Precision medicine for prostate cancer: An international perspective.

Greater personalization of cancer medicine continues to shape therapy development and patient selection accordingly. The treatment of prostate cancer has evolved considerably since the discovery of androgen deprivation therapy. The comprehensive profiling of the prostate cancer genome has mapped the targetable molecular landscape of the disease and identified opportunities for the implementation of novel and combination therapies.

Detection of PSMA expression on circulating tumor cells by blood-based liquid biopsy in prostate cancer.

Background: For patients with mCRPC, PSMA-targeted radioligand treatment has significantly improved the clinical outcome. A blood-based liquid biopsy assay for recognizing PSMA protein expression on circulating tumor cells may be beneficial for better informing therapeutic decision-making and identifying the patients most likely to benefit from PSMA-targeted radioligand therapy.

Methods: Using high-throughput imaging and digital AI pathology algorithms, a four-color immunofluorescence assay has been developed to find PSMA protein expression on CTCs on a glass slide.

Metastatic Hormone-Sensitive Prostate Cancer: Toward an Era of Adaptive and Personalized Treatment.

The advent of more effective treatment combinations for metastatic hormone-sensitive prostate cancer (mHSPC) has been built on successes in therapy development for metastatic, castration-resistant prostate cancer (mCRPC). Both disease phases hold similar challenges and questions. Is there an optimal therapy sequence to maximize disease control and balance treatment burden? Are there clinical and biologically based subgroups that inform personalized and/or adaptive strategies? How can clinicians interpret data from clinical trials in the context of rapidly evolving technologies? Herein, we review the contemporary landscape of treatment for mHSPC, including disease subgroups informing both intensification and potential deintensification strategies.

A novel prostate cancer subtyping classifier based on luminal and basal phenotypes.

Background: Prostate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression-based subtyping model based on prostate-specific biological processes was sought.

Methods: Unsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology.

Clinical testing of transcriptome-wide expression profiles in high-risk localized and metastatic prostate cancer starting androgen deprivation therapy: an ancillary study of the STAMPEDE abiraterone Phase 3 trial.

Metastatic and high-risk localized prostate cancer respond to hormone therapy but outcomes vary. Following a pre-specified statistical plan, we used Cox models adjusted for clinical variables to test associations with survival of multi-gene expression-based classifiers from 781 patients randomized to androgen deprivation with or without abiraterone in the STAMPEDE trial. Decipher score was strongly prognostic (p<2×10) and identified clinically-relevant differences in absolute benefit, especially for localized cancers.

Navigating the Current Landscape of Non-Clear Cell Renal Cell Carcinoma: A Review of the Literature.

Non-clear cell renal cell carcinoma (nccRCC) is an entity comprised of a heterogeneous constellation of RCC subtypes. Genomic profiling has broadened our understanding of molecular pathogenic mechanisms unique to individual nccRCC subtypes. To date, clinical trials evaluating the use of immunotherapies and targeted therapies have predominantly been conducted in patients with clear cell histology.

Outcomes in men with metastatic castration-resistant prostate cancer who received sipuleucel-T and no immediate subsequent therapy: experience at Dana Farber and in the PROCEED Registry.

Background: Sipuleucel-T has demonstrated survival benefit in phase 3 trials but is utilized in few men with metastatic castration-resistant prostate cancer (mCRPC) in part due to low rates of PSA and objective response. Given the requirement to develop immune-mediated antitumor activity as vaccine-based therapy, sipuleucel-T may have delayed clinical activity. We explored this in a cohort of men from PROCEED (NCT01306890), an FDA-requested outcomes registry, and in a separate institutional cohort of mCRPC patients treated with sipuleucel-T at Dana-Farber Cancer Institute (DFCI).

Lifetime Health and Economic Outcomes of Active Surveillance, Radical Prostatectomy, and Radiotherapy for Favorable-Risk Localized Prostate Cancer.

Objectives: To estimate the lifetime health and economic outcomes of selecting active surveillance (AS), radical prostatectomy (RP), or radiation therapy (RT) as initial management for low- or favorable-risk localized prostate cancer.

Methods: A discrete-event simulation model was developed using evidence from published randomized trials. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs).

Prevalence and clinical impact of tumor BRCA1 and BRCA2 mutations in patients presenting with localized or metastatic hormone-sensitive prostate cancer.

Background: The appropriate management of localized or metastatic hormone-sensitive prostate cancer (HSPC) patients harboring tumor BRCA mutations (tBRCAm) is not well-characterized. We sought to evaluate the prevalence and clinical outcomes of patients with tBRCAm and localized or de novo metastatic HSPC.

Methods: We performed a multicenter, international, retrospective cohort study of localized (cohort 1) and de novo metastatic (cohort 2) HSPC patients who underwent tumor BRCA1 and BRCA2 sequencing from 2013 to 2019.

A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer.

Background: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer).

Methods: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer.

EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.

Prostate cancers are considered to be immunologically 'cold' tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs.

NF-κB Blockade with Oral Administration of Dimethylaminoparthenolide (DMAPT), Delays Prostate Cancer Resistance to Androgen Receptor (AR) Inhibition and Inhibits AR Variants.

NF-κB activation has been linked to prostate cancer progression and is commonly observed in castrate-resistant disease. It has been suggested that NF-κB-driven resistance to androgen-deprivation therapy (ADT) in prostate cancer cells may be mediated by aberrant androgen receptor (AR) activation and AR splice variant production. Preventing resistance to ADT may therefore be achieved by using NF-κB inhibitors.

A Risk-benefit Analysis of Prophylactic Anticoagulation for Patients with Metastatic Germ Cell Tumours Undergoing First-line Chemotherapy.

Background: It remains unclear which patients with metastatic germ cell tumours (mGCTs) need prophylactic anticoagulation to prevent venous thromboembolic events (VTEs).

Objective: To assess the risk and onset of VTEs stratified by risk factors.

Design, Setting, And Participants: This multi-institutional retrospective dataset included mGCT patients treated with first-line platinum-based chemotherapy.

Association between CD8 and PD-L1 expression and outcomes after radical prostatectomy for localized prostate cancer.

Background: Characterization of markers of both immune suppression and activation may provide more prognostic information than assessment of single markers in localized prostate cancer. We therefore sought to determine the association between CD8 and PD-L1 expression in localized prostate tumors and biochemical recurrence (BCR) and metastasis-free survival (MFS).

Methods: Tissue microarrays were constructed on 109 men undergoing radical prostatectomy (RP) for localized prostate cancer at Dana-Farber Cancer Institute between 1991 and 2008.

Impact of baseline serum IL-8 on metastatic hormone-sensitive prostate cancer outcomes in the Phase 3 CHAARTED trial (E3805).

Background: The immunosuppressive cytokine interleukin- 8 (IL-8), produced by tumor cells and some myeloid cells, promotes inflammation, angiogenesis, and metastasis. In our discovery work, elevated serum IL-8 at androgen deprivation therapy (ADT) initiation portended worse overall survival (OS). Leveraging serum samples from the phase 3 CHAARTED trial of patients treated with ADT +/- docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC), we validated these findings.

Nursing Implications of Recent Changes in Management Practices for Metastatic Prostate Cancer.

Objective: Prostate cancer is one of the most common male cancers in the world and accounts for substantial morbidity, mortality, loss of disability-adjusted life-years, and financial burden to patients and to the community. Metastatic prostate cancer has been managed for over 70 years with androgen deprivation therapy, but further life-prolonging therapies were not available until 2004. Since then, drugs such as docetaxel, abiraterone, enzalutamide, cabazitaxel, radium-223 dichloride, and (not available in Australia) sipuleucel-T have all demonstrated efficacy in prolongation of survival in castrate-resistant prostate cancer, and improvement in cancer-related morbidity.

FiTAc-seq: fixed-tissue ChIP-seq for H3K27ac profiling and super-enhancer analysis of FFPE tissues.

Fixed-tissue ChIP-seq for H3K27 acetylation (H3K27ac) profiling (FiTAc-seq) is an epigenetic method for profiling active enhancers and promoters in formalin-fixed, paraffin-embedded (FFPE) tissues. We previously developed a modified ChIP-seq protocol (FiT-seq) for chromatin profiling in FFPE. FiT-seq produces high-quality chromatin profiles particularly for methylated histone marks but is not optimized for H3K27ac profiling.

Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: a retrospective international multicenter study.

Background: There is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations.

Methods: This multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months.

Outcome of Men With Relapses After Adjuvant Bleomycin, Etoposide, and Cisplatin for Clinical Stage I Nonseminoma.

Purpose: Clinical stage I (CSI) nonseminoma (NS) is a disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant chemotherapy. Little is known about the outcome of patients who experience relapse after such treatment.

Large retroperitoneal lymphadenopathy and increased risk of venous thromboembolism in patients receiving first-line chemotherapy for metastatic germ cell tumors: A study by the global germ cell cancer group (G3).

Background: Metastatic germ cell tumor (mGCT) patients receiving chemotherapy have increased risk of life-threatening venous thromboembolism (VTE). Identifying VTE risk factors may guide thromboprophylaxis in this highly curable population.

Methods: Data were collected from mGCT patients receiving first-line platinum-based chemotherapy at 22 centers.