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Grant Details

Grant Number: 5R21CA157254-02 Interpret this number
Primary Investigator: Shepherd, John
Organization: University Of California, San Francisco
Project Title: Subregional Breast Density and Cancer Risk
Fiscal Year: 2013


DESCRIPTION (provided by applicant): Identifying women at risk for breast cancer is not part of the current clinical paradigm for women's health even though strong risk factors, such as breast density, have been identified. A high percentage of dense parenchyma on mammograms appears to give a 4-6 fold risk to develop breast cancer. The biological cause for the association is unclear even after 20 years of study. The long-term goal of this proposed research is to determine the best global or local measure of breast density for risk assessment of high-mortality cancers. The objective of this application is to describe the relationship of specific local measures of volume breast density and density morphology to cancer risk for invasive cancers as well as DCIS cases, and to discover what serum, tissue, or clinical biomarkers act as a determinant of the macro distribution of dense breast tissue. The central hypothesis is that subregional measurements of the percent fibroglandular volume density are more strongly associated with local and global breast cancer risk. Very little is known of the distribution of dense tissue within breast tissue in women with cancer versus those without because an in vivo description of dense tissue distribution has not been available. Our secondary hypothesis is that specific biomarkers of breast density act as morphostats for density macro structure. Our approach is unique in that we will be using a novel pixel-by-pixel measure of volumetric breast density called Single X-ray Absorptiometry (SXA). Our first specific aim is to identify subregions of dense breast volume associated with subsequent breast cancer in women undergoing mammography. The working hypothesis for this aim is that subregions of the breast may be stronger risk predictor of local cancer in that region than global breast density. In addition, subregional density may be a stronger risk predictor of a woman's risk of breast cancer than global breast density due to the exclusion of peripheral adipose that envelopes the parenchyma. Our second specific aim is to Identify the association of breast morphology to risk and to key tissue, serum, and clinical correlates to test the morphostatic behavior of breast density. The coarse distribution of density is known to show morphostatic qualities between women as well as between a woman's two breasts. Our working hypothesis is that there may be a particular spatial distribution, or morphology, of dense tissue that is associated with cancer risk independent of the magnitude of the density. Our expected outcome will include: development of new regions of local breast density that will be made available for future studies using our large cohort, confirmation of breast density as either a local or global risk factor, and the identification of the most likely biomarker candidates driving breast density morphometry. Our findings will reduce the risks of harms for women undergoing mammography by providing a cancer risk marker to intelligently reduce the screening frequency of very low risk women. It will aid in the decreased mortality of high risk women by their more accurate identification and targeting for use of more sensitive imaging and risk reduction strategies.


Mammographic texture and risk of breast cancer by tumor type and estrogen receptor status.
Authors: Malkov S. , Shepherd J.A. , Scott C.G. , Tamimi R.M. , Ma L. , Bertrand K.A. , Couch F. , Jensen M.R. , Mahmoudzadeh A.P. , Fan B. , et al. .
Source: Breast cancer research : BCR, 2016-12-06; 18(1), p. 122.
EPub date: 2016-12-06.
PMID: 27923387
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Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease.
Authors: Horne H.N. , Sherman M.E. , Pfeiffer R.M. , Figueroa J.D. , Khodr Z.G. , Falk R.T. , Pollak M. , Patel D.A. , Palakal M.M. , Linville L. , et al. .
Source: Breast cancer research : BCR, 2016-02-18; 18(1), p. 24.
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Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities.
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Source: Cancer prevention research (Philadelphia, Pa.), 2016 Feb; 9(2), p. 149-58.
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Leukocyte telomere length and its association with mammographic density and proliferative diagnosis among women undergoing diagnostic image-guided breast biopsy.
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Source: BMC cancer, 2015-10-30; 15, p. 823.
EPub date: 2015-10-30.
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Relationship of serum estrogens and metabolites with area and volume mammographic densities.
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Source: Hormones & cancer, 2015 Jun; 6(2-3), p. 107-19.
EPub date: 2015-03-11.
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Comparison of mammographic density assessed as volumes and areas among women undergoing diagnostic image-guided breast biopsy.
Authors: Gierach G.L. , Geller B.M. , Shepherd J.A. , Patel D.A. , Vacek P.M. , Weaver D.L. , Chicoine R.E. , Pfeiffer R.M. , Fan B. , Mahmoudzadeh A.P. , et al. .
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Enhancement of mammographic density measures in breast cancer risk prediction.
Authors: Cheddad A. , Czene K. , Shepherd J.A. , Li J. , Hall P. , Humphreys K. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2014 Jul; 23(7), p. 1314-23.
EPub date: 2014-04-10.
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Agreement of mammographic measures of volumetric breast density to MRI.
Authors: Wang J. , Azziz A. , Fan B. , Malkov S. , Klifa C. , Newitt D. , Yitta S. , Hylton N. , Kerlikowske K. , Shepherd J.A. .
Source: PloS one, 2013; 8(12), p. e81653.
EPub date: 2013-12-04.
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