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Mammographic density: a potential monitoring biomarker for adjuvant and preventative breast cancer endocrine therapies.

ABSTRACT: Increased mammographic density (MD) has been shown beyond doubt to be a marker for increased breast cancer risk, though the underpinning pathobiology is yet to be fully elucidated. Estrogenic activity exerts a strong influence over MD, which consequently has been observed to change predictably in response to tamoxifen anti-estrogen therapy, although results for other selective estrogen receptor modulators and aromatase inhibitors are less consistent. In both primary and secondary prevention settings, tamoxifen-associated MD changes correlate with successful modulation of risk or outcome, particularly among pre-menopausal women; an observation that supports the potential use of MD change as a surrogate marker where short-term MD changes reflect longer-term anti-estrogen efficacy. Here we summarize endocrine therapy-induced MD changes and attendant outcomes and discuss both the need for outcome surrogates in such therapy, as well as make a case for MD as such a monitoring marker. We then discuss the process and steps required to validate and introduce MD into practice as a predictor or surrogate for endocrine therapy efficacy in preventive and adjuvant breast cancer treatment settings.

SUBMITTER: Shawky MS

PROVIDER: S-EPMC5354931 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Mammographic density: a potential monitoring biomarker for adjuvant and preventative breast cancer endocrine therapies.

Shawky Michael S MS Martin Hilary H Hugo Honor J HJ Lloyd Thomas T Britt Kara L KL Redfern Andrew A Thompson Erik W EW

Oncotarget 20170101 3

Increased mammographic density (MD) has been shown beyond doubt to be a marker for increased breast cancer risk, though the underpinning pathobiology is yet to be fully elucidated. Estrogenic activity exerts a strong influence over MD, which consequently has been observed to change predictably in response to tamoxifen anti-estrogen therapy, although results for other selective estrogen receptor modulators and aromatase inhibitors are less consistent. In both primary and secondary prevention sett ...[more]

PMID: 27894075

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Project description:BackgroundHigh mammographic breast density (MBD) is a strong risk factor for breast cancer development, but the biological mechanisms underlying MBD are unclear. Lipids play important roles in cell differentiation, and perturbations in lipid metabolism are implicated in cancer development. Nevertheless, no study has applied untargeted lipidomics to profile the lipidome of MBD. Through this study, our goal is to characterize the lipidome of MBD in premenopausal women.MethodsPremenopausal women were recruited during their annual screening mammogram at the Washington University School of Medicine in St. Louis, MO. Untargeted lipidomic profiling for 982 lipid species was performed at Metabolon (Durham, NC®), and volumetric measures of MBD (volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV)) was assessed using Volpara 1.5 (Volpara Health®). We performed multivariable linear regression models to investigate the associations of lipid species with MBD and calculated the covariate-adjusted least square mean of MBD by quartiles of lipid species. MBD measures were log10 transformed, and lipid species were standardized. Linear coefficients of MBD were back-transformed and considered significant if the Bonferroni corrected p-value was < 0.05.ResultsOf the 705 premenopausal women, 72% were non-Hispanic white, and 23% were non-Hispanic black. Mean age, and BMI were 46 years and 30 kg/m2, respectively. Fifty-six lipid species were significantly associated with VPD (52 inversely and 4 positively). The lipid species with positive associations were phosphatidylcholine (PC)(18:1/18:1), lysophosphatidylcholine (LPC)(18:1), lactosylceramide (LCER)(14:0), and phosphatidylinositol (PI)(18:1/18:1). VPD increased across quartiles of PI(18:1/18:1): (Q1 = 7.5%, Q2 = 7.7%, Q3 = 8.4%, Q4 = 9.4%, Bonferroni p-trend = 0.02). The lipid species that were inversely associated with VPD were mostly from the triacylglycerol (N = 43) and diacylglycerol (N = 7) sub-pathways. Lipid species explained some of the variation in VPD. The inclusion of lipid species increased the adjusted R2 from 0.45, for a model that includes known determinants of VPD, to 0.59.ConclusionsWe report novel lipid species that are associated with MBD in premenopausal women. Studies are needed to validate our results and the translational potential.

Project description:Introduction Mammographic density (MD), as assessed from film screen mammograms, is determined by the relative content of adipose, connective and epithelial tissue in the female breast. In epidemiological studies, a high percentage of MD confers a four to six fold risk elevation of developing breast cancer, even after adjustment for other known breast cancer risk factors. However, the biologic correlates of density are little known. Methods Gene expression analysis using whole genome arrays was performed on breast biopsies from 143 women; 79 women with no malignancy (healthy women) and 64 newly diagnosed breast cancer patients, both included from mammographic centres. Percent MD was determined using a previously validated, computerized method on scanned mammograms. Significance analysis of microarrays (SAM) was performed to identify genes influencing MD and generalized regression models were used to assess the independent contribution from different variables to MD. Results SAM-analysis identified 24 genes differentially expressed between samples from breasts with high and low MD. These genes included three uridine 5'-diphospho-glucuronosyltransferase (UGT) genes and the oestrogen receptor gene (ESR1). These genes were down-regulated in samples with high MD compared to those with low MD. The UGT gene products, which are known to inactivate oestrogen metabolites, were also down-regulated in tumour samples compared to samples from healthy individuals. Several single nucleotide polymorphisms (SNPs) in the UGT genes associated with the expression of UGT and other genes in their vicinity were identified. Conclusions Three UGT enzymes were lower expressed both in breast tissue biopsies from healthy women with high MD and in biopsies from newly diagnosed breast cancers. The association was strongest among young women and women using hormonal therapy. UGT2B10 predicts MD independently of age, hormone therapy and parity. Our results indicate that down-regulation of UGT genes in women exposed to female sex hormones is associated with high MD and might increase the risk of breast cancer.

Dataset Information

Mammographic density: a potential monitoring biomarker for adjuvant and preventative breast cancer endocrine therapies.

Publications

Mammographic density: a potential monitoring biomarker for adjuvant and preventative breast cancer endocrine therapies.

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