Search Results (13)

Purpose: Accurate survival prediction is essential for optimizing the treatment planning in patients with castration-resistant prostate cancer (CRPC). However, the traditional statistical models often underperform due to limited variable inclusion and an inability to account for complex, multidimensional data interactions. Methods: We retrospectively collected 46 clinical, laboratory, and pathological variables from 801 patients with CRPC, covering the disease course from the initial disease diagnosis to CRPC progression. Multiple machine learning (ML) models, including random survival forests (RSFs), XGBoost, LightGBM, and logistic regression, were developed to predict cancer-specific mortality (CSM), overall mortality (OM), and 2- and 3-year survival status. The dataset was split into training and test cohorts (80:20), with 10-fold cross-validation. The performance was assessed using the C-index for regression models and the AUC, accuracy, precision, recall, and F1-score for classification models. Model interpretability was assessed using SHapley Additive exPlanations (SHAP). Results: Over a median follow-up of 24 months, 70.6% of patients experienced CSM. RSFs achieved the highest C-index in the test set for both CSM (0.772) and OM (0.771). For classification tasks, RSFs demonstrated a superior performance in predicting 2-year survival, while XGBoost yielded the highest F1-score for 3-year survival. The SHAP analysis identified time to first-line CRPC treatment and hemoglobin and alkaline phosphatase levels as key predictors of survival outcomes. Conclusion: The RSF and XGBoost ML models demonstrated a superior performance over that of traditional statistical methods in predicting survival in CRPC. These models offer accurate and interpretable prognostic tools that may inform personalized treatment strategies. External validation and the integration of emerging therapies are warranted for broader clinical applicability. Full article

Background: Metastatic castration-resistant prostate cancer (mCRPC) remains challenging due to progression despite androgen deprivation therapy (ADT). Current treatments, including androgen receptor-targeted agents, chemotherapy, bone-targeted agents, and PARP inhibitors, extend survival but face challenges, such as resistance, adverse effects, and limited durability. Metastasis-directed therapies (MDTs), such as stereotactic ablative radiotherapy (SABR), show promise in oligometastatic disease, but their role in oligoprogressive mCRPC is unclear. Salvage lymphadenectomy is rarely pursued due to invasiveness and limited data. This is the first report of robotic surgery as an MDT in this setting, demonstrating the potential of salvage robot-assisted video-endoscopic inguinal lymphadenectomy (RAVEIL) to manage oligoprogressive mCRPC and delay systemic progression. Methods: A 47-year-old male with metastatic hormone-sensitive prostate cancer (Gleason 10) underwent ADT, docetaxel chemotherapy, and radical retropubic prostatectomy with super-extended pelvic and retroperitoneal lymphadenectomy. Upon progression to oligoprogressive mCRPC, 68Ga-PSMA PET/CT detected a single metastatic inguinal lymph node. Salvage RAVEIL was performed using the da Vinci X™ Surgical System, guided by preoperative ultrasound mapping. Results: Histopathology confirmed metastasis in one of the eight excised lymph nodes. The patient achieved undetectable PSA levels and prolonged biochemical progression-free survival. Minor complications (lymphorrhea, cellulitis) resolved without sequelae. No further progression was observed for over 14 months. Conclusions: This case highlights RAVEIL as a viable MDT option for oligoprogressive mCRPC, potentially extending progression-free intervals while minimizing systemic treatment. Full article

Prostate cancer (PC) is one of the most commonly diagnosed tumours among men. Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone acetate (AbA) and enzalutamide (ENZ), are currently used in the management of metastatic castration-resistant PC (mCRPC). However, the treatment is challenging due to the lack of prognostic biomarkers. Meanwhile, single-nucleotide polymorphisms (SNPs) have emerged as potential prognostic indicators of mCRPC. Thus, this study evaluated the impact of relevant SNPs on the treatment outcomes of 123 mCRPC patients enrolled in a hospital-based cohort study. The CYP17A1 rs2486758 C allele was associated with a 50% reduction in the risk of developing castration resistance (hazard ratio (HR) = 0.55; p = 0.003). Among patients without metastasis at tumour diagnosis and under AbA, a marginal association between YBX1 rs10493112 and progression-free survival was detected (log-rank test, p = 0.056). In the same subgroup, significant associations of HSD3B1 rs1047303 (CC/CA vs. AA; HR = 3.41; p = 0.025), YBX1 rs12030724 (AT vs. AA; HR = 3.54; p = 0.039) and YBX1 rs10493112 (log-rank test, p = 0.041; CC vs. AA/AC; HR = 3.22; p = 0.053) with overall survival were also observed, which were confirmed by multivariate Cox analyses. Although validation with larger cohorts is required, these findings suggest that SNPs could enhance the prognosis assessment of mCRPC patients, leading to a more personalised treatment. Full article

Background: Prostate cancer is a malignant neoplasm of the male genitourinary system with the highest incidence worldwide. Susceptibility genes related to aggressiveness and prognosis, such as BRCA1/2, ATM, PTEN, have been identified. Currently, reports related to germline mutations in patients with prostate cancer in Latin American populations are very limited or absent. In the Mexican population, reports are also limited, especially in the context of metastatic prostate cancer. Determining the prevalence of these mutations is relevant to predict the potential aggressiveness of tumors and allow the use of targeted therapies, such as PARPi inhibitors. Objective: Determine the prevalence of germline mutations in patients with metastatic prostate cancer and establish their clinical characteristics at diagnosis. Material and Methods: Sixty-nine patients with metastatic PCa underwent testing and genetic analysis using the Comprehensive Multi-Cancer Hereditary Cancer Panel. The prevalence of germline mutations was assessed, and the cohort was divided into two groups for the evaluation and analysis of clinical characteristics between the mutated and non-mutated populations. Results: We identified mutations in 15 out of 69 patients (21.73%), while 54 patients (78.26%) had no mutations. Pathogenic mutations were observed in 15.9% of patients, Variants of Uncertain Significance (VUS) in 34.78%, and 5.79% had both. The most frequent mutations included ATM (11.54%), BRCA1 (11.54%), BRCA2 (7.69%), FANCA (7.69%), and FANCM (7.69%). No statistically significant differences were found in PSA levels, age at diagnosis, and resistance to castration between the two groups. Conclusions: Our study unveiled a mutation rate of 21.73%, marked by a significant prevalence of ATM, FANCA, FANCM, and Variants of Uncertain Significance (VUS). This pattern deviates from findings in other series, underscoring the necessity for improved access to clinical genetic testing in our population. Full article

Prostate cancer liver metastasis (PCLM), seen in upwards of 25% of metastatic castration-resistant PC (mCRPC) patients, is the most lethal site of mCRPC with a median overall survival of 10–14 months. Despite its ominous prognosis and anticipated rise in incidence due to longer survival with contemporary therapy, PCLM is understudied. This review aims to summarize the existing literature regarding the risk factors associated with the development of PCLM, and to identify areas warranting further research. A literature search was conducted through Ovid MEDLINE from 2000 to March 2023. Relevant subject headings and text words were used to capture the following concepts: “Prostatic Neoplasms”, “Liver Neoplasms”, and “Neoplasm Metastasis”. Citation searching identified additional manuscripts. Forty-one studies were retained for detailed analysis. The clinical risk factors for visceral/liver metastasis included <70 years, ≥T3 tumor, N1 nodal stage, de novo metastasis, PSA >20 ng/mL, and a Gleason score >8. Additional risk factors comprised elevated serum AST, LDH or ALP, decreased Hb, genetic markers like RB1 and PTEN loss, PIK3CB and MYC amplification, as well as numerous PC treatments either acting directly or indirectly through inducing liver injury. Further research regarding predictive factors, early detection strategies, and targeted therapies for PCLM are critical for improving patient outcomes. Full article

Background: prostate-specific membrane antigen (PSMA) ligand PET has been recently incorporated into international guidelines for several different indications in prostate cancer (PCa) patients. However, there are still some open questions regarding the role of PSMA ligand PET in castration-resistant prostate cancer (CRPC). The aim of this work is to assess the clinical value of PSMA ligand PET/CT in patients with CRPC. Results: PSMA ligand PET has demonstrated higher detection rates in comparison to conventional imaging and allows for a significant reduction in the number of M0 CRPC patients. However, its real impact on patients’ prognosis is still an open question. Moreover, in CRPC patients, PSMA ligand PET presents some sensitivity and specificity limitations. Due to its heterogeneity, CRPC may present a mosaic of neoplastic clones, some of which could be PSMA−/FDG+, or vice versa. Likewise, unspecific bone uptake (UBU) and second primary neoplasms (SNPs) overexpressing PSMA in the neoangiogenic vessels represent potential specificity issues. Integrated multi-tracer imaging (PSMA ligand and [¹⁸F]FDG PET) together with a multidisciplinary discussion could allow for reaching the most accurate evaluation of each patient from a precision medicine point of view. Full article

Measuring serum testosterone determination during medical castration is recommended by prostate cancer (PCa) guidelines to assess its efficacy and define castration resistance. It has been suggested that other biochemical compounds, such as free testosterone or luteinising hormone (LH), could also assess castration efficacy. We aimed to analyse the current evidence for serum biochemical compounds that could be appropriate candidates for evaluating medical castration efficacy. A systematic review was conducted after two investigators independently searched the literature in the PubMed, Cochrane Library, and EMBASE databases published between January 1980 and February 2023. Their searches used the medical subject headings ‘prostatic neoplasms’, ‘testosterone and androgen antagonists’, ‘gonadotropin-releasing hormone/analogues and derivatives’, ‘free testosterone’, and ‘luteinising hormone’. Studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria, and their eligibility was based on the Participants, Intervention, Comparator, and Outcome strategy. The search was limited to original articles published in English. Among the 6599 initially identified titles, 15 original studies analysing the clinical impact of serum testosterone levels in PCa patients undergoing androgen deprivation therapy (ADT) were selected for evidence acquisition. The risk of bias in individual studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. All selected studies used immunoassays to measure serum testosterone, although only methods based on liquid or gas chromatography and mass spectrometry are recommended to measure low testosterone concentrations. The reported series were not uniform in clinical stage, ADT types, and the time or number of serum testosterone measurements. Only some studies found low serum testosterone levels (<20 or <32 ng/dL) associated with greater survival free of biochemical progression and castration resistance. We conclude that little current evidence justifies the measurement of serum testosterone during ADT using no appropriate methods. No reported longitudinal studies have examined the clinical impact of serum testosterone measured using liquid chromatography with tandem mass spectrometry (LC-MSMS), free testosterone, or LH in PCa patients undergoing medical castration. We conclude that well-designed longitudinal studies examining the clinical impact of serum testosterone measured with LC-MSMS, serum-free testosterone, and LH on biochemical progression and castration resistance in PCa patients undergoing neo-adjuvant castration in radiation therapy or continuous castration are needed. Full article

Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer. Full article

Herein, we analyze answers achieved, open questions, and future perspectives regarding the analysis of the pathogenetic variants (PV) of DNA damage response (and repair) (DDR) genes in prostate cancer (PC) patients. The incidence of PVs in homologous recombination repair (HRR) genes among men with metastatic PC varied between 11% and 33%, which was significantly higher than that in non-metastatic PC, and BRCA2 mutations were more frequent when compared to other DDR genes. The determination of the somatic or germline PVs of BRCA2 was able to define a tailored therapy using PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC) progression after first-line therapy, with significant improvements in the radiologic progression-free survival (rPFS) and overall survival (OS) rates. We propose testing all metastatic PC patients for somatic and germline HRR mutations. Somatic determination on the primary site or on historic paraffin preparations with a temporal distance of no longer than 5 years should be preferred over metastatic site biopsies. The prognostic use of DDR PVs will also be used in selected high-risk cases with non-metastatic stages to better arrange controls and therapeutic primary options. We anticipate that the use of poly-ADP-ribose polymerase (PARP) inhibitors in hormone-sensitive prostate cancer (HSPC) and in combination with androgen receptor signaling inhibitors (ARSI) will be new strategies. Full article

The purpose of this study was to evaluate the impact of progressive site-directed therapy (PSDT) for oligometastatic castration-resistant prostate cancer (OM-CRPC) on the efficacy of subsequent androgen receptor axis-targeted (ARAT) drugs, and to demonstrate the possibility of prolonging overall survival (OS). We performed a retrospective analysis of 15 OM-CRPC patients who underwent PSDT and subsequently received first-line ARAT drugs (PSDT group) and 13 OM-CRPC patients who were treated with first-line ARAT drugs without PSDT (non-PSDT group). PSDT was performed with the intention of treating all progressing sites detected by whole-body diffusion-weighted MRI with radiotherapy. Thirteen patients (86.7%) treated with PSDT had a decrease in PSA levels, which was at least 50% in 10 (66.7%) patients. The median PSA progression-free survival (PFS) for PSDT was 7.4 months. The median PSA-PFS for ARAT was 27.2 months in patients in the PSDT group and 11.7 months in the non-PSDT group, with a significant difference between the two groups (hazard ratio [HR], 0.28; p = 0.010). The median OS was not reached in the PSDT group and was significantly longer than 44.5 months in the non-PSDT group (HR, 0.11; p = 0.014). In OM-CRPC, PSDT may improve the efficacy of subsequent ARAT and OS. Full article

Tumour molecular features are increasingly linked to treatment response and patient prognosis in advanced prostate cancer. Plasma cell-free circulating tumour DNA (ctDNA) isolated from a minimally invasive blood draw offers a convenient source of tumour material to develop clinical biomarkers. Importantly, the burden of ctDNA in the blood has strong prognostic implications at different points during the natural history of metastatic progression. In prostate cancer, the identification of somatic profiles from ctDNA requires a broad next-generation sequencing approach because of the low mutation rate and frequent structural rearrangements. Nevertheless, comparison of genomic profiles between liquid and tissue biopsies has demonstrated that ctDNA is a surrogate for tumour tissue in the metastatic setting. Our understanding of resistance to androgen receptor (AR) directed therapies has been significantly augmented by the frequent detection of AR gene amplifications, mutations, and structural rearrangements via liquid biopsy. Furthermore, early studies suggest that distinct molecular subtypes derived from ctDNA profiling can help determine the optimal therapeutic regimen for an individual patient and enable real-time monitoring for therapy response and resistance. Indeed, in clinical trials targeting the DNA damage repair pathway in prostate cancer, ctDNA-based assessment of DNA repair status is already under evaluation as a predictive biomarker. Recent advances in the study of circulating DNA fragments now make it possible to interrogate aspects of the epigenome. In this review, we describe the various applications of plasma ctDNA in metastatic prostate cancer, including its potential role as a clinically informative liquid biomarker. Full article

Prostate cancer is the second most common and fifth most aggressive neoplasm among men worldwide. It is particularly incident in high human development index (HDI) nations, with an estimated one in seven men in the US receiving a prostate cancer diagnosis in their lifetime. A rapid rise and then fall in prostate cancer incidence in the US and Europe corresponded to the implementation of widespread prostate specific antigen (PSA) testing in 1986 and then subsequent fall from favor due to high rates of false positives, overdiagnosis, and overtreatment (as many as 20–50% of men diagnosed could have remained asymptomatic in their lifetimes). Though few risk factors have been characterized, the best known include race (men of African descent are at higher risk), genetics (e.g., BRCA1/2 mutations), and obesity. The Gleason scoring system is used for histopathological staging and is combined with clinical staging for prognosis and treatment. National guidelines have grown more conservative over the past decades in management, recommending watchful waiting and observation in older men with low to intermediate risk disease. Among higher risk patients, prostatectomy (robotic is preferred) and/or external beam radiotherapy is the most common interventions, followed by ADT maintenance. Following progression on androgen deprivation therapy (ADT) (known as castration-resistance), next generation endocrine therapies like enzalutamide, often in combination with cytotoxic agent docetaxel, are standard of care. Other promising treatments include Radium-223 for bone metastases, pembrolizumab for programmed death ligand-1 (PDL1) and microsatellite instability (MSI) high disease, and poly ADP ribose polymerase (PARP) inhibitors for those with mutations in homologous recombination (most commonly BRCA2). Full article

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies, mainly originating from hormone-secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout the multiple endocrine neoplasia type 1 (MEN-1) gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signalling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the role and the potential therapeutic implications of gene mutations and NOTCH signalling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential role across all NEN subtypes is required. Full article