https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(08)60269-X.pdf

Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies

Cells within tissues are continuously exposed to physical forces including hydrostatic pressure, shear stress, and compression and tension forces. Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. They also sense these forces through mechanoreceptors and respond by exerting reciprocal actomyosin- and cytoskeletal-dependent cell-generated force by a process termed 'mechanoreciprocity'. Loss of mechanoreciprocity has been shown to promote the progression of disease, including cancer. Moreover, the mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk. Thus, the changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.

/pdf/a-tense-situation-forcing-tumour-progression-4myf9i89al.pdf

A Tense Situation: Forcing Tumour Progression

Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood. To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen. Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (p < 0.00001) and results in a significantly more invasive phenotype with approximately three times more lung metastasis (p < 0.05). Furthermore, the increased invasive phenotype of tumor cells that arose within collagen-dense mammary tissues remains after tumor explants are cultured within reconstituted three-dimensional collagen gels. To better understand this behavior we imaged live tumors using nonlinear optical imaging approaches to demonstrate that local invasion is facilitated by stromal collagen re-organization and that this behavior is significantly increased in collagen-dense tissues. In addition, using multiphoton fluorescence and spectral lifetime imaging we identify a metabolic signature for flavin adenine dinucleotide, with increased fluorescent intensity and lifetime, in invading metastatic cells. This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.

/pdf/collagen-density-promotes-mammary-tumor-initiation-and-3cbt6f92sy.pdf

Collagen density promotes mammary tumor initiation and progression

Obesity is a risk factor for the development of new cases of breast cancer and also affects survival in women who have already been diagnosed with breast cancer. Early studies of obesity and breast cancer survival have been summarised in two meta-analyses, but the latest of these only included studies that recruited women diagnosed as recently as 1991. The primary aim of this study was to conduct a meta-analysis that included the more recent studies. A systematic search of MEDLINE, EMBASE and CINAHL was conducted to identify original data evaluating the effects of obesity on survival in newly diagnosed breast cancer patients. Adjusted hazard ratios (HR) from individual studies were pooled using a random effects model. A series of pre-specified sensitivity analyses were conducted on factors such as overall versus breast cancer survival and treatment versus observational cohort. The meta-analysis included 43 studies that enrolled women diagnosed with breast cancer between 1963 and 2005. Sample size ranged from 100 to 424168 (median 1192). The meta-analysis showed poorer survival among obese compared with non-obese women with breast cancer, which was similar for overall (HR = 1.33; 95% confidence interval (CI): 1.21, 1.47) and breast cancer specific survival (HR = 1.33; 95% CI: 1.19, 1.50). The survival differential varied only slightly, depending on whether body mass index (1.33; 1.21, 1.47) or waist-hip ratio (1.31; 1.08, 1.58) was used as the measure of obesity. There were larger differences by whether the woman was pre-menopausal (1.47) or post-menopausal (1.22); whether the cohort included women diagnosed before (1.31) or after 1995 (1.49); or whether the women were in a treatment (1.22) or observational cohort (1.36), but none of the differences were statistically significant. Women with breast cancer, who are obese, have poorer survival than women with breast cancer, who are not obese. However, no study has elucidated the causal mechanism and there is currently no evidence that weight loss after diagnosis improves survival. Consequently, there is currently no reason to place the additional burden of weight loss on women already burdened with a diagnosis of cancer. Further research should concentrate on assessing whether factors such as diabetes or type of chemotherapy modify the obesity effect and on understanding the causal mechanism, in particular the role of relative under-dosing.

https://espace.library.uq.edu.au/view/UQ:217734/UQ217734.pdf

Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis

Overweight and obesity have become a major public health problem in both developing and developed countries as they are causally related to a wide spectrum of chronic diseases including type II diabetes, cardiovascular diseases and cancer. However, uncertainty regarding the most appropriate means by which to define excess body weight remains. Traditionally, body mass index (BMI) has been the most widely used method by which to determine the prevalence of overweight in, and across, populations as well as an individual's level of risk. However, in recent years, measures of central obesity, principally waist circumference and the waist:hip ratio and to a lesser extent the waist:height ratio, which more accurately describe the distribution of body fat compared with BMI, have been suggested to be more closely associated with subsequent morbidity and mortality. There is also uncertainty about how these measures perform across diverse ethnic groups; earlier, most of the evidence regarding the relationships between excess weight and risk has been derived chiefly from Caucasian populations, and hence, it remains unclear whether the relationships are consistent in non-Caucasian populations. The purpose of this review, therefore, is to provide an overview of the current evidence-base focusing predominantly on three main questions: (1) Which, if any, of the commonly used anthropometric measures to define excess weight is more strongly associated with cardiovascular risk? (2) Which of the anthropometric measures is a better discriminator of risk? and (3) Are there any notable differences in the strength and nature of these associations across diverse ethnic groups?

Body mass index, waist circumference and waist:hip ratio as predictors of cardiovascular risk—a review of the literature

Background: We have examined the relationships between the measured properties of breast tissue and mammographic density and other risk factors for breast cancer, using breast tissue obtained at forensic autopsy and not selected for the presence of abnormalities.

Methods: We used randomly selected tissue blocks taken from breast tissue slices obtained by s.c. mastectomy at the time of forensic autopsy to measure histologic features using quantitative microscopy. The proportions of the biopsy occupied by cells (estimated by nuclear area), glandular structures, and collagen were determined. These measurements were examined in relation to the percent density in the faxitron image of the tissue slice from which the biopsy was taken and other risk factors for breast cancer.

Results: The percent mammographic density was associated with the proportion of the area of the biopsy occupied by nuclei, both epithelial and nonepithelial, and by collagen and the area of glandular structures. Several other risk factors for breast cancer, notably body weight, parity, and number of births, and menopausal status, that are associated with variations in mammographic density, were also associated with differences in one or more of these tissue features.

Conclusion: All risk factors for breast cancer must ultimately exert their influence by an effect on the breast, and these findings suggest that, for some risk factors, this influence includes an effect on the number of cells and the quantity of collagen.

https://cebp.aacrjournals.org/content/cebp/14/2/343.full.pdf

The Association of Measured Breast Tissue Characteristics with Mammographic Density and Other Risk Factors for Breast Cancer

Epidemiological studies have identified body weight as a risk factor for breast cancer. Beyond the amount of adipose tissue a woman has, its distribution, particularly abdominally, may be a risk factor in breast cancer etiology. Body fat distribution is commonly measured by a waist-to-hip circumference ratio (WHR). We performed a meta-analysis to summarize the published literature on WHR and breast cancer risk. After assembling all published studies, we extracted mean WHRs for study participants and adjusted risk estimates comparing highest with lowest partition of WHR and calculated weighted mean differences in WHR between cases and noncases and summary risk estimates based on study design and menopausal status. The weighted mean difference was 0.016 [95% confidence interval (CI) = 0.005-0.028] for all studies combined. The summary risk estimates were 1.80 (95% CI = 1.29-2.50) for case-control studies and 1.27 (95% CI = 1.07-1.51) for cohort studies. By menopausal status, the summary risks were...

A meta-analysis of published literature on waist-to-hip ratio and risk of breast cancer.

Background: Mammographic density has been found to be a strong risk factor for breast cancer and to be associated with age, body weight, parity, and menopausal status. Most studies to date have been carried out in Western populations. The purpose of the study described here was to determine in a cross-sectional study in a Singaporean Chinese population the demographic, menstrual, reproductive, and anthropometric factors that are associated with quantitative variations in age-adjusted percentage mammographic densities and to examine the association of these factors with the dense and nondense areas of the mammogram.

Method: We used mammograms and questionnaire data collected from subjects in the Singapore Breast Screening Project. Women ages 45 to 69 years participated and 84% of those screened were Chinese. Mammograms were digitized and percentage density was measured and analyzed in relation to the questionnaire data.

Results: Percentage mammographic density was associated with several risk factors for breast cancer, most of them also associated, in opposite directions, with the dense and nondense components of the image. Percentage density was associated with age and weight (both negatively), height and age at first birth (both positively), and number of births and postmenopausal status (both negatively). Percentage density was weakly associated with a previous breast biopsy but was not associated with age at menarche or menopause, with use of hormones, or with a family history of breast cancer.

Conclusion: Percentage mammographic density in Singaporean Chinese women has similar associations with risk factors for breast cancer to those seen in Caucasians.

/pdf/risk-factors-for-breast-cancer-associated-with-mammographic-2frde70py3.pdf

Risk Factors for Breast Cancer Associated with Mammographic Features in Singaporean Chinese Women

This study aims at understanding mammographic density profile in China by comparing the density between women in China and Australia.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/ajco.13763

Understanding mammographic breast density profile in China: A Sino‐Australian comparative study of breast density using real‐world data from cancer screening programs

We have developed a method to perform quantitative volumetric analysis of mammographic density (VBD) from digitized screen-film mammograms. The method is being tested on two different ethnic groups of women aged 50 years or older, having greatly different risks of breast cancer. The average VBD in the lower risk group of women was found to be significantly lower than that in the higher risk group. The average entrance exposure (mR) for the lower risk group was also found to be much lower, despite similar average compressed breast thickness obtained for the two groups of women.

Tong Li

Papers

The Association of Measured Breast Tissue Characteristics with Mammographic Density and Other Risk Factors for Breast Cancer

A meta-analysis of published literature on waist-to-hip ratio and risk of breast cancer.

Risk Factors for Breast Cancer Associated with Mammographic Features in Singaporean Chinese Women

Understanding mammographic breast density profile in China: A Sino‐Australian comparative study of breast density using real‐world data from cancer screening programs

Volumetric Breast Density Estimation on Digitized Mammograms — A Preliminary Clinical Study