Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance.

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50's utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. TP53 gene alterations were more common in nonresponders, although this did not reach statistical significance (P = 0.055). AR gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets-including those linked to low AR transcriptional activity and a stemness program-were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance

A Timeline of Immune Checkpoint Inhibitor Approvals in Small Cell Lung Cancer.

In this commentary, we review the timeline of clinical trials and regulatory actions of approved immune checkpoint inhibitors for small cell lung cancer, discuss challenges faced by regulatory agencies, and highlight paradoxical lessons that emerge. Accelerated approvals may fail to expedite drugs to market in this setting and further research on overall survival benefit is needed to prove drug efficacy

Persistence in breast cancer disparities between African Americans and whites in Wisconsin.

BACKGROUND: Breast cancer (BC) mortality is higher in African American women compared to white women despite having a lower incidence. The reasons for this remain unclear, despite decades of research. Reducing BC health disparities is a priority but has had limited success. OBJECTIVE: To assess progress in eliminating breast cancer-related health disparities in Wisconsin by comparing trends in breast cancer outcomes in African American and white women from 1995 to 2006 and comparing results nationally. METHODS: Age-adjusted breast cancer (BC) incidence and stage data from the Wisconsin Cancer Reporting System and age-adjusted mortality data from National Center of Health Statistics were used to evaluate trends in incidence and mortality from 1995 to 2006 for African Americans and whites. The relative disparity was evaluated by rate ratios. Trends in distribution of in situ vs malignant disease were examined. National trend data were obtained from the National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database. RESULTS: Age-adjusted incidence decreased 10% in Wisconsin compared to 7% nationally. Incidence of BC was lower in African American compared to white women. BC mortality in African American women declined in Wisconsin, but remained higher than white females. Age-adjusted mortality in Wisconsin declined approximately 23%, matching national trends. Non age-adjusted stage data trended toward a decrease in malignant, but increased in situ disease. CONCLUSIONS: Despite an overall reduction in BC mortality from 1995 to 2006, a persistent disparity in mortality remains for African American women, demonstrating no significant progress in reducing BC health disparities

Expression Microarray Meta-Analysis Identifies Genes Associated with Ras/MAPK and Related Pathways in Progression of Muscle-Invasive Bladder Transition Cell Carcinoma

<div><p>The effective detection and management of muscle-invasive bladder Transition Cell Carcinoma (TCC) continues to be an urgent clinical challenge. While some differences of gene expression and function in papillary (Ta), superficial (T1) and muscle-invasive (≥T2) bladder cancers have been investigated, the understanding of mechanisms involved in the progression of bladder tumors remains incomplete. Statistical methods of pathway-enrichment, cluster analysis and text-mining can extract and help interpret functional information about gene expression patterns in large sets of genomic data. The public availability of patient-derived expression microarray data allows open access and analysis of large amounts of clinical data. Using these resources, we investigated gene expression differences associated with tumor progression and muscle-invasive TCC. Gene expression was calculated relative to Ta tumors to assess progression-associated differences, revealing a network of genes related to Ras/MAPK and PI3K signaling pathways with increased expression. Further, we identified genes within this network that are similarly expressed in superficial Ta and T1 stages but altered in muscle-invasive T2 tumors, finding 7 genes (COL3A1, COL5A1, COL11A1, FN1, ErbB3, MAPK10 and CDC25C) whose expression patterns in muscle-invasive tumors are consistent in 5 to 7 independent outside microarray studies. Further, we found increased expression of the fibrillar collagen proteins COL3A1 and COL5A1 in muscle-invasive tumor samples and metastatic T24 cells. Our results suggest that increased expression of genes involved in mitogenic signaling may support the progression of muscle-invasive bladder tumors that generally lack activating mutations in these pathways, while expression changes of fibrillar collagens, fibronectin and specific signaling proteins are associated with muscle-invasive disease. These results identify potential biomarkers and targets for TCC treatments, and provide an integrated systems-level perspective of TCC pathobiology to inform future studies.</p> </div

KEGG pathway enrichment of genes differentially expressed in T2 versus Ta and T1 stage bladder tumors.

(*)<p>indicates KEGG pathways that involve mechanisms of signal transduction. P value represents the results of Fisher's Exact tests reported by WebGestalt.</p

Literature-based associations of selected genes and characteristics associated with advanced or metastatic cancers, identified using Chilibot [11].

*<p>denotes identification of relationships between the terms and gene.</p

KEGG pathway enrichment of genes differentially expressed in T1–T4 staged bladder tumors versus Ta-stage tumors.

(*)<p>indicates KEGG pathways that involve mechanisms of signal transduction. P value represents the results of Fisher's Exact tests reported by WebGestalt.</p

Average normalized median expression of selected genes differentially expressed in non-invasive and muscle-invasive TCC in at least 3 datasets within the Oncomine Collection.

<p>Genes selected based on significance (p<0.05) or near-significance (p<0.10) as determined by one-sided Mann-Whitney Rank-Sum tests. “References” contain the citations of the studies from which data analyzed by Oncomine were derived.</p