Research Article: Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

Date Published: June 30, 2017

Publisher: Public Library of Science

Author(s): Anya Burton, Gertraud Maskarinec, Beatriz Perez-Gomez, Celine Vachon, Hui Miao, Martín Lajous, Ruy López-Ridaura, Megan Rice, Ana Pereira, Maria Luisa Garmendia, Rulla M. Tamimi, Kimberly Bertrand, Ava Kwong, Giske Ursin, Eunjung Lee, Samera A. Qureshi, Huiyan Ma, Sarah Vinnicombe, Sue Moss, Steve Allen, Rose Ndumia, Sudhir Vinayak, Soo-Hwang Teo, Shivaani Mariapun, Farhana Fadzli, Beata Peplonska, Agnieszka Bukowska, Chisato Nagata, Jennifer Stone, John Hopper, Graham Giles, Vahit Ozmen, Mustafa Erkin Aribal, Joachim Schüz, Carla H. Van Gils, Johanna O. P. Wanders, Reza Sirous, Mehri Sirous, John Hipwell, Jisun Kim, Jong Won Lee, Caroline Dickens, Mikael Hartman, Kee-Seng Chia, Christopher Scott, Anna M. Chiarelli, Linda Linton, Marina Pollan, Anath Arzee Flugelman, Dorria Salem, Rasha Kamal, Norman Boyd, Isabel dos-Santos-Silva, Valerie McCormack, Garnet Anderson

Abstract: BackgroundMammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known.Methods and findingsWe examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature.ConclusionsDeclines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.

Partial Text: Mammographic density (MD), a measure of the amount of radiopaque fibroglandular as opposed to fat tissue in the breast, is amongst the strongest of breast cancer risk factors [1–3]. Parallels have been drawn between life-course trajectories of MD and Pike’s model for the rate of breast tissue ageing [1–4]. The latter model hypothesizes that Clemmesen’s hook (the slowing of the rate of increase of age-specific breast cancer incidence rates after menopause, S1 Fig) is due to a reduction in the rate of breast tissue ageing in postmenopausal women [4–6]. MD also declines during the menopausal transition and with ageing; thus, MD may be a tissue-specific marker of the biological processes underlying the rate of breast tissue ageing and, ultimately, the shape of the breast cancer incidence–age curve [2,7,8]. The nature and drivers of the cumulative MD profile thus become of interest to inform which periods in life MD reductions may be best targeted to.

Ethics approvals for ICMD were obtained from the International Agency for Research on Cancer (IEC 12–34). Each individual participating study had received local ethical approval at the time of the original conduct of the study and again to contribute to the consortium.

The 11,423 ICMD women ranged in age from 35 to 85 years at mammography, with at least 500 women in each 5-year age category from 35 to 70 (Table 1). Mean age at mammography was 45.6 (SD 4.9) in premenopausal women and 57.5 years (SD 6.4) in the 59% of women who were postmenopausal. East Asian women had both the smallest mean BMI and the smallest mean breast area for BMI (√breast area 0.2 to 1.2 cm smaller than ICMD average) (S2 Fig), and black women had the largest mean breast area for BMI (√breast area 0.5 to 1.3 cm larger than ICMD average). Crude trends for PD and dense area with age were inverse, held across most population groups, and appeared steeper around age 50 years than at either extreme of the age range studied (Figs 1 and S3).



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