Citations

Abstract Introduction: Atypical hyperplasia (also known as proliferative disease with atypia), while categorized as a benign finding, has been consistently associated with an increased risk of subsequent breast cancer that persists for decades after initial diagnosis. There are various other lesions that are classified as benign breast disease (BBD) that are routinely identified by pathologists that may also increase risk and be of use to inform breast cancer risk models. We sought to identify which BBD lesions were associated with increased risk of breast cancer in an African American (AA) cohort. Methods: Benign breast biopsies from 3,895 AA women diagnosed with BBD between 1997 and 2010 in metropolitan Detroit were reviewed for 12 benign features including columnar alterations, ductal ectasia, ductal hyperplasia, fibrosis, apocrine metaplasia, lobular hyperplasia, calcifications, cysts, intraductal papilloma, radial scar, sclerosing adenosis, and fibroadenomas. Women were followed for subsequent breast cancer using the Metropolitan Detroit Cancer Surveillance System, part of the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Associations between BBD features and subsequent breast cancer were examined using chi-square tests. Features that had a significant chi-square test result were also combined into scores describing the overall number of BBD features identified, termed busy breast score. Multivariable log-binomial regression with backward selection based on BIC criteria was performed to assess risk ratio and 95% confidence intervals of breast cancer on 12 candidate features. Multivariable log-binomial regression was performed for busy breast score as well. All regression models were adjusted for age at biopsy and overall impression for presence of proliferative disease with or without atypia using non-proliferative disease as the reference. Models were checked for multicollinearity using a variable inflation factor (VIF). Results: Of the 3,895 AA women in the BBD cohort, 210 developed a subsequent breast cancer. The median age at biopsy among those without a subsequent cancer (controls) was 47 years of age, while cases were 53 years of age (p-value<0.001). In univariate analyses, ductal hyperplasia (p-value=0.001), lobular hyperplasia (p-value<0.001), calcifications (p-value<0.004), cysts (p-value=0.003), intra-ductal papilloma (p-value=0.005), sclerosing adenosis (p-value=0.002), columnar alterations (p-value<0.001) and radial scar (p-value=0.001) were associated with subsequent breast cancer. Fibroadenomas were inversely associated with subsequent breast cancer (p-value<0.001). In multivariable model after backwards selection, presence of columnar alterations was associated with increased risk of breast cancer, (RR=1.57, 95% CI: 1.16, 2.13). Combining the 9 BBD features associated with subsequent breast cancer in univariate analysis, those with a busy breast score of 5+ was associated with 2.5 times increased risk compared to those with none of these features (RR=2.52, 95% CI: 1.41, 4.49). As a continuous variable for busy breast score, each additional feature conferred a 20% increase in risk of breast cancer (RR=1.20, 95% CI: 1.10, 1.31). Conclusions: Columnar alterations confer increased risk of breast cancer beyond the risks associated with atypical hyperplasia, as does the presence of multiple types of BBD lesions in a single biopsy. These estimates may help improve the current risk assessment models for African American women and highlight the need for additional research regarding the utility of closer surveillance and potentially chemoprevention for reduction of breast cancer in these women. Citation Format: Michele L. Cote, Wei Chen, Julie J. Ruterbusch, Eman Abdulfatah, Visakha Pardeshi, Asra N. Shaik, Marcel T. Ghanim, MHD Fayez Daaboul, Daniel W. Visscher, Sudeshna Bandyopadhyay, Rouba Ali-Fehmi. Benign breast disease and subsequent breast cancer risk: The Detroit cohort. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A25.

Abstract Introduction: The majority of the 1.6 million breast biopsies performed annually in the United States are benign; however, several breast cancer risk models consider a benign biopsy a factor that increases risk of subsequent breast cancer. Fibroadenomas (FA), benign tumors of epithelial and stromal tissue, occur frequently in premenopausal women and more frequently in African American (AA) women than European American (EA) women. A small increased risk of subsequent breast cancer due to FA has been reported in some studies of EA women. We sought to investigate whether the risk of this lesion differs for AA women. Methods: Benign breast biopsies from 3895 AA women diagnosed between 1997 and 2010 in metropolitan Detroit were reviewed for 12 benign features including FA, ductal ectasia, fibrosis, apocrine metaplasia, ductal hyperplasia, lobular hyperplasia, calcifications, cysts, intraductal papilloma, radial scar, sclerosing adenosis, and columnar alterations. These features were also used to categorize FA into simple and complex FA, where complex FA occurs when FA is accompanied by at least one of the following features: cysts, calcifications, apocrine metaplasia or intraductal papilloma. Women were followed for subsequent breast cancer using the Detroit Surveillance, Epidemiology, and End Results (SEER) cancer registry. Associations between FA and other benign lesions were examined using chi-square tests. Risk of breast cancer was estimated by relative risk ratios and 95% confidence intervals calculated using logistic regression. All models were adjusted for age at biopsy and additionally adjusted for presence of proliferative disease with or without atypia. Results: Of the 3895 AA women, 46.5% presented with FA on biopsy. FA occurred more frequently in biopsies of younger women (p-value < 0.001) and were less likely to include the other benign lesions assessed (all p-value < 0.001). Of the 210 identified breast cancers that developed in this cohort, 72 cancers developed in women with FA on biopsy. FA were associated with a reduction in risk of breast cancer after adjusting for age at biopsy (RR=0.64, 95% CI: 0.48, 0.86) compared to women without FA on biopsy. Reduction in risk was somewhat attenuated when analysis was adjusted for proliferative disease with or without atypia (RR = 0.67, 95%CI: 0.48, 0.936). Similar associations were seen with simple FA (RR =0.61, 95% CI: 0.35, 1.01) and complex FA (RR =0.70, 95% 0.35, 1.01) after adjustment for age at biopsy and proliferative disease with or without atypia. Conclusions: FA are negatively associated with other benign breast disease features. Risk of breast cancer may be reduced in women with FA compared to women with other types of benign lesions. These findings have important implications for modeling breast cancer risk particularly among AA women for whom FAs are common. Citation Format: Asra N. Shaik, Julie J. Ruterbusch, Eman Abdulfatah, Marcel T. Ghanim, MHD Fayez Daaboul, Visakha Pardeshi, Rouba Ali-Fehmi, Daniel W. Visscher, Sudeshna Bandyopadhyay, Michele L. Cote. Fibroadenomas on benign breast biopsy and subsequent breast cancer risk in an African American cohort. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A16.

Abstract Background: MicroRNAs (miRNA) are small, noncoding RNAs with important regulatory roles in tissue development, differentiation, proliferation, and when deregulated tumor formation. The goal of this study was to characterize the miRNA profile of normal breast tissue from carriers of either BRCA1 or BRCA2 mutations, with and without a prior history of cancer, for biomarker discovery for future prevention studies in high risk patient populations. Methods: MicroRNA profiling was conducted using a panel of breast candidate miRNAs and normal ‘non-cancerous’ tissue biopsy from 15 BRCA1 mutation carriers, 15 BRCA2 mutation carriers and 15 BRCA screened mutation negative subjects from high risk families. Results: While small differences were observed for any individual miRNA between groups, the most striking observation was the presence of a clear BRCA1 miRNA signature that was distinct from that in BRCA2 subjects or in the high-risk, non-mutation carriers. The BRCA1 pattern was present in normal appearing tissue biopsy independent of previous history of cancer, treatment for cancer, age, menopausal status or oophorectomy. BRCA2 carriers and high risk, mutation negative subjects showed an overall shared miRNA expression pattern. MicroRNA species that distinguished the groups included differences in the expressed levels of let-7a, let-7b, miR-125b, miR-145, miR-15b and members of the miR-181 family. Ongoing efforts include pathway modeling to gain insight on novel targets for prevention along with RT-PCR confirmation of differentiating microRNA species as well the potential downstream targets for example of miR-181b target genes including HOXA7, HOXA9, HOXA11 and PBX3. Conclusion: The presence of a distinctive miRNA profile in normal appearing tissue of BRCA1 mutation carriers suggest a major role of BRCA1 mutation status on the normal tissue not previously reported. If corroborated, miRNA profiling studies of normal breast tissue may prove useful in both risk assessment as well as providing insight on deregulated pathways for pharmacologic intervention for risk reduction in the BRCA carrier population. Citation Format: Sandhya Pruthi, Julie Buckmeier, Christina Preese, Vera J. Suman, Rachel M. Hurley, Patricia Thompson. microRNA expression profiling in normal breast epithelium of BRCA1 and BRCA2 carriers as prevention targets. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C47.

ObjectiveThe purpose of this article was to provide a combined pathologic and radiologic review of previous pathologically diagnosed facial nerve “hemangiomas” to confirm that these lesions are most characteristic of venous malformations rather than neoplasms.Study DesignRetrospective radiologic, clinical, and histopathologic review of all patients with a previous pathologically diagnosed facial nerve hemangioma of the temporal bone who underwent computed tomography or magnetic resonance imaging (MRI) were included. A consensus radiologic review for characteristic features and pathologic analysis was performed.Materials and MethodsA panel of 4 neuroradiologists retrospectively analyzed CT and MRI exams for 11 facial nerve hemangiomas and provided a consensus agreement on the characteristic imaging features. Concurrently, two neuropathologists reevaluated archived tissue specimens from these lesions and applied additional immunohistochemical and histochemical stains including D240, CD31, smooth muscle actin (SMA), Verhoeff Van Gieson (VVG) and glucose transporter 1 (GLUT1).ResultsLesions were composed of dilated vascular spaces with a simple, CD31‐positive endothelial lining and a smooth muscle component. All lesions were negative for markers found in arterial and lymphatic malformations and infantile hemangiomas. They had characteristic radiologic features previously ascribed to facial nerve hemangiomas. Namely, these lesions are typically T1 isointense or hypointense and T2 hyperintense relative to cerebral cortex and heterogeneously enhance on MRI. Bony canal expansion and erosion, intralesional calcification, and intracranial extension are common.ConclusionsOn the basis of this radiologic and pathologic review, these lesions are best characterized as venous malformations.Level of Evidence4

The catechol-O-methyltransferase Val158Met polymorphism has been associated with alterations in pain perception, but the influence of the polymorphism on pain perception in patients with chronic pain receiving daily opioid therapy has not been previously reported. The primary aim of this study was to investigate the effects of the catechol-O-methyltransferase Val158Met polymorphism on heat pain perception in a cohort of adults receiving daily opioid therapy for chronic pain. Adults with chronic pain consecutively admitted to an outpatient pain rehabilitation program who met inclusion criteria and were receiving daily opioid therapy were recruited for study participation (N = 142). Individuals were genotyped for catechol-O-methyltransferase Val158Met (rs4680), and the polymorphism was analyzed using an additive and codominant genotype models. The distribution of the Val158Met genotypes was 25% for Val/Val, 41% for Val/Met and 34% for Met/Met (Hardy–Weinberg, P > 0.05). A main effect of genotype was observed for heat pain perception ( P = 0.028). Under the codominant model of allele effects, exploratory post hoc pairwise comparisons adjusted for morphine equivalent dose and pain catastrophizing demonstrated that individuals with the Val/Met genotype were hyperalgesic compared to individuals with the Val/Val ( P = 0.039) and Met/Met ( P = 0.023) genotypes. No significant association was observed between heat pain perception and genotype under the additive model of allele effects. Among patients with chronic pain who were receiving daily opioids, the Val/Met genotype was associated with hyperalgesia using a measure of heat pain perception that has been previously indicative of opioid-induced hyperalgesia in other heterogeneous samples of adults with chronic pain. This study contributes to the emerging understanding of how catechol-O-methyltransferase activity affects pain perception in the context of daily opioid use, and these findings may be useful in the design of future trials aimed at investigating the potential efficacy of ß-2 adrenergic receptor antagonism for opioid-induced hyperalgesia.

European Americans (EA) have a better antihypertensive response to β‐blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post–metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses‐2 (PEAR‐2) study and tested for replication in the atenolol‐treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β‐blockers in the PEAR‐2 study (P = 3.41 × 10−6, β = −2.70) and replicated (P = 0.01, β = −1.17) in the PEAR study. Post–meta‐analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β‐blockers (P = 3.43 × 10−6, β = 4.57) and was replicated in the atenolol add‐on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β‐blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β‐blockers.