Impact of molecular tumour board discussion on targeted therapy allocation in advanced prostate cancer.

BACKGROUND: Molecular tumour boards (MTB) optimally match oncological therapies to patients with genetic aberrations. Prostate cancer (PCa) is underrepresented in these MTB discussions. This study describes the impact of routine genetic profiling and MTB referral on the outcome of PCa patients in a tertiary referral centre. METHODS: All PCa patients that received next-generation sequencing results and/or were discussed at an MTB between Jan 1, 2017 and Jan 1, 2020 were included. Genetically matched therapies (GMT) in clinical trials or compassionate use were linked to actionable alterations. Response to these agents was retrospectively evaluated. RESULTS: Out of the 277 genetically profiled PCa patients, 215 (78%) were discussed in at least one MTB meeting. A GMT was recommended to 102 patients (47%), of which 63 patients (62%) initiated the GMT. The most recommended therapies were PARP inhibitors (n = 74), programmed death-(ligand) 1 inhibitors (n = 21) and tyrosine kinase inhibitors (n = 19). Once started, 41.3% had a PFS of ≥6 months, 43.5% a PSA decline ≥50% and 38.5% an objective radiographic response. CONCLUSION: Recommendation for a GMT is achieved in almost half of the patients with advanced prostate cancer, with GMT initiation leading to durable responses in over 40% of patients. These data justify routine referral of selected PCa patients to MTB's.

Reovirus mutant jin-3 exhibits lytic and immune-stimulatory effects in preclinical human prostate cancer models.

Treatment of castration-resistant prostate cancer remains a challenging clinical problem. Despite the promising effects of immunotherapy in other solid cancers, prostate cancer has remained largely unresponsive. Oncolytic viruses represent a promising therapeutic avenue, as oncolytic virus treatment combines tumour cell lysis with activation of the immune system and mounting of effective anti-tumour responses. Mammalian Orthoreoviruses are non-pathogenic human viruses with a preference of lytic replication in human tumour cells. In this study, we evaluated the oncolytic efficacy of the bioselected oncolytic reovirus mutant jin-3 in multiple human prostate cancer models. The jin-3 reovirus displayed efficient infection, replication, and anti-cancer responses in 2D and 3D prostate cancer models, as well as in ex vivo cultured human tumour slices. In addition, the jin-3 reovirus markedly reduced the viability and growth of human cancer cell lines and patient-derived xenografts. The infection induced the expression of mediators of immunogenic cell death, interferon-stimulated genes, and inflammatory cytokines. Taken together, our data demonstrate that the reovirus mutant jin-3 displays tumour tropism, and induces potent oncolytic and immunomodulatory responses in human prostate cancer models. Therefore, jin-3 reovirus represents an attractive candidate for further development as oncolytic agent for treatment of patients with aggressive localised or advanced prostate cancer.

Probing single-cell metabolism reveals prognostic value of highly metabolically active circulating stromal cells in prostate cancer.

Despite their important role in metastatic disease, no general method to detect circulating stromal cells (CStCs) exists. Here, we present the Metabolic Assay-Chip (MA-Chip) as a label-free, droplet-based microfluidic approach allowing single-cell extracellular pH measurement for the detection and isolation of highly metabolically active cells (hm-cells) from the tumor microenvironment. Single-cell mRNA-sequencing analysis of the hm-cells from metastatic prostate cancer patients revealed that approximately 10% were canonical EpCAM+ hm-CTCs, 3% were EpCAM- hm-CTCs with up-regulation of prostate-related genes, and 87% were hm-CStCs with profiles characteristic for cancer-associated fibroblasts, mesenchymal stem cells, and endothelial cells. Kaplan-Meier analysis shows that metastatic prostate cancer patients with more than five hm-cells have a significantly poorer survival probability than those with zero to five hm-cells. Thus, prevalence of hm-cells is a prognosticator of poor outcome in prostate cancer, and a potentially predictive and therapy response biomarker for agents cotargeting stromal components and preventing epithelial-to-mesenchymal transition.

Prior PSMA PET-CT Imaging and Hounsfield Unit Impact on Tumor Yield and Success of Molecular Analyses from Bone Biopsies in Metastatic Prostate Cancer.

Developing and optimizing targeted therapies in metastatic castration-resistant prostate cancer (mCRPC) necessitates molecular characterization. Obtaining sufficient tumor material for molecular characterization has been challenging. We aimed to identify clinical and imaging variables of imaging-guided bone biopsies in metastatic prostate cancer patients that associate with tumor yield and success in obtaining molecular results, and to design a predictive model: Clinical and imaging data were collected retrospectively from patients with prostate cancer who underwent a bone biopsy for histological and molecular characterization. Clinical characteristics, imaging modalities and imaging variables, were associated with successful biopsy results. In our study, we included a total of 110 bone biopsies. Histological conformation was possible in 84 of all biopsies, of which, in 73 of the 84, successful molecular characterization was performed. Prior use of PSMA PET-CT resulted in higher success rates in histological and molecular successful biopsies compared to CT or MRI. Evaluation of spine biopsies showed more often successful results compared to other locations for both histological and molecular biopsies (p = 0.027 and p = 0.012, respectively). Low Hounsfield units (HUs) and deviation (Dev), taken at CT-guidance, were associated with histological successful biopsies (p = 0.025 and p = 0.023, respectively) and with molecular successful biopsies (p = 0.010 and p = 0.006, respectively). A prediction tool combining low HUs and low Dev resulted in significantly more successful biopsies, histological and molecular (p = 0.023 and p = 0.007, respectively). Based on these results, we concluded that site selection for metastatic tissue biopsies with prior PSMA PET-CT imaging improves the chance of a successful biopsy. Further optimization can be achieved at CT-guidance, by selection of low HU and low Dev lesions. A prediction tool is provided to increase the success rate of bone biopsies in mCRPC patients, which can easily be implemented in daily practice.

Responsiveness to Immune Checkpoint Inhibitors Is Associated With a Peripheral Blood T-Cell Signature in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Although most patients with microsatellite instable (MSI) metastatic castration-resistant prostate cancer (mCRPC) respond to immune checkpoint blockade (ICB), only a small subset of patients with microsatellite stable (MSS) tumors have similar benefit. Biomarkers defining ICB-susceptible subsets of patients with MSS mCRPC are urgently needed. METHODS: Using next-generation T-cell repertoire sequencing, we explored immune signatures in 54 patients with MSS and MSI mCRPC who were treated with or without ICB. We defined subset-specific immune metrics as well as T-cell clusters and correlated the signatures with treatment benefit. RESULTS: Consistent overlaps between tumor and peripheral T-cell repertoires suggested that blood was an informative material to identify relevant T-cell signatures. We found considerably higher blood T-cell richness and diversity and more shared T-cell clusters with low generation probability (pGen) in MSI versus MSS mCRPC, potentially reflecting more complex T-cell responses because of a greater neoepitope load in the MSI subset. Interestingly, patients with MSS mCRPC with shared low pGen T-cell clusters showed significantly better outcomes with ICB, but not with other treatments, compared with patients without such clusters. Blood clearance of T-cell clusters on ICB treatment initiation seemed to be compatible with T-cell migration to the primary tumor or metastatic sites during the process of clonal replacement as described for other tumors receiving ICB. CONCLUSION: The MSI mCRPC subset shows a distinct T-cell signature that can be detected in blood. This signature points to immune parameters that could help identify a subset of patients with MSS mCRPC who may have an increased likelihood of responding to ICB or to combination approaches including ICB.

68Ga-PSMA-Guided Bone Biopsies for Molecular Diagnostics in Patients with Metastatic Prostate Cancer.

For individual treatment decisions in patients with metastatic prostate cancer (mPC), molecular diagnostics are increasingly used. Bone metastases are frequently the only source for obtaining metastatic tumor tissue. However, the success rate of CT-guided bone biopsies for molecular analyses in mPC patients is approximately only 40%. PET using 68Ga prostate-specific membrane antigen (68Ga-PSMA) is a promising tool to improve the harvest rate of bone biopsies for molecular analyses. The aim of this study was to determine the success rate of 68Ga-PSMA-guided bone biopsies for molecular diagnostics in mPC patients. Methods: Within a prospective multicenter whole-genome sequencing trial (NCT01855477), 69 mPC patients underwent 68Ga-PSMA PET/CT before bone biopsy. The primary endpoint was the success rate (tumor percentage ≥ 30%) of 68Ga-PSMA-guided bone biopsies. At biopsy sites, 68Ga-PSMA uptake was quantified using rigid-body image registration of 68Ga-PSMA PET/CT and interventional CT. Actionable somatic alterations were identified. Results: The success rate of 68Ga-PSMA-guided biopsies for molecular analyses was 70%. At biopsy sites categorized as positive, inconclusive, or negative for 68Ga-PSMA uptake, 70%, 64%, and 36% of biopsies were tumor-positive (≥30%), respectively (P = 0.0610). In tumor-positive biopsies, 68Ga-PSMA uptake was significantly higher (P = 0.008), whereas radiodensity was significantly lower (P = 0.006). With an area under the curve of 0.84 and 0.70, both 68Ga-PSMA uptake (SUVmax) and radiodensity (mean Hounsfield units) were strong predictors for a positive biopsy. Actionable somatic alterations were detected in 73% of the sequenced biopsies. Conclusion: In patients with mPC, 68Ga-PSMA PET/CT improves the success rate of CT-guided bone biopsies for molecular analyses, thereby identifying actionable somatic alterations in more patients. Therefore, 68Ga-PSMA PET/CT may be considered for guidance of bone biopsies in both clinical practice and clinical trials.

The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact.

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12-/- and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12-/- and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.

Molecular biomarkers to guide precision medicine in localized prostate cancer.

INTRODUCTION: Major advances through tumor profiling technologies, that include next-generation sequencing, epigenetic, proteomic and transcriptomic methods, have been made in primary prostate cancer, providing novel biomarkers that may guide precision medicine in the near future. Areas covered: The authors provided an overview of novel molecular biomarkers in tissue, blood and urine that may be used as clinical tools to assess prognosis, improve selection criteria for active surveillance programs, and detect disease relapse early in localized prostate cancer. Expert commentary: Active surveillance (AS) in localized prostate cancer is an accepted strategy in patients with very low-risk prostate cancer. Many more patients may benefit from watchful waiting, and include patients of higher clinical stage and grade, however selection criteria have to be optimized and early recognition of transformation from localized to lethal disease has to be improved by addition of molecular biomarkers. The role of non-invasive biomarkers is challenging the need for repeat biopsies, commonly performed at 1 and 4 years in men under AS programs.