Correlative Analysis of ATM, RB1, ERCC2, and FANCC Mutations and Pathologic Complete Response After Neoadjuvant Chemotherapy in Patients with Muscle-invasive Bladder Cancer: Results from the SWOG S1314 Trial.

We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC).

Markers of bone metabolism and overall survival in men with bone-metastatic hormone sensitive prostate cancer (HSPC): A subset analysis of SWOG S1216, a phase III trial of androgen deprivation with or without orteronel.

Background: Circulating biomarkers of bone metabolism are significantly associated with overall survival (OS) in men with advanced prostate cancer. In the SWOG S1216 phase III trial, we showed that elevated bone biomarkers are significantly associated with an increased risk of death in hormone-sensitive prostate cancer (HSPC) regardless of the status of bone metastases, identifying three risk groups with differential OS outcomes based on bone biomarker status. Here we report the association of bone biomarkers with OS in men with HSPC and documented skeletal metastases as part of a planned subset analysis of S1216.

mA epitranscriptome analysis reveals differentially methylated transcripts that drive early chemoresistance in bladder cancer.

-Methyladenosine (mA) RNA modifications dynamically regulate messenger RNA processing, differentiation and cell fate. Given these functions, we hypothesized that mA modifications play a role in the transition to chemoresistance. To test this, we took an agnostic discovery approach anchored directly to chemoresistance rather than to any particular mA effector protein.

Association of Molecular Subtypes with Pathologic Response, PFS, and OS in a Phase II Study of COXEN with Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer.

Purpose: The Coexpression Extrapolation (COXEN) gene expression model with chemotherapy-specific scores [for methotrexate, vinblastine, adriamycin, cisplatin (ddMVAC) and gemcitabine/cisplatin (GC)] was developed to identify responders to neoadjuvant chemotherapy (NAC). We investigated RNA-based molecular subtypes as additional predictive biomarkers for NAC response, progression-free survival (PFS), and overall survival (OS) in patients treated in S1314.

Experimental Design: A total of 237 patients were randomized between four cycles of ddMVAC (51%) and GC (49%).

Long-term Outcomes from a Phase 2 Study of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer (SWOG S1314; NCT02177695).

Background: The COXEN gene expression model was evaluated for prediction of response to neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC).

Objective: To conduct a secondary analysis of the association of each COXEN score with event-free survival (EFS) and overall survival (OS) and by treatment arm.

Design, Setting, And Participants: This was a randomized phase 2 trial of neoadjuvant gemcitabine-cisplatin (GC) or dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) in MIBC.

Cell-free DNA Methylation as a Predictive Biomarker of Response to Neoadjuvant Chemotherapy for Patients with Muscle-invasive Bladder Cancer in SWOG S1314.

Background: Neoadjuvant chemotherapy (NAC) is the standard of care in muscle-invasive bladder cancer (MIBC). However, treatment is intense, and the overall benefit is small, necessitating effective biomarkers to identify patients who will benefit most.

Objective: To characterize cell-free DNA (cfDNA) methylation in patients receiving NAC in SWOG S1314, a prospective cooperative group trial, and to correlate the methylation signatures with pathologic response at radical cystectomy.

Bone Biomarkers and Subsequent Survival in Men with Hormone-sensitive Prostate Cancer: Results from the SWOG S1216 Phase 3 Trial of Androgen Deprivation Therapy with or Without Orteronel.

Background: Bone biomarkers are strongly prognostic for overall survival (OS) in men with castration-resistant prostate cancer but not fully established for hormone-sensitive prostate cancer (HSPC).

Objective: Bone biomarkers in HSPC were prospectively evaluated as part of a phase 3 study of androgen deprivation therapy ± the CYP17 inhibitor orteronel.

Design, Setting, And Participants: Patients were randomly divided into training (n = 316) and validation (n = 633) sets.

Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial).

Purpose: Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting.

External Validation of Association of Baseline Circulating Tumor Cell Counts with Survival Outcomes in Men with Metastatic Castration-Sensitive Prostate Cancer.

Approximately 20% of men with metastatic castration-sensitive prostate cancer (mCSPC) progress within 1 year of treatment, and biomarkers to identify them up front are lacking. In a randomized phase III trial in men with mCSPC (SWOG S1216), higher baseline circulating tumor cells (CTCs) were prognostic of inferior outcomes. We aimed to validate these findings and interrogate corresponding tumor genomic profiles.

Integration of Liquid Biopsies in Clinical Management of Metastatic Prostate Cancer.

Purpose Of Review: The field of liquid biopsies is constantly evolving through novel technologies. This review outlines current data on liquid biopsies and application to clinical management of metastatic prostate cancer.

Recent Findings: To date, there are three platforms with FDA approval for use in the setting of metastatic prostate cancer and others which have been clinically validated.

Orteronel for Metastatic Hormone-Sensitive Prostate Cancer: A Multicenter, Randomized, Open-Label Phase III Trial (SWOG-1216).

Purpose: Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer.

Methods: In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm).

FOXC1 Binds Enhancers and Promotes Cisplatin Resistance in Bladder Cancer.

Chemotherapy resistance is traditionally attributed to DNA mutations that confer a survival advantage under drug selection pressure. However, in bladder cancer and other malignancies, we and others have previously reported that cancer cells can convert spontaneously to an aggressive drug-resistant phenotype without prior drug selection or mutational events. In the current work, we explored possible epigenetic mechanisms behind this phenotypic plasticity.

Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time.

Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitochondrial gene expression and a corresponding metabolic shift towards the tricarboxylic acid cycle and oxidative phosphorylation.

Non-Invasive Profiling of Advanced Prostate Cancer via Multi-Parametric Liquid Biopsy and Radiomic Analysis.

Integrating liquid biopsies of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) with other minimally invasive measures may yield more comprehensive disease profiles. We evaluated the feasibility of concurrent cellular and molecular analysis of CTCs and cfDNA combined with radiomic analysis of CT scans from patients with metastatic castration-resistant PC (mCRPC). CTCs from 22 patients were enumerated, stained for PC-relevant markers, and clustered based on morphometric and immunofluorescent features using machine learning.

A Randomized Phase II Study of Coexpression Extrapolation (COXEN) with Neoadjuvant Chemotherapy for Bladder Cancer (SWOG S1314; NCT02177695).

Purpose: Dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) and gemcitabine-cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer. The aim of this study was to validate the score from a coexpression extrapolation (COXEN) algorithm-generated gene expression model (GEM) as a biomarker in patients undergoing radical cystectomy.

Patients And Methods: Eligibility included cT2-T4a N0 M0, urothelial bladder cancer, ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy; 237 patients were randomized between ddMVAC, given every 14 days for four cycles, and GC, given every 21 days for four cycles.

Baseline Circulating Tumor Cell Count as a Prognostic Marker of PSA Response and Disease Progression in Metastatic Castrate-Sensitive Prostate Cancer (SWOG S1216).

Purpose: In metastatic castrate-sensitive prostate cancer (mCSPC), combined androgen axis inhibition is a standard of care. Noninvasive biomarkers that guide initial therapy decisions are needed. We hypothesized that CellSearch circulating tumor cell (CTC) count, an FDA-cleared assay in metastatic castrate-resistant prostate cancer (mCRPC), is a relevant biomarker in mCSPC.

Cancer transcriptomic profiling from rapidly enriched circulating tumor cells.

Transcriptomic profiling of metastatic cancer can illuminate mechanisms of progression and lead to new therapies, but standard biopsy is invasive and reflects only a single metastatic site. In contrast, circulating tumor cell (CTC) profiling is noninvasive and repeatable, reflecting the dynamic and systemic nature of advanced disease. To date, transcriptomic profiling of CTCs has not delivered on its full potential, because white blood cells (WBCs) vastly outnumber CTCs.

Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype.

Highly tumorigenic, drug-resistant cancer stem-like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem-like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility.

Current status of liquid biopsies for the detection and management of prostate cancer.

In recent years, new therapeutic options have become available for prostate cancer (PC) patients, generating an urgent need for better biomarkers to guide the choice of therapy and monitor treatment response. Liquid biopsies, including circulating tumor cells (CTCs), circulating nucleic acids, and exosomes, have been developed as minimally invasive assays allowing oncologists to monitor PC patients with real-time cellular or molecular information. While CTC counts remain the most extensively validated prognostic biomarker to monitor treatment response, recent advances demonstrate that CTC morphology and androgen receptor characterization can provide additional information to guide the choice of treatment.

Randomized Phase II Trial of Abiraterone Alone or With Dasatinib in Men With Metastatic Castration-resistant Prostate Cancer (mCRPC).

Background: Signaling via the Src pathway is thought to be a mediator of resistance to androgen targeted therapy in prostate cancer. We studied whether adding the Src inhibitor dasatinib to abiraterone would delay progression.

Patients And Methods: Eligible patients had metastatic castration-resistant prostate cancer (mCRPC), without prior chemotherapy.

Multiparametric liquid biopsy analysis in metastatic prostate cancer.

Molecular profiling of prostate cancer with liquid biopsies, such as circulating tumor cells (CTCs) and cell-free nucleic acid analysis, yields informative yet distinct data sets. Additional insights may be gained by simultaneously interrogating multiple liquid biopsy components to construct a more comprehensive molecular disease profile. We conducted an initial proof-of-principle study aimed at piloting this multiparametric approach.

Liquid Biopsy in Prostate Cancer: Circulating Tumor Cells and Beyond.

Prostate cancer is a common malignancy impacting countless men without curative options in the advanced state. Numerous therapies have been introduced in recent years improving survival and symptom control, yet optimal methods for predicting or monitoring response have not been developed. In the era of precision medicine, characterization of individual cancers is necessary to inform treatment decisions.

A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors.

Purpose: Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib.

Development of a translational medicine protocol for an NCTN genitourinary clinical trial: Critical steps, common pitfalls and a basic guide to translational clinical research.

Translational medicine (TM) components of prospective clinical trials provide an invaluable opportunity to test hypotheses that contribute to our knowledge of human disease biology and/or the mechanism of action of a given therapeutic intervention. Our ability to sample tumors and their microenvironment, and the depth and breadth of biological information that can be extracted from them, has increased exponentially in recent years. This information is critical to guide the next steps clinical research if we are to accelerate the pace of progress in cancer treatment.