Citations

Abstract Background: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer–metabolite associations using two-sample Mendelian randomization (MR). Methods: The case–control portion of the study was conducted in nine UK centers with men ages 50–69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Results: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. Conclusions: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. Impact: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

Abstract Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Abstract Introduction: Defining the histologic correlates of mammographic breast density (MD) may provide insights into why elevated MD is related to increased breast cancer risk. Studies suggest that reduced terminal ductal lobular (TDLU) involution is associated with elevated MD, and both are independent breast cancer risk factors among women who have undergone a biopsy for benign breast disease (BBD). Prior digital histologic analyses of normal breast tissues revealed epithelial nuclear density (END) and TDLU involution are correlated. Accordingly, we examined associations of END with TDLU involution and MD in clinical biopsies. Methods: We analyzed 262 image-guided breast biopsies diagnosed as BBD from 224 women. TDLU involution was visually assessed as TDLU count/mm2 and TDLU span (inversely related to level of involution) in background normal tissue, evaluated using digitized images. The Genie Classifier (Aperio) was applied to images to estimate nuclei count per unit epithelial area, (END). Single X-ray Absorptiometry of pre-biopsy craniocaudal digital mammograms was applied to measure global MD (percent fibroglandular volume (%FGV)). Analysis of covariance, adjusted for age and body mass index, examined mean END differences across tertiles of TDLU/MD measures. Analyses were conducted at the biopsy level using SAS PROC GENMOD to account for within-woman correlations. All tests were two-tailed. Results: Overall, 67% of BBD biopsies were proliferative. Higher END was observed among proliferative than non-proliferative BBD (median END: 10,187 vs. 9,953 respectively; p=0.04). Among all women, END significantly increased with increasing tertiles of TDLU measures (p-trends: TDLU count/100mm2=0.0001, TDLU span=0.046). Whereas TDLU metrics were positively associated with %FGV, no relationship was observed between END and %FGV. In analyses stratified by BBD severity, however, END and %FGV were positively associated among women with non-proliferative disease (p-trend=0.04), findings not observed with proliferative disease. Conclusions: Automated END and visually assessed TDLU involution metrics were positively associated with each other and with MD. However, associations were diluted for proliferative lesions, suggesting that applying automated digital pathology tools to unsegmented digital images of whole sections of BBD biopsies does not demonstrate the same associations with MD as visual assessment of TDLU involution. Citation Format: Maeve Mullooly, Samantha Puvanesarajah, Shaoqi Fan, Ruth M. Pfeiffer, Linnea Olsson, Manila Hada, Erin L. Kirk, Pamela M. Vacek, Donald L. Weaver, John A. Shepherd, Amir P. Mahmoudzadeh, Jeff Wang, Stephen M. Hewitt, Sally D. Herschorn, Mark E. Sherman, Melissa A. Troester, Gretchen L. Gierach. Utilizing digital pathology to understand breast epithelial characteristics of benign breast disease among women undergoing diagnostic image-guided breast biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3260.

Abstract Fatty Acid Synthase (FASN), the key multienzyme in de novo lipogenesis, is upregulated and activated in numerous carcinomas, including breast cancer. Fatty acids play a fundamental role in cellular structure, energy production and storage and are intermediates in the biosynthesis of hormones and other biologic molecules. Therefore, FASN is a novel therapeutic target for treatment in cancer cells that have upregulated FASN protein. BT474 breast cancer cells, which overexpress FASN, were treated with a pharmacologic FASN inhibitor and resulted in apoptosis in a dose-dependent manner. Inhibition of FASN simultaneously upregulates the pro-apoptotic BCL2 family members Bim, Puma, and Noxa; additionally, FASN inhibition alters the NDAPH/NADP+ balance and induces reactive oxygen species (ROS) production. Most significantly, FASN inhibition induces sensitization of breast cancer cells to the BH3 mimetic navitoclax, a potential opportunity to use BH3 mimetics for the treatment of breast carcinomas. These results support further preclinical and potentially clinical development of a dual FASN and Bcl-2 treatment for breast cancer tumors that express FASN. In addition to apoptosis, there is an increase in cellular senescence in breast cancer cells overexpressing FASN when treated with FASN inhibitors. The increase in ROS, a known effect of FASN inhibition, is known to induce cellular stress, resulting in both apoptosis and senescence. Increased senescence was initially observed by x-gal staining of BT474 cells treated with FASN inhibitors via microscopy and FLOW. We also observed an increased expression of several pro-senescent genes both at the protein and mRNA levels, including p16/INK4a, p14ARF/p19ARF, p15, and p21. A hallmark of age-induced cellular senescence is the shortening of telomeres. However, telomere shortening was not observed, suggesting that senescence was a result of FASN inhibition and activation of senescence-induced genes. Therefore, inhibition of FASN appears to be an ideal target for therapeutic treatment of breast cancers that overexpress FASN through both apoptosis and senescence. Citation Format: Travis Vander Steen, Ruth Lupu. Inhibition of FASN induces apoptosis and senescence in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 318.