictures but cannot predict three-dimensional volumes. Fourth, use of the craniocaudal mammographic view alone excludes much of the breast (which is the denominator in the volume ratio). Fifth, on two-dimensional imaging, there is no definition of where the breast ends, and there is considerable variability in how the breasts are positioned, making accurate calculation of the tissue-volume ratio impossible. I have seen cases in which same-day repositioning of the breast halved the measured percentage of tissue density. Finally, it is not possible to establish whether biases are systematic and will wash out with large numbers of cases. Before strong conclusions can be made about the relationship between breast-tissue density and the risk of breast cancer, more accurate data must be obtained. Preferably, three-dimensional imaging techniques such as magnetic resonance imaging, computed tomography, or digital breast tomosynthesis should be used.
Daniel B. Kopans, M.D.
Harvard Medical School, Boston, MA 02115To the Editor:
Boyd and colleagues provide much useful information about the relationship between mammographic density and the risk of breast cancer. However, the comparison of attributable risks for women at different ages with the use of a fixed threshold may be confounded by the lower breast density in general in older women. Age-specific risks (and risks specific to the body-mass index) are needed for different density values. Mammographic density is an enrollment criterion for the International Breast Cancer Intervention Study II, along with other factors. Learning how to combine these factors in an optimal way is a priority for prevention research.
Jack Cuzick, Ph.D.
Wolfson Institute of Preventive Medicine, London EC1M 6BQ, United Kingdom
jack.cuzick@cancer. org. uk To the Editor:
Boyd et al. do not indicate that the positive correlation between mammographic breast density and the risk of breast cancer is independent of the method used to detect the cancer. They do not mention intergroup assessment of pain or the use of analgesics or compressive forces. Women with dense breasts often experience pain while undergoing mammography. Pain is a universal warning sign of tissue damage and may be associated with an increased risk of breast cancer,1 yet women who experience severe pain during mammography are often advised to override this warning sign with the use of medication or by other means.
1 ReferencesJohannes P. van Netten, Ph.D.
Christina J. van Netten-Thomas
University of Victoria, Victoria, BC V8W 3N5, Canada
jpvannetten@shaw.ca Christine L. Fletcher, B.Sc.
British Columbia Cancer Agency, Victoria, BC V8R 6V5, Canada1
Crandall CJ ,Karlamangla A ,Huang MH ,Ursin G ,Guan M ,Greendale GA . Association of new-onset breast discomfort with an increase in mammographic density during hormone therapy. Arch Intern Med 2006;166:1578-1584[Erratum, Arch Intern Med 2006;166:2176.]
CrossRef | Web of Science | Medline
Author/Editor Response
Dandolu and Hernandez point out that the statistical power of our study could have been increased with the use of more than one randomly selected control subject per case subject. However, the levels of statistical significance shown in our report do not suggest that lack of power was a limiting factor. Mammography was the only method used at screening in one program in our study and was the predominant method in the other two programs, and more than half the cancers that developed in women with extensive mammographic density were detected at screening.
We have previously noted the limitations of existing methods of assessing mammographic density referred to by Kopans.1 None of those methods take breast thickness into account and are thus based on the projected area, rather than on the volume of breast tissue. Current computer-assisted methods of measurement require a dichotomous threshold between dense and nondense tissue, and uncontrolled sources of variation, in positioning, exposure, and processing, may be present. However, in prospective studies such as ours in which mammography is used 1 to 8 years before diagnosis, these sources of error are expected to affect equally women in whom breast cancer will develop and those in whom it will not and to attenuate estimates of risk. We may thus be underestimating the true underlying risk of breast cancer associated with mammographic density.
Notwithstanding these limitations, as discussed by Kerlikowske2 and shown in a recent systematic review,3 there is now a substantial body of consistent evidence showing that the relative risks of breast cancer associated with mammographic density, as currently measured, are greater than for most other risk factors for this disease; that these risks persist after adjustment for other risk factors and, as we show, over time; and that they are present for both breast cancers detected by screening and those not detected by screening. Studies of the limitations of existing methods of measurement may further increase risk estimates.4
Cuzick points out that the attributable risk (which we report) and the predictive value are different measures of the importance and usefulness of a risk factor. It is unlikely that the number of subjects in the present study is large enough to provide precise estimates specific to age and body-mass index.
In response to van Netten et al., who raise the interesting question of whether pain during mammography may be a risk factor for breast cancer, we are not able to examine this issue with the available data.
4 ReferencesNorman Boyd, M.D., D.Sc.
Campbell Family Institute for Breast Cancer Research, Toronto, ON M5G 2M9, Canada
boyd@uhnres.utoronto. ca Salomon Minkin, Ph.D.
Ontario Cancer Institute, Toronto, ON M5G 2M9, CanadaMartin Yaffe, Ph.D.
Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada1
Boyd NF ,Rommens JM ,Vogt K , et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 2005;6:798-808[Erratum, Lancet Oncol 2005;6:826.]
CrossRef | Web of Science | Medline2
Kerlikowske K . The mammogram that cried Wolfe. N Engl J Med 2007;356:297-300
Full Text | Web of Science | Medline3
McCormack VA ,dos Santos Silva I . Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2006;15:1159-1169
CrossRef | Web of Science | Medline4
Pawluczyk O ,Augustine BJ ,Yaffe MJ , et al. A volumetric method for estimation of breast density on digitized screen-film mammograms. Med Phys 2003;30:352-364
CrossRef | Web of Science | Medline
