Citations

AbstractIntroductionThe objective of our study was to investigate cross‐sectional associations of atrial fibrillation with neuroimaging measures of cerebrovascular disease and Alzheimer's disease and their interactions with mild cognitive impairment (MCI).MethodsMagnetic resonance imaging scans of individuals from a population‐based study were analyzed for infarctions, total gray matter, and hippocampal and white matter hyperintensity volumes. A subsample underwent positron emission tomography imaging.ResultsAtrial fibrillation was associated with infarctions and lower total gray matter volume. Compared with subjects with no atrial fibrillation and no infarction, the odds ratio (95% confidence intervals) for MCI was 2.99 (1.57–5.70; P = .001) among participants with atrial fibrillation and infarction, 0.90 (0.45–1.80; P = .77) for atrial fibrillation and no infarction, and 1.50 (0.96–2.34; P = .08) for no atrial fibrillation and any infarction.DiscussionParticipants with both atrial fibrillation and infarction are more likely to have MCI than participants with either infarction or atrial fibrillation alone.

Objectives To determine the association between multiple chronic conditions and risk of incident mild cognitive impairment ( MCI ) and dementia. Design Prospective cohort study. Setting Olmsted County, Minnesota. Participants Cognitively normal individuals (N = 2,176) enrolled in the Mayo Clinic Study of Aging ( MCSA ). Measurements Participants were randomly selected from the community, evaluated by a physician, and underwent neuropsychometric testing at baseline and at 15‐month intervals to assess diagnoses of MCI and dementia. Information on International Classification of Diseases, Ninth Revision codes for chronic conditions in the 5 years before enrollment was electronically captured using the Rochester Epidemiology Project medical records linkage system. Multimorbidity was defined as having two or more chronic conditions, and the association between multimorbidity and MCI and dementia was examined using Cox proportional hazards models. Results Of 2,176 cognitively normal participants (mean age ± standard deviation 78.5 ± 5.2; 50.6% male), 1,884 (86.6%) had multimorbidity. The risk of MCI or dementia was higher in persons with multimorbidity (hazard ratio ( HR ) = 1.38, 95% confidence interval ( CI ) = 1.05–1.82) than in those with one or no chronic condition. The HR was of greater magnitude in persons with four or more conditions ( HR = 1.61, 95% CI = 1.21–2.13) than in those with two or three conditions ( HR = 1.03, 95% CI = 0.76–1.39) and for men with multimorbidity( HR = 1.53, 95% CI = 1.01–2.31) than for women with multimorbidity ( HR = 1.20, 95% CI = 0.83–1.74), compared to those with one or no chronic condition. Conclusion In older adults, having multiple chronic conditions is associated with greater risk of MCI and dementia. This is consistent with the hypothesis that multiple etiologies may contribute to MCI and late‐life dementia. Preventing chronic diseases may be beneficial in delaying or preventing MCI and dementia.

Abstract Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). Results: We observed no significant association between genetic variants and prostate cancer survival. Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study. Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes. Cancer Epidemiol Biomarkers Prev; 24(11); 1796–800. ©2015 AACR.

Abstract About 25% of breast carcinomas are characterized by over-expression and/or amplification of the HER2 receptor, one of four members of the HER family of receptor tyrosine kinases. The strong correlation between HER2 levels/activity with more aggressive breast cancer disease, poor prognosis as well as resistance to chemo- and endocrine therapies made it a preferred target for anti-cancer therapy. However, current treatment strategies are only partially effective and the majority of breast cancer patients who initially respond favorably rapidly develop resistance to treatments for still not fully understood reasons. Thus, novel strategies/agents are in need. Structural analyses revealed that sub-domain III in the extracellular domain (ECD) of the HER family members is responsible for dimerization. We hypothesized that disrupting the dimerization loop in the HER2-ECD sub-domain III would ultimately convert HER2 to a non-functional receptor with diminished transforming capacity. To this end, we generated a series of HER2-ECD deletion mutants located in sub-domain III and assessed their oncogenic potential compared to the HER2-wild type (WT) after their expression in MCF10A cells. Importantly, a small deletion (16 amino acids) of the HER2 extracellular domain (named HER2Δ6) abolished its homo- and hetero-dimerization and profoundly affected HER2-catalyzed activation of the HER network. Moreover, this mutant was not able to transform MCF10 cells as it failed to promote anchorage-independent growth and interfered with the activation/Tyr phosphorylation of HER1, HER2 and HER3. Compared to HER2-WT-expressing cells, the HER2α6 mutant proved to be even more effective in inhibiting the oncogenic properties of the receptor than the current drugs of choice such as Trastuzumab and Pertuzumab alone or in combination. In addition, while expression of HER2-WT conferred resistance of MCF10A cells to Paclitaxel, the HER2Δ6 variant failed to do so. To determine the molecular mechanisms underlying this behavior, we assessed the mutant and WT expressing cells lines morphologically and biochemically and demonstrated that the HER2Δ6 is absent from the plasma membrane (PM) in MCF10A cells. Interestingly, we found that the mutant receptor displayed an intracellular trafficking defect and was trapped in the endoplasmic reticulum (ER). Our results reveal that the HER2-ECD bears an essential “activating” region that is indispensable for HER2-mediated oncogenic transformation. Targeting and eliminating this “activating” element in HER2 seems to provide a strong innovative approach for developing a valuable novel anti-HER2 therapeutic drug that would specifically benefit patients with HER2 positive tumors resistant to current therapies. Citation Format: Barbara Schroeder, Ghiara Lugo, Javier Menendez, Ingrid Espinoza, Ruth Lupu. Identification of a key region in the HER2 subdomain III required for transformation capability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 133. doi:10.1158/1538-7445.AM2015-133

Abstract Purpose: Breast biopsies with benign findings (benign breast disease [BBD]) outnumber biopsies revealing in-situ or invasive cancer 4:1, providing an opportunity to identify histopathological features that predict breast cancer risk. Greater degrees of involution of terminal duct lobular units (TDLUs), the structures within the breast that produce milk and the primary source of breast cancer precursors, have been inversely associated with breast cancer risk among women with BBD. We recently developed measures to quantitate levels of TDLU involution, which demonstrate high inter/intra pathologist reproducibility. Here we assessed whether TDLU counts/100mm2 and median TDLU span (microns), two measures inversely related to degree of TDLU involution, are associated with subsequent breast cancer risk among women with BBD. Methods: From the Mayo BBD cohort (n = 9,376), we evaluated benign biopsies from 99 women who later developed breast cancer (cases) and 145 age-matched controls who did not develop breast cancer. Digitized images of biopsy sections were reviewed to enumerate TDLUs/mm2 and measure median TDLU span (microns) for up to ten normal TDLUs. Breast cancer risk factors were available from questionnaires or medical records. To assess associations with breast cancer risk, subjects were categorized into quartile levels of TDLU counts and median TDLU spans, based on data from controls. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using multivariable conditional logistic regression models, adjusted for histologic type of BBD, family history of breast cancer and menopausal hormone use. Results: Compared to controls, women who developed breast cancer had higher median number of TDLU counts/100mm2 (28 vs 20, p = 0.03) and larger TDLU spans (300 vs 267 microns, p = 0.14). In multivariable models higher TDLU counts (quartile4 vs. quartile1, OR = 2.44, 95%CI = 0.96-6.19, ptrend = 0.02) and larger TDLU span measures (quartile4 vs. quartile1, OR = 2.83, 95%CI = 1.13-7.06, ptrend = 0.03) were associated with subsequent diagnosis of breast cancer. Combinatorial metrics of TDLU counts with median TDLU span measures identified women at higher risk; specifically, women above the median for both TDLU span and TDLU counts had an OR = 3.75 (95%CI = 1.40-10.00, ptrend = 0.008), compared with women below the median for TDLU span and TDLU counts. Conclusion: These data show that lack of TDLU involution, as measured by increased persistence of TDLU counts, larger median TDLU spans and cross-classification using these measures was associated with increased breast cancer risk among women with BBD, extending prior work in this cohort based on other TDLU involution metrics. Future studies to identify determinants of TDLU involution, its association with breast cancer risk and its potential as an intermediate endpoint in prevention studies warrant consideration. Citation Format: Jonine D. Figueroa, Ruth Pfeiffer, Maya Palakal, Amy C. Degnim, Derek Radisky, Lynn C. Hartmann, Marlene Frost, Melody L. Stallings Mann, Louise A. Brinton, Daphne Papathomas, Daniel Visscher, Mark E. Sherman. Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4682. doi:10.1158/1538-7445.AM2015-4682

Abstract Introduction: Increased levels of circulating estrogens are associated with elevated risks of postmenopausal breast cancer. Previously, we showed that levels of sex steroid hormones in breast adipose tissue are positively correlated with circulating hormones. Further evaluation of hormone levels in breast tissues may help to explain the relationship between estrogens and breast cancer risk. Specifically, data suggest that focal breast lesions consisting of macrophages encircling dying adipocytes, referred to as “crown-like structures (CLS)”, are associated with increased aromatase activity, which could increase conversion of androgens to estrogens locally in the breast. Therefore, we assessed whether the presence of CLS affects the correlations between blood and breast adipose tissue hormone levels. Methods: Participants included 84 postmenopausal women with invasive breast cancer in the Polish Breast Cancer Study, a population based case-control study conducted from 2000 to 2003. We previously reported sex steroid hormone levels in cancer-free breast adipose tissue removed as part of breast excisions performed for cancer. Here, using immunohistochemical stains, we evaluated the number of CD68 positive macrophages and the presence of full CLS (i.e., complete adipocyte encirclement) in benign breast tissue sections prepared from surgical pathology specimens containing breast cancer. The relationship between the number of CD68 positive macrophages per unit area of fat and hormone levels was examined using Spearman rank correlations (rs). We assessed potential effect modification of the association between blood and tissue hormone levels by presence or absence of CLS by including an interaction term in linear regression models. Results: The number of CD68 positive macrophages per unit area of fat was not significantly correlated with levels of estrone, estradiol, androstenedione or testosterone measured in blood (rs = 0.001, -0.04, -0.07, and -0.09, respectively; p>0.05) or breast adipose tissue (rs = -0.15, 0.06, -0.06, and -0.08, respectively; p>0.05). Correlations between serum and adipose tissue hormones did not statistically significantly differ between women with CLS (n = 30) compared to those without CLS (n = 54). CLS were found more frequently in breast adipose tissue from overweight (i.e., women with a body mass index (BMI) between 25 and 29.9) (43%) and obese women (BMI >30) (30%) versus normal weight women, with (BMI between 18.5 and 24.9), (27%); (p = 0.04, χ2 test). The number of CD68 positive macrophages per unit area of fat was not significantly related to BMI (p = 0.31). Conclusion: Among postmenopausal women with invasive breast cancer, the presence of CLS was more common among overweight and obese women, but CLS did not influence the correlation between circulating and breast adipose tissue sex steroid hormone levels. Citation Format: Maeve Mullooly, Hannah P. Yang, Roni T. Falk, Sarah Nyante, Renata Cora, Ruth M. Pfeiffer, Derek C. Radisky, Daniel W. Visscher, Lynn C. Hartmann, Amy C. Degnim, Frank Z. Stanczyk, Jonine F. Figueroa, Montserrat Garcia-Closas, Jolanta Lissowska, Melissa T. Troester, Louise A. Brinton, Mark E. Sherman, Gretchen L. Gierach. Investigation of the relationship between crown-like structures and adipose tissue hormone levels among postmenopausal women with breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2767. doi:10.1158/1538-7445.AM2015-2767