Raised mammographic density: causative mechanisms and biological consequences

Authorship

Raised mammographic density: causative mechanisms and biological consequences by Michael J. Sherratt, James C. McConnell and Charles H. Streuli

2016

Affiliations of authors

Faculties of Life and Medical and Human Sciences, University of Manchester, Oxford Road, Manchester

Key outtakes

  • “High mammographic density is the most important risk factor for breast cancer, after ageing.”
  • “Epidemiologically, the risk of developing breast cancer is significantly greater in those women with raised MD (‘mammographic density’).”
  • “MD is therapeutically modifiable, patient tolerance to long-term endocrine treatments (‘Tamoxifen’) is low…”
  • “MD is highly variable between women, ranging from a minimum of 3 % by volume, to very high levels of 25 % (Volpara measurements; the latter high level is equivalent to 75 % density in VAS).”
  • “The current understanding of the link between MD and breast cancer was reviewed extensively in 2014, with over 180 of the previous papers on this topic examined. Numerous studies, originating in 1976, have revealed that high MD is strongly linked with the susceptibility for breast cancer.”
  • “Indeed, women with high-dense breasts have a four-to sixfold greater risk of getting cancer than those with the lowest MD density.”
  • “More recently, it was found that the percentage of high MD is a stronger risk factor for breast cancer than absolute dense area.”
  • “Breast cancer is a major disease that affects 12 % of the female population at some point during their lifetime, and is the global cause of death for nearly 500,000 women per year.”
  • “Although there is a link between BMI and cancer, there is no direct association between BMI and MD.”
  • “Regardless of the role played by cellular hypertrophy, an altered stromal composition in women aged 50–69 years correlates with increased MD, although there is no difference in the amount of epithelial lobules or ducts.”
  • “It seems likely that raised MD is associated with a complex pattern of upregulation and downregulation of ECM proteins.”
  • “There are several therapeutic strategies to reduce or eliminate breast cancer from those who have it. The American Cancer Society sanctions six major kinds of treatment, including surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapy, and bone-directed therapy.”
  • “With high MD now being recognised as a major risk factor for cancer, the therapeutics that are used so far to reduce density and thereby to potentially protect against cancer arising from high MD mainly include selective ER modulators. For example, the anti-oestrogenic compounds tamoxifen, its relatives such as raloxifene and aromatase inhibitors, are prescribed to patients with high MD but yet have no signs of acquiring breast cancer.”
  • “Interestingly, breast cancer-specific survival occurred in tamoxifen-treated women who showed a reduction in MD.”
  • “…taking advantage of combined strategies to detect and/or revert high MD could reduce the incidence and mortality of breast cancer by more than 20 %.”

Paper

The full paper can be found here: Click here

 

 

International Consortium on Mammographic Density: Methodology and population diversity captured across 22 countries

Authorship

International Consortium on Mammographic Density: Methodology and population diversity captured across 22 countries

Valerie A. McCormacka-a, Anya Burtona-a, Isabel dos-Santos-Silva-b, John H. Hipwell-c, Caroline Dickens-d, Dorria Salem-e, Rasha Kamal-f, Mikael Hartman-g, Charmaine Pei Ling Lee-g-h, Kee-Seng Chia-h, Vahit Ozmen-i, Mustafa Erkin Aribal-i, Anath Arzee Flugelman-j, Martín Lajous-k-l, Ruy Lopez-Riduara-l, Megan Rice-m, Isabelle Romieu-n, Giske Ursin-o-p-q, Samera Qureshi-r, Huiyan Ma-s, Eunjung Lee-q, Carla H. van Gils-t, Johanna O.P. Wanders-t, Sudhir Vinayak-u, Rose Ndumia-u, Steve Allen-v, Sarah Vinnicombe-w, Sue Moss-x, Jong Won Lee-y, Jisun Kim-y, Ana Pereira-z, Maria Luisa Garmendia-z, Reza Sirous-A, Mehri Sirous-A, Beata Peplonska-B, Agnieszka Bukowska-B, Rulla M. Tamimi-m, Kimberly Bertrand-C, Chisato Nagata-D, Ava Kwong-E, Celine Vachon-F, Christopher Scott-F, Beatriz Perez-Gomez-G, Marina Pollan-G, Gertraud Maskarinec-H, Graham Giles-I-J, John Hopper-J, Jennifer Stone-K, Nadia Rajaram-L, Soo-Hwang Teo-L-M, Shivaani Mariapun-L, Martin J. Yaffe-N, Joachim Schüz-a, Anna M. Chiarelli-O, Linda Linton-P, Norman F. Boyd-P

  • a) Section of Environment and Radiation, International Agency for Research on Cancer, Lyon, France
  • b) Dept of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
  • c) Centre for Medical Image Computing, University College London, UK
  • d) University of the Witwatersrand, South Africa
  • e) Cairo University, Egypt
  • f) Woman Imaging Unit, Radiodiagnosis Department, Kasr El Aini, Cairo University Hospitals, Cairo, Egypt
  • g) Department of Surgery, Yong Loo Lin School of Medicine and Saw Swee Hock School of Public Health, National University of Singapore, Singapore
  • h) NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
  • i) Istanbul University, Turkey
  • j) National Cancer Control Center, Israel
  • k) Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, USA
  • l) Center for Research on Population Health, Instituto Nacional de Salud Pública, Mexico, Mexico City, Mexico
  • m) Channing Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, USA
  • n) Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France o Cancer Registry of Norway, Oslo, Norway
  • p) Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
  • q) Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA
  • r) Norwegian Center for Minority Health Research (NAKMI), Oslo, Norway
  • s) Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, USA
  • t) Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands
  • u) Aga Khan University Hospital, Nairobi, Kenya
  • v) Department of Imaging, Royal Marsden NHS Foundation Trust, London, UK
  • w) Division of Cancer Research, Ninewells Hospital & Medical School, Dundee, UK
  • x) Wolfson Institute of Preventive Medicine, Queen Mary University of London, UK
  • y) Asan Medical Center, Seoul, Republic of Korea
  • z) Institute of Nutrition and Food Technology, University of Chile, Chile
  • A) Isfahan University of Medical Sciences, Isfahan, Iran
  • B) Nofer Institute of Occupational Medicine, Łód z, Poland
  • C) Slone Epidemiology Center, Boston University, Boston, MA, USA
  • D) Gifu University, Gifu, Japan
    E) Division of Breast Surgery, The University of Hong Kong Faculty of Medicine, and Department of Surgery, Hong Kong Sanatorium and Hospital, Hong Kong, Peoples Republic of China
  • F) Dept Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  • G) Cancer Epidemiology Unit, Instituto de Salud Carlos III and CIBERESP, Madrid, Spain
  • H) University of Hawaii Cancer Center, Honolulu, Hawaii, USA
  • I) Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
  • J) School of Population and Global Health, The University of Melbourne, Australia
  • K) Centre for Genetic Origins of Health and Disease, University of Western Australia, Australia
  • L) Breast Cancer Research Group, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
  • M) Cancer Research Malaysia, Subang Jaya, Malaysia
  • N) Medical Biophysics, University of Toronto, Canada
  • O) Ontario Breast Screening Program, Cancer Care Ontario, Toronto, Canada
  • P) Princess Margaret Cancer Centre, Toronto, Canada

2015

Study scope/scale

The International Consortium of Mammographic Density (ICMD) is co-ordinated by the International Agency for Research on Cancer (IARC). In ICMD, we pooled individual-level MD and epidemiologic data from studies of breast cancer-free women worldwide. ICMD includes 11755 women from 27 studies across 22 countries.

Key outtakes

  • “Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk.”
  • “Since Wolfe’s first studies linking mammographic parenchymal patterns to breast cancer (BC) risk in 1976, breast density – typically measured on a mammogram as mammographic density (MD) – is now recognized as one of the strongest risk factors for this malignancy.”
  • “Several observations suggest that MD is on a causal pathway for BC, including that tumours arise within localised areas of dense tissue, MD and BC have a partially shared genetic basis, the effects of several BC risk factors have concordant effects on MD, and some may be mediated through MD.”
  • “The International Consortium of Mammographic Density (ICMD) is co-ordinated by the International Agency for Research on Cancer (IARC).”

Paper

The full paper can be found here: Click here

Mammographic Features and Breast Cancer Risk: Effects With Time, Age, and Menopause Status

Authorship

Mammographic Features and Breast Cancer Risk: Effects With Time, Age, and Menopause Status by Celia Byrne, Catherine Schairer, John Wolfe, Navin Parekh, Martine Salane, Louise A. Brinton, Robert Hoover, Robert Haile of Environmental Epidemiology Branch, Division of Cancer Etiology, National Cancer Institute, Bethesda, MD, the Department of Radiology, Hutzel Hospital, Detroit, MI and Department of Epidemiology. University of California. Los Angeles, School of Public Health.

1995

Study scope/scale

Analysis of detailed information from a large, nested case—control study with 16 years of follow-up. This study used information from both screening and follow-up phases of the Breast Cancer Detection Demonstration Project, a nationwide program that offered annual breast cancer screening for more than 280 000 women from 1973 to 1980.

Key outtakes

  • “The purpose of this study was twofold: 1) to evaluate the associations between mammographic features and other breast cancer risk factors and 2) to assess effects of mammographic features on breast cancer risk by time, age, and menopause status.”
  • “Of the breast cancer risk factors assessed in the participants, high- density mammographic parenchymal patterns, as measured by the proportion of breast area composed of epithelial and stromal tissue, had the greatest impact on breast cancer risk. Of the breast cancers in this study, 28% were attributable to having 50% or greater breast density.”
  • “…consistent twofold to sixfold increased risk of breast cancer associated with various categorizations of patterns of mammographic features.”
  • “Increasing total breast size was not associated with higher breast cancer risk in this study.”
  • “Regardless of the age of the women at the time of the mammographic examination, breast cancer risk rose with increasing percent density. The relative magnitude of this increase, however, was somewhat greater for older women. Mammographic density measured from either premenopausal or postmenopausal mammograms was associated with an increased risk of breast cancer.”
  • “For women with any mammographic density, the breast cancer risk rose twofold. For those women with breast density of 75% or more, the breast cancer risk rose more than fourfold.”
  • “In contrast to these other recognized risk factors (28) in which substantially elevated risks apply to a relatively small segment of the population, a large segment of the population has sufficient mammographic density to place it in categories with markedly elevated risk.”
  • “The implications of the high prevalence of mammographic density to the attributable risk or etiologic fraction are obvious. Assuming that density is involved in a causal manner with breast cancer risk, then in our study the presence of any density was responsible for 46.2% of all breast cancers, breast density of 50% or more accounted for 28.2%, and breast density of 75% or more explained 8.2% of all breast cancers.”
  • “…because the proportion of the breast occupied by mammographic density is one risk factor that may identify a group at high risk for breast cancer, the implications of the findings of this study for intervention, both for screening strategies and prevention trials, should be considered.”
  • ” This study, with information from 16 years of the BCDDP, has demonstrated that an easily measured feature from a screening mammographic examination—the percent breast density— had a greater effect on breast cancer risk than most other breast cancer risk factors and could not be explained by these other factors. In addition, percent breast density was not an artifact of a masking bias and applied to women of all ages. Thus, in efforts either to prevent breast cancers or to detect breast cancers earlier, the impact of the percent breast density on breast cancer risk can no longer be ignored.”

Paper

The full paper can be found here: Click here

Mammographic Densities and Breast Cancer Risk

Authorship

Mammographic Densities and Breast Cancer Risk by N.F. Boyd, G.A. Lockwood, L.J. Martina, J.A. Knight, J.W. Byng, M.J. Yae and D.L. Tritchler of Division of Epidemiology and Statistics, Ontario Cancer Institute, Toronto, Canada, Division of Preventive Oncology, Cancer Care Ontario, Toronto, Canada, Imaging Research, Sunnybrook Health Sciences Centre, Toronto, Canada

1998

Key outtakes

  • “Individuals with extensive areas of radiologically dense breast tissue on the mammogram have been found to have a risk of breast cancer that is four to six times higher than women with little or no density. In this paper, we propose a model for the relation- ship of mammographic densities”
  • “Considerable evidence now indicates that mammographic densities are strongly related to the risk of breast cancer.”
  • “Because mammographic densities are strongly related to risk of breast cancer, factors that cause mammographic density also are likely to contribute to the causes of cancer. The identification of factors that change density may lead to the development of methods for preventing breast cancer.”
  • “We propose that the risk of breast cancer associated with mammographically dense breast tissue is due to the combined effects of two processes: cell proliferation (mitogenesis), and damage to the DNA of dividing cells (mutagenesis).”
  • “An association between the mammographic pattern of the breast and risk of breast cancer was first proposed in 1976 by the late John Wolfe, using a four category classification …”
  • “…at least 15 cohort studies… have since confirmed that Wolfe’s classification of mammographic pattern is associated with variations in risk of breast cancer…”
  • “Definitions of the categories of density compared varied between studies, but all found significantly elevated summary odds ratios between extreme categories of the classification used.”
  • “Odds ratios varied between 2.8 and 6.0 for different observers and types of density, but each of the eight studies contained an odds ratio of at least 4.0.”
  • “Two studies showed persistence of increased risk associated with extensive dense tissue for at least 5 years, and one showed that risk persisted for at least 10 years.”
  • “Risk of hyperplasia was 30 times greater, and risk of atypical hyperplasia and in situ carcinoma was 8 times greater in women with extensive densities compared to those with none.”
  • “The evidence that the tissue responsible for mammographic densities is hormonally responsive comes from the consistent associations found with age, which is at least partly due to the effect of menopause, and from the observed effects of exogenous hormones on the radiology of the breast.”
  • “Mammographic densities consistently are associated with a much greater relative risk of breast cancer than are other risk factors.”
  • “…mammographic densities are associated with a much larger attributable risk of breast cancer than atypical hyperplasia or BRCA1 and BRCA2 mutations. Further, in contrast to other risk factors, mammographic densities can be changed by hormonal or dietary interventions.”
  • “…abundant evidence indicates that mammographic densities are related to risk of breast cancer from middle age onward…”
  • “Several aspects of the association of mammographic densities with breast cancer risk meet criteria for causality and suggest that mammographic densities may be closely related to factors that are important causes of this disease.”

Paper

The full paper can be found here: Click here

Breast Density and Parenchymal Patterns as Markers of Breast Cancer Risk: A Meta-analysis

Authorship

Breast Density and Parenchymal Patterns as Markers of Breast Cancer Risk: A Meta-analysis by Valerie A. McCormack and Isabel dos Santos Silva Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom.

2006 American Association for Cancer Research.

Study scope/scale

A review of 42 articles for the main analysis. The 42 articles represent aggregate data for a total of 14,134 cases and 226,871 non-cases, arising from 17 incidence studies (6,967 cases) and 17 prevalence studies (4,983 cases) in the general population and 9 studies (2,184 cases) in symptomatic (breast cancer) populations (some studies contribute to more than one category).

Key outtakes

  • “This review explains some of the heterogeneity in associations of breast density with breast cancer risk and shows that, in well-conducted studies, this is one of the strongest risk factors for breast cancer.”
  • “Breast density, a measure of the extent of radiodense fibroglandular tissue in the breast, has the potential to be used as a predictor of breast cancer risk, to monitor risk-lowering interventions and as an intermediate end point in studies of breast cancer etiology. More than 40 studies have assessed associations with Wolfe grade or percentage breast density and the majority reported 2-to-6-fold increased risks for the highest compared with the lowest risk categories…”
  • “The combined data presented here confirm that breast density, measured using either Wolfe grade or percentage density, is strongly associated with breast cancer risk…”
  • “The true association may be even stronger, as nondifferential measurement error of breast density would lead to underestimation of associations.”
  • “We found little evidence of interactions between other risk factors for breast cancer and breast density. Importantly, the combined data suggest that breast density measured at both premenopausal and postmenopausal ages is a marker of subsequent breast cancer risk and that there is no clear evidence that the strength of this association differs between these ages.”
  • “The strength of the association of breast density with breast cancer risk is greater than that for most other established breast cancer risk factors, with the exception of age and some genetic factors.”
  • “…there was no threshold level below which density was not associated with risk. Shifting the entire breast density distribution downwards by a few percentage (if possible) might reduce overall breast cancer rates. Breast density may be amenable to change.”
  • “Well-conducted incidence studies suggest that increasing breast density is associated with an increased risk of breast cancer and that the magnitude of this association is 4.64-fold (3.64-5.91) for the most dense (>75%) compared with the least dense category (<5%).”
  • “This marker (breast density) has great potential to be used for research into the etiology and prevention of breast cancer.”

Paper

The full paper can be found here: Click here