Grace L. Chew

Mammographic density—a review on the current understanding of its association with breast cancer

Abstract There has been considerable recent interest in the genetic, biological and epidemiological basis of mammographic density (MD), and the search for causative links between MD and breast cancer (BC) risk. This report will critically review the current literature on MD and summarize the current evidence for its association with BC. Keywords ‘mammographic dens*’, ‘dense mammary tissue’ or ‘percent dens*’ were used to search the existing literature in English on PubMed and Medline. All reports were critically analyzed. The data were assigned to one of the following aspects of MD: general association with BC, its relationship with the breast hormonal milieu, the cellular basis of MD, the generic variations of MD, and its significance in the clinical setting. MD adjusted for age, and BMI is associated with increased risk of BC diagnosis, advanced tumour stage at diagnosis and increased risk of both local recurrence and second primary cancers. The MD measures that predict BC risk have high heritability, and to date several genetic markers associated with BC risk have been found to also be associated with these MD risk predictors. Change in MD could be a predictor of the extent of chemoprevention with tamoxifen. Although the biological and genetic pathways that determine and perhaps modulate MD remain largely unresolved, significant inroads are being made into the understanding of MD, which may lead to benefits in clinical screening, assessment and treatment strategies. This review provides a timely update on the current understanding of MD’s association with BC risk.

Molecular profiling of human mammary gland links breast cancer risk to a p27(+) cell population with progenitor characteristics.

Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44(+) progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44(+)p27(+) cells in parous women and showed, using explant cultures, that parity-related signaling pathways play a role in regulating the number of p27(+) cells and their proliferation. Our results suggest that pathways controlling p27(+) mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention.

High mammographic density in women is associated with protumor inflammation

BackgroundEpidemiological studies have consistently shown that increased mammographic density (MD) is a strong risk factor for breast cancer. We previously observed an elevated number of vimentin+/CD45+ leukocytes in high MD (HMD) epithelium. In the present study, we aimed to investigate the subtypes of immune cell infiltrates in HMD and low MD (LMD) breast tissue.MethodsFifty-four women undergoing prophylactic mastectomy at Peter MacCallum Cancer Centre or St. Vincent’s Hospital were enrolled. Upon completion of mastectomy, HMD and LMD areas were resected under radiological guidance in collaboration with BreastScreen Victoria and were subsequently fixed, processed, and sectioned. Fifteen paired HMD and LMD specimens were further selected according to their fibroglandular characteristics (reasonable amount [> 20%] of tissue per block on H&E stains) for subsequent IHC analysis of immune cell infiltration.ResultsOverall, immune cell infiltrates were predominantly present in breast ducts and lobules rather than in the stroma, with CD68+ macrophages and CD20+ B lymphocytes also surrounding the vasculature. Macrophages, dendritic cells (DCs), B lymphocytes, and programmed cell death protein 1 (PD-1) expression were significantly increased in HMD epithelium compared with LMD. Moreover, significantly higher levels of DCs, CD4+ T cells, and PD-1 were also observed in HMD stroma than in LMD stroma. The increased expression of interleukin (IL)-6 and IL-4, with unaltered interferon-γ, indicate a proinflammatory microenvironment.ConclusionsOur work indicates that the immune system may be activated very early in breast cancer development and may in part underpin the breast cancer risk associated with HMD.

Outcomes for minimally invasive parathyroidectomy: widening inclusion criteria based on preoperative imaging results

Primary hyperparathyroidism is caused by a single adenoma in at least 80% of cases. Minimally invasive parathyroidectomy (MIP) has overtaken bilateral neck exploration as the gold standard for treatment in cases with adequate preoperative localization. There is evidence that, following careful review of preoperative imaging by the surgeon, increasing numbers of patients can successfully undergo MIP.