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Background Cyclin pathway gene alterations are frequent in urothelial tumors and may co-exist with other important aberrations, leading to therapeutic opportunities. We characterized the landscape of cyclin gene alterations in urothelial and non-urothelial urinary tract (UT) malignancies. Patients and Methods Overall, 6842 urothelial and 897 non-urothelial UT cancers were analyzed (hybrid-capture-based comprehensive genomic profile (Foundation Medicine)). Alteration frequency in cyclin-sensitizing and -resistance genes, and co-occurrence with fibroblast growth factor receptor (FGFR) gene abnormalities were evaluated. Results Cyclin-activating gene alterations were detected in 47.3% of urothelial and 37.9% of non-urothelial UT cancers. Frequency varied by histology and tumor site. CDKN2A and CDKN2B loss were the most frequent alterations in urothelial tumors (present in 38.5% and 30.4% of patients, respectively). Both genes were less frequently altered in adenocarcinomas (15.2% and 8.9%), but commonly altered in squamous cell carcinomas (74.4% and 39%). Tumors of neuroendocrine origin were relatively silent in activating cyclin alterations, but frequently displayed Rb1 alterations (86% and 83.7% of neuroendocrines and small cell carcinomas). Urachal tumors (n = 79) presented a distinct landscape of cyclin alterations relative to other UT cancers, with less frequent alterations overall. FGF/FGFR genes were altered in 34.9% of urothelial (22.1% in FGFR3), and 19.4% of non-urothelial urinary tract tumors (6.8% FGFR3). Cyclin-activating alterations frequently co-occurred with FGF/FGFR alterations but were in general mutually exclusively with cyclin resistance alterations (RB1/CCNE1). Conclusions Cyclin pathway activating alterations are common in urinary tract tumors, but frequency varies with histology and tumors sites. Co-occurrence of cyclin and FGFR pathway alterations may inform therapeutic opportunities.

Chromatin regulation involves four subfamilies composed of ATP-dependent multifunctional protein complexes that remodel the way DNA is packaged. The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex subfamily mediates nucleosome reorganization and hence activation/repression of critical genes. The SWI/SNF complex is composed of the BRG-/BRM-associated factor and Polybromo-associated BAF complexes, which in turn have multiple subunits. Significantly, ~20% of malignancies harbor alterations in >1 of these subunits, making the genes encoding SWI/SNF family members among the most vulnerable to genomic aberrations in cancer. ARID1A is the largest subunit of the SWI/SNF complex and is altered in ~40%–50% of ovarian clear cell cancers and ~15%–30% of cholangiocarcinomas, in addition to a variety of other malignancies. Importantly, outcome was improved after immune checkpoint blockade (ICB) in patients with ARID1A-altered versuss wild-type tumors, and this result was independent of microsatellite instability or tumor mutational burden. Another subunit—PBRM1—is mutated in ~40% of clear cell renal cell carcinomas and ~12% of cholangiocarcinomas; there are contradictory reports regarding ICB responsiveness. Two other SWI/SNF subunits of interest are SMARCA4 and SMARCB1. SMARCA4 loss is the hallmark of small cell carcinoma of the ovary hypercalcemic type (and is found in a variety of other malignancies); SMARCA4 germline alterations lead to rhabdoid tumor predisposition syndrome-2; SMARCB1 germline alterations, rhabdoid tumor predisposition syndrome-1. Remarkable, although anecdotal, responses to ICB have been reported in both SMARCA4-aberrant and SMARCB1-aberrant advanced cancers. This review focuses on the role that SWI/SNF chromatin remodeling subunits play in carcinogenesis, the immune microenvironment, and in immunotherapy responsiveness.

Pancreatic cancer is an almost uniformly lethal malignancy, in large part because is it rarely detected in its early, curable stages. We recently conducted a study to evaluate the use of proteins associated with extracellular vesicles (EVs) isolated using an alternating current electrokinetic (ACE) system for the early detection of pancreatic ductal adenocarcinoma. Because earlier detection of pancreatic cancer greatly improves outcomes, we sought to devise a blood-based test with high specificity for detecting early-stage PDAC based on identification of EV-bound biomarkers. EVs were purified from control or stage I-II pancreatic ductal adenocarcinoma (PDAC) patient plasma using an ACE microelectrode array. Following collection of EVs onto the electrodes, contaminating plasma elements were washed away, and the electric field was turned off to release EVs into buffer. The isolated EV/exosome samples were then tested using bead-based multiplex immunoassay kits to determine relative concentrations of biomarkers of interest. Sample cohorts were divided into a training set (controls, N=146; PDAC cases, N=33) to develop a logistic regression-based classification model, and a validation set (controls, N=139; PDAC cases, N=35) to generate a probability-based score for predicting the presence of PDAC. For the training set, the algorithm identified six protein biomarkers associated with the presence of stages I-II cancer in PDAC patient plasma, with a receiver-operating characteristic (AUC) of 0.997 (95% CI: 0.978-1.000) compared to control plasma samples. For the validation set, the algorithm had a sensitivity of 82.9% (95% CI: 67.3% - 91.9%) at a specificity of 99.3% (95% CI: 96.0% - 99.9%), generating an AUC = 0.978 (95% CI=0.954-0.995). The exosomal PDAC assay shows feasibility for developing minimally invasive liquid biopsies that allow low-risk, routine screening of high-risk patients. Those patients identified by the test would be able to undergo additional testing to determine if there is PDAC present. The additional screening and testing of these patients may increase the likelihood of curative treatment. Further work in large datasets is warranted. Citation Format: Juan P. Hinestrosa, Jean M. Lewis, Heath I. Balcer, Razelle Kurzrock, Scott Lippman, Rajaram Krishnan. Blood-based extracellular vesicle biomarker test for detection of early-stage pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5960.

The heterogeneity and complexity of advanced cancers strongly support the rationale for an enhanced focus on molecular prevention as a priority strategy to reduce the burden of cancer. Molecular prevention encompasses traditional chemopreventive agents as well as vaccinations and therapeutic approaches to cancer-predisposing conditions. Despite challenges to the field, we now have refined insights into cancer etiology and early pathogenesis; successful risk assessment and new risk models; agents with broad preventive efficacy (eg, aspirin) in common chronic diseases, including cancer; and a successful track record of more than 10 agents approved by the US Food and Drug Administration for the treatment of precancerous lesions or cancer risk reduction. The development of molecular preventive agents does not differ significantly from the development of therapies for advanced cancers, yet it has unique challenges and special considerations given that it most often involves healthy or asymptomatic individuals. Agents, biomarkers, cohorts, overall design, and endpoints are key determinants of molecular preventive trials, as with therapeutic trials, although distinctions exist for each within the preventive setting. Progress in the development and evolution of molecular preventive agents has been steadier in some organ systems, such as breast and skin, than in others. In order for molecular prevention to be fully realized as an effective strategy, several challenges to the field must be addressed. Here, the authors provide a brief overview of the context for and special considerations of molecular prevention along with a discussion of the results from major randomized controlled trials.

Patients with Barrett's Esophagus (BE) have an increased risk of developing esophageal adenocarcinoma. Preclinical models of BE and esophageal cancer have demonstrated the antitumor activity of the green-tea derived Polyphenon E (Poly E) and identified potential biomarkers for following its activity in clinical specimens. We conducted a multicenter trial of Poly E in patients with BE with or without low-grade dysplasia. Subjects were randomized to a 6-month, twice daily (BID) treatment of either placebo or Poly E (200 mg, 400 mg, 600 mg dose cohorts). Endoscopic evaluation, including multiple biopsies, was performed at baseline and after treatment. The primary objective of this study was to demonstrate safety (i.e., determine the maximum tolerated dose (MTD). Secondary objectives investigated accumulation of Poly E catechin constituents (e.g., EGCG) in esophageal tissue and biologic effects of Poly E in clinical specimens, including high throughput effects on mucosal protein expression using functional proteomics. Of the 44 randomized subjects, 11 received placebo, and 33 received Poly E (200 mg (6), 400 mg (7), 600 mg (20)). No dose-limiting toxicities were encountered, and the MTD was 600 mg BID. The most common treatment-related adverse events (AEs) reported in Poly E-treated subjects were grade 1-2 nausea (12%), grade 1 burping (6%), and grade 1 elevated serum LDH (6%). No treatment-related AEs were reported in placebo-treated subjects, aside from grade 1 laboratory abnormalities. Pill counts and daily patient diaries were not consistently collected, and compliance was difficult to determine for the majority of subjects. However, based on an intention-to-treat analysis there was a dose-exposure relationship (p=0.01, Spearman correlation test) between the dose of Poly E and EGCG levels in esophageal mucosa – mean changes (pmol/g) with treatment were 1.68 (placebo; n=9), 6.06 (200 mg; n=5), 31.66 (400 mg; n=6), and 30.86 (600 mg, n=10). There was a possible relationship between the dose of Poly E and urine PGEM concentration – mean urine PGEM concentrations (ng/mg creatinine) with treatment were 4.86 (placebo; n=9), 6.78 (200 mg; n=3), 9.02 (400 mg; n=5), and 7.89 (600 mg; n=11); however, this was not statistically significant. Treatment with Poly E or placebo did not reduce the length of Barrett's epithelium and did not lead to any statistically significant changes in mucosal protein expression. However, Poly E treatment may have affected the expression of stearoyl-CoA desaturase (SD1), PI3Kinase-alpha, and acetyl Coenzyme A Carboxylase (ACC); p-values ≥ 0.05, although false discovery rates were 0.93. In conclusion, Poly E was well-tolerated in all dose cohorts, with only grade 1 AEs seen more commonly in Poly E-treated subjects. There were no apparent significant effects of treatment on either tissue histology or mucosal biomarker expression. However, treatment with Poly E (400 mg and 600 mg) but not Poly E (200 mg) or placebo resulted in clinically relevant and detectable EGCG accumulation in the target organ, esophageal mucosa. Clinical development of this compound may include a phase 2 trial of Poly E administered at the 600 mg BID dose for a longer duration. Supported by NCI, DCP Contract N01-CN-035159 to the UT MD Anderson Early Phase Chemoprevention Consortium Citation Format: Andrew K. Joe, Felice Schnoll-Sussman, Robert S. Bresalier, Julian A. Abrams, Hanina H. Hibshoosh, Kenneth Cheung, Richard A. Friedman, Chung S. Yang, Ginger Milne, Diane D. Liu, Kazeem Abdul, Michelle Bigg, Jessica Foreman, Shing Lee, Tao Su, Aqeel Ahmed, Alfred I. Neugut, Esther Akpa, Scott Lippman, Marjorie Perloff, Powel H. Brown, Charles J. Lightdale. Phase Ib randomized, double-blinded, placebo-controlled, dose escalation study of Polyphenon E in patients with Barrett's esophagus. [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 C48.