Associations between lifestyle, health, and clinical characteristics and circulating oxysterols and cholesterol precursors in women diagnosed with breast cancer: a cross-sectional study.

Despite increasing evidence that cholesterol precursors and oxysterols, oxidized cholesterol metabolites, play a role in numerous pathological processes and diseases including breast cancer, little is known about correlates of these sterols in women with breast cancer. In this study, 2282 women with breast cancer and blood draw post diagnosis were included and cross-sectional associations between circulating levels of 15 sterols/oxysterols and (a) lifestyle, anthropometric, reproductive characteristics, (b) comorbidities and medication use, and (c) breast cancer tumor and treatment characteristics were calculated using generalized linear models. Obesity was strongly associated with circulating levels of 7-dehydrocholesterol (DC) (body mass index ≥ 30 vs. 18.5-24.9 kg/m2: 51.7% difference) and 7-ketocholesterol (KC) (40.0% difference). After adjustment for BMI, comorbidities such as cardiovascular disease were associated with higher levels of 7-DC (26.1% difference) and lower levels of desmosterol (- 16.4% difference). Breast cancer tumor characteristics including hormone receptor status, tumor stage, and endocrine therapy were associated with lanosterol, 24-DHLan, 7b-HC, and THC (e.g., THC; tumor stage IIIa vs. I: 36.9% difference). Weaker associations were observed for lifestyle characteristics and for any of the other oxysterols. The findings of this study suggest that cholesterol precursors are strongly associated with metabolic factors, while oxysterols are associated with breast cancer tumor characteristics, warranting further investigation into the role of cholesterol precursors and oxysterols in women with breast cancer and other populations.

Circulating oxysterols and prognosis among women with a breast cancer diagnosis: results from the MARIE patient cohort.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer in women worldwide, and underlying mechanistic pathways associated with breast cancer-specific and non-breast cancer-related deaths are of importance. Emerging evidence suggests a role of oxysterols, derivates of cholesterol, in multiple chronic diseases including breast cancer and coronary artery diseases. However, associations between oxysterols and survival have been minimally studied in women diagnosed with breast cancer. In this large breast cancer patient cohort, we evaluated associations between a panel of circulating oxysterols and mortality and recurrence outcomes. METHODS: Concentrations of 13 circulating oxysterols representing different pathways of cholesterol metabolism were quantified using liquid-chromatography mass-spectrometry. Associations between baseline levels of oxysterols and cause-specific mortality outcomes and recurrence following a breast cancer diagnosis were assessed in 2282 women from the MARIE study over a median follow-up time of 11 years. We calculated hazard ratios (HR) and 95% confidence intervals (CI) using multivariable Cox proportional hazard models and competing risks models. RESULTS: We observed no associations for circulating oxysterols and breast cancer-specific outcomes. Higher levels of six oxysterols were associated with an increased risk of cardiovascular disease death, including 24S-hydroxycholesterol (alternative bile acid pathway, HRlog2 = 1.73 (1.02, 2.93)), lanosterol (cholesterol biosynthesis pathway, HRlog2 = 1.95 (1.34, 2.83)), 7-ketocholesterol (HRlog2 = 1.26 (1.03, 1.55)), 5α,6α-epoxycholesterol (HRlog2 = 1.34 (1.02-1.77)), and 5a,6ß-dihydroxycholestanol (HRlog2 = 1.34 (1.03, 1.76)). After adjusting for multiple comparisons, none of the associations were statistically significant. CONCLUSION: We provide first evidence on a range of circulating oxysterols and mortality following a breast cancer diagnosis, contributing to a better understanding of associations between different pathways of cholesterol metabolism and prognosis in women with a breast cancer diagnosis. The findings of this study suggest circulating oxysterols may be associated with cardiovascular mortality among women diagnosed with breast cancer. Further studies are needed to evaluate these oxysterols as potential markers of risk for cardiovascular mortality among women with a breast cancer diagnosis as well as their clinical potential.

Endogenous estrogen receptor modulating oxysterols and breast cancer prognosis: Results from the MARIE patient cohort.

BACKGROUND: 27-hydroxycholesterol (HC) and 25-HC were identified as endogenous selective estrogen receptor modulators (SERMs) and estrogen receptor (ER) modulators, respectively. They are hypothesized to play a role in multiple physiologic processes and pathologies, including breast cancer development and progression. METHODS: We evaluated circulating 27-HC and 25-HC, and outcomes following a breast cancer diagnosis in 2282 women from the MARIE study over median follow-up of 11.6 years. 27-HC and 25-HC were quantified by liquid chromatography-mass spectrometry. We calculated hazard ratios (HR) and 95% confidence intervals [CI] using multivariable Cox Proportional Hazards regression. RESULTS: We observed no associations between 27-HC and breast cancer prognosis overall. Associations between 27-HC and survival differed by circulating estradiol concentrations and endocrine therapy, but not by hormone receptor status. Among women with estradiol levels below the median (0.08 nM), 27-HC was associated with higher risk of all-cause mortality (HRlog2 = 1.80 [1.20-2.71]) and breast cancer-specific mortality (HRlog2 = 1.95 [1.14-3.31]). No associations were observed in women with estradiol levels above the median. Higher 25-HC levels were associated with lower risk of recurrence (HRlog2 = 0.87 [0.77-0.98]). CONCLUSION: Associations between 27-HC and breast cancer prognosis varied by circulating estradiol levels and endocrine therapy. Less consistent results were observed for 25-HC.

Association of circulating free and total oxysterols in breast cancer patients.

OBJECTIVES: Oxysterols, a family of oxidized cholesterol derivates, are of increasing interest due to their role in cancer development and progression. Some oxysterols are estrogen receptor modulators and thus of particular interest in breast cancer research. In human studies, two forms of circulating oxysterols are commonly evaluated: "free" (unesterified) and "total" (esterified and unesterified). However, associations between free and total oxysterols are not well established. We addressed this knowledge gap in a pilot study by evaluating correlations between the free and the total form of each of the circulating oxysterols (free vs. total), and pairwise associations within the panel of total oxysterols (total vs. total) and the panel of free oxysterols (free vs. free). METHODS: Concentrations of oxysterols and other non-cholesterol sterols were quantified in blood samples of 27 breast cancer patients from the MARIE breast cancer patient cohort using liquid chromatography mass spectrometry. We used Spearman rank correlations to assess associations. Overall, 12 oxysterols (including 27-hydroxycholesterol (HC), 25-HC, 24S-HC, 7a-HC, 5a6a-epoxycholesterol) and five sterols (including lanosterol and desmosterol) were analyzed. RESULTS: Strong correlations (r≥0.82) were observed for seven circulating free and total oxysterols/sterols. The free and total form of 27-HC (r=0.63), 25-HC (r=0.54), and two more oxysterols were weaker correlated. Correlation patterns in the panel of total oxysterols/sterols and the panel of free oxysterols/sterols were similar. CONCLUSIONS: These findings demonstrate that concentrations of most free and total oxysterols/sterols are strongly correlated. We provide further insight into the interrelationships between oxysterols in breast cancer patients.