Novel systems biology experimental pipeline reveals matairesinol's antimetastatic potential in prostate cancer: an integrated approach of network pharmacology, bioinformatics, and experimental validation.

Matairesinol (MAT), a plant lignan renowned for its anticancer properties in hormone-sensitive cancers like breast and prostate cancers, presents a promising yet underexplored avenue in the treatment of metastatic prostate cancer (mPC). To elucidate its specific therapeutic targets and mechanisms, our study adopted an integrative approach, amalgamating network pharmacology (NP), bioinformatics, GeneMANIA-based functional association (GMFA), and experimental validation. By mining online databases, we identified 27 common targets of mPC and MAT, constructing a MAT-mPC protein-protein interaction network via STRING and pinpointing 11 hub targets such as EGFR, AKT1, ERBB2, MET, IGF1, CASP3, HSP90AA1, HIF1A, MMP2, HGF, and MMP9 with CytoHuba. Utilizing DAVID, Gene Ontology (GO) analysis highlighted metastasis-related processes such as epithelial-mesenchymal transition, positive regulation of cell migration, and key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including cancer, prostate cancer, PI3K-Akt, and MAPK signaling, while the web resources such as UALCAN and GEPIA2 affirmed the clinical significance of the top 11 hub targets in mPC patient survival analysis and gene expression patterns. Our innovative GMFA enrichment method further enriched network pharmacology findings. Molecular docking analyses demonstrated substantial interactions between MAT and 11 hub targets. Simulation studies confirmed the stable interactions of MAT with selected targets. Experimental validation in PC3 cells, employing quantitative real-time reverse-transcription PCR and various cell-based assays, corroborated MAT's antimetastatic effects on mPC. Thus, this exhaustive NP analysis, complemented by GMFA, molecular docking, molecular dynamics simulations, and experimental validations, underscores MAT's multifaceted role in targeting mPC through diverse therapeutic avenues. Nevertheless, comprehensive in vitro validation is imperative to solidify these findings.

Effect of BMI and hemoglobin A1c on survival of veterans with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide.

BACKGROUND: Abiraterone acetate and enzalutamide are two common therapies for metastatic castration-resistant prostate cancer (mCRPC) that have shown improved overall survival (OS). The drugs have different mechanisms of action with limited comparative trials to evaluate treatment in patients with comorbidities such as obesity and diabetes. This is important since abiraterone requires the co-administration of prednisone. We assessed the relationship between body mass index (BMI), hemoglobin A1c (HbA1c), treatment, and survival in mCRPC. METHODS: Veterans treated with abiraterone or enzalutamide within the Veterans Health Administration between September 10, 2014 and June 2, 2017 with BMI and HbA1c were identified. Additional variables included age, baseline prostate-specific antigen at first treatment for mCRPC, race, and the Charlson comorbidity index. Differences in survival were compared using the Kaplan-Meier method. Cox proportional hazards regression modeling was used to assess the association between initial treatment, BMI, and HbA1c while adjusting for confounding variables. RESULTS: A total of 5231 patients were identified with a mean age of 75.2 years and 1241 (23.7%) were of black race. BMI was associated with OS with longest median survival of 29.8 months in BMI ≥ 30 (n = 1903), 23.9 months in BMI 25-30 (n = 1879), 15.9 months in BMI 18.5-25 (n = 1336), and 9.2 months in BMI < 18.5 (n = 113, p < 0.001). In a multivariable model compared to normal BMI, increased mortality was observed in BMI < 18.5 (adjusted hazard ratio (aHR) = 1.583, 95% confidence interval [CI]: 1.29-1.94) and a decreased mortality in BMI 25-30 (aHR = 0.751, 95% CI: 0.69-0.81) and BMI > 30 (aHR = 0.644, 95% CI: 0.59-0.70). In 3761 patients with BMI > 25, there was longer OS in patients treated with enzalutamide (28.4 months, n = 1615) compared to abiraterone (25.8 months, n = 2146, p = 0.002). In 1470 patients with BMI < 25, there was no difference in OS between patients treated with enzalutamide (16.0 months, n = 597, p = 0.513) or abiraterone (16.1 months, n = 873). In 1333 veterans with HbA1c ≥ 6.5%, initial prescription of enzalutamide was associated with longer OS compared with abiraterone (24.4 vs. 20.5 months, p = 0.0005). In 2088 patients with HbA1c < 6.5%, there was no difference in OS in patients who were initially prescribed enzalutamide versus abiraterone (25.7 vs. 23.5 months, p = 0.334). CONCLUSIONS: In veterans with mCRPC, increased BMI was associated with longer survival. Veterans with BMI > 25 had longer survival with enzalutamide compared to abiraterone. In patients with HbA1c ≥ 6.5%, enzalutamide was associated with longer survival compared to abiraterone. These results may facilitate prognostication of survival and improve treatment selection based on patient comorbidities.

Natural course of metastatic castration-resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone-sensitive setting.

BACKGROUND: Androgen deprivation therapy (ADT) intensification (ADTi) (i.e., ADT with androgen receptor pathway inhibitor or docetaxel, or both) has significantly improved survival outcomes of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of prior ADTi in the mHSPC setting on the disease presentation and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) is not well characterized. In this study, our objective was to compare the disease characteristics and survival outcomes of patients with new mCRPC with respect to receipt of intensified or nonintensified ADT in the mHSPC setting. METHODS: In this institutional review board-approved retrospective study, eligibility criteria were as follows: patients diagnosed with mCRPC, treated with an approved first-line mCRPC therapy, and who received either intensified or nonintensified ADT in the mHSPC setting. Progression-free survival (PFS) was defined from the start of first-line therapy for mCRPC to progression per Prostate Cancer Working Group 2 criteria or death, and overall survival (OS) was defined from the start of first-line therapy for mCRPC to death or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for potential confounders. RESULTS: Patients (n = 387) treated between March 20, 2008, and August 18, 2022, were eligible and included: 283 received nonintensified ADT, whereas 104 were treated with ADTi. At mCRPC diagnosis, patients in the ADTi group were significantly younger, had more visceral metastasis, lower baseline prostate-specific antigen (all p < 0.01), and lower hemoglobin (p = 0.027). Furthermore, they had significantly shorter PFS (median 4.8 vs. 8.4 months, adjusted hazard ratio [HR]: 1.46, 95% confidence interval [95% CI]: 1.07-2, p = 0.017) and OS (median 21.3 vs. 33.1 months, adjusted HR: 1.53, 95% CI: 1.06-2.21, p = 0.022) compared to patients in the nonintensified ADT group. CONCLUSION: Patients treated with ADTi in the mHSPC setting and experiencing disease progression to mCRPC had more aggressive disease features of mCRPC (characterized by a higher number of poor prognostic factors at mCRPC presentation). They also had shorter PFS on first-line mCRPC treatment and shorter OS after the onset of mCRPC compared to those not receiving ADTi in the mHSPC setting. Upon external validation, these findings may impact patient counseling, prognostication, treatment selection, and design of future clinical trials in the mCRPC setting. There remains an unmet need to develop novel life-prolonging therapies with new mechanisms of action to improve mCRPC prognosis in the current era.

Impact of PSA nadir, PSA response and time to PSA nadir on overall survival in real-world setting of metastatic hormone-sensitive prostate cancer patients.

BACKGROUND: To evaluate the impact of prostate-specific antigen (PSA) nadir, PSA response and time to PSA nadir (TTN) in metastatic hormone-sensitive prostate cancer (mHSPC) patients on overall survival (OS) in the era of combination therapies. METHODS: Different PSA nadir cut-offs (including ultra-low PSA) were tested for OS analyses. Additionally, PSA response ≥99% was evaluated, as well as TTN categorized as <3 versus 3-6 versus 6-12 versus >12 months. Multivariable Cox regression models predicted the value of PSA nadir cut-offs, PSA response and TTN on OS. Sensitivity analyses were performed in de novo and high volume mHSPC patients. RESULTS: Of 238 eligible patients, PSA cut-offs of <0.2 versus 0.2-4.0 versus >4.0 ng/mL differed significantly regarding median OS (96 vs. 56 vs. 44 months, p < 0.01), as well as in subgroup analyses of de novo mHSPC patients and multivariable Cox regression models. A more stringent PSA cut-off of <0.02 versus 0.02-0.2 versus >0.2 ng/mL also yielded significant median OS differences (not reached vs. 96 vs. 50 months, p < 0.01), even after additional multivariable adjustment. A PSA response ≥99% was also significantly associated with better OS than counterparty with <99% response, even after multivariable adjustment (both p < 0.02). When TTN groups were compared, patients with longer TTN harbored more extended OS than those with short TTN (<3 vs. 3-6 vs. 6-12 vs. >12 months: 34 vs. 50 vs. 67 vs. 96 months, p < 0.01). Virtually similar results were observed in sensitivity analyses for high volume mHSPC patients. CONCLUSIONS: In times of combination therapies for mHSPC, a PSA nadir of respectively, <0.2 and <0.02 ng/mL are associated with best OS rates. Moreover, a relative PSA response ≥99% and a longer TTN are clinical important proxies for favorable OS estimates.

Survival of patients with lymph node versus bone versus visceral metastases according to CHAARTED/LATITUDE criteria in the era of intensified combination therapies for metastatic hormone-sensitive prostate cancer.

BACKGROUND: The first approvals of novel systemic therapies within recent years for metastatic hormone-sensitive (mHSPC) were mainly based on improved overall survival (OS) and time to castration resistance (ttCRPC) in mHSPC patients stratified according to CHAARTED low (LV) versus high volume (HV) and LATITUDE low (LR) versus high-risk (HR) disease. METHODS: Relying on our institutional tertiary-care database we identified all mHSPC stratified according to CHAARTED LV versus HV, LATITUDE LR versus HR and the location of the metastatic spread (lymph nodes (M1a) versus bone (M1b) versus visceral/others (M1c) metastases. OS and ttCRPC analyses, as well as Cox regression models were performed according to different metastatic categories. RESULTS: Of 451 mHSPC, 14% versus 27% versus 48% versus 12% were classified as M1a LV versus M1b LV versus M1b HV versus M1c HV with significant differences in median OS: 95 versus 64 versus 50 versus 46 months (p < 0.001). In multivariable Cox regression models HV M1b (Hazard Ratio: 2.4, p = 0.03) and HV M1c (Hazard Ratio: 3.3, p < 0.01) harbored significant worse than M1a LV mHSPC. After stratification according to LATITUDE criteria, also significant differences between M1a LR versus M1b LR versus M1b HR versus M1c HR mHSPC patients were observed (p < 0.01) with M1b HR (Hazard Ratio: 2.7, p = 0.03) and M1c HR (Hazard Ratio: 3.5, p < 0.01), as predictor for worse OS. In comparison between HV M1b and HV M1c, as well as HR M1b versus HR M1c no differences in ttCRPC or OS were observed. CONCLUSIONS: Significant differences exist between different metastatic patterns of HV and LV and HR and LR criteria. Best prognosis is observed within M1a LV and LR mHSPC patients.

A single-center retrospective review of metastatic prostate cancer on PSMA position emission tomography/computed tomography: Beyond lymph nodes and bones.

BACKGROUND: Prostate-specific membrane antigen (PSMA) Positron emission tomography/computed tomography (PET/CT) has become a crucial imaging modality for the staging of patients with prostate cancer. The purpose of this study is to retrospectively determine the frequency, anatomical distribution, and clinical-pathologic correlates of extra-nodal and extra-osseous metastatic prostate cancer detected on PSMA PET/CT. METHODS: All available 650 PSMA PET/CT performed in patients with biopsy-proved prostate cancer in our institution between September 2021 and December 2023 were reviewed for the presence of extra-nodal and extra-osseous metastatic disease (M1C disease). Thirty-four patients with M1C disease were identified. RESULTS: The most frequent sites of visceral/soft tissue metastases were the lungs (58.8%), liver (23.5%) and adrenal glands (20.6%). 75% of patients with lung metastases detected on PSMA PET/CT had concurrent intrathoracic lymph node involvement. A higher frequency of patients with M1C disease (55.9%) had a high Gleason score. The median prostate-specific antigen (PSA) level at the time of the PSMA scan was 20.16 ng/mL. There was a statistically significant association between PSA level and osseous disease (p = 0.004), as well as PSA level and nodal disease (p = 0.008). While a large number of patients had concurrent osseous and nodal disease (82.4% and 79.4%, respectively), no visceral/soft tissue sites demonstrated a significant association with the presence of osseous or nodal involvement. CONCLUSIONS: Given the increasing utilization of PSMA PET/CT, increased knowledge of the location and pattern of distribution of visceral/soft tissue metastatic sites is crucial not only for staging but also to better understand patterns of therapeutic response. We identified the lungs, liver and adrenal glands as the most common visceral/soft tissue metastatic sites from prostate cancer. We found that higher PSA levels at the time of PSMA PET/CT imaging were positively associated with concurrent osseous and nodal involvement.

Early response monitoring during [177Lu]Lu-PSMA I&T therapy with quantitated SPECT/CT predicts overall survival of mCRPC patients: subgroup analysis of a Swiss-wide prospective registry study.

PURPOSE: To assess early tumor response with quantitated SPECT/CT and to correlate it with clinical outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with 177Lutetium-PSMA I&T therapy. METHODS: Single-center, observational study, part of the prospective Swiss national cancer registry study investigating the safety and efficacy of [177Lu]Lu-PSMA I&T (EKNZ: 2021-01271) in mCRPC patients treated with at least two cycles of [177Lu]Lu-PSMA I&T 6-weekly. After the first and second cycle quantitated SPECT/CT (Symbia Intevo, Siemens) was acquired 48 h after injection (three fields of view from head to thigh, 5 s/frame) and reconstructed using xQuant® (48i, 1 s, 10-mm Gauss). Image analysis: The PSMA-positive total tumor volumes (TTV) were semi-automatically delineated using a SUV threshold of 3 with MIMencore® (version 7.1.3, Medical Image Merge Software Inc.). Changes in TTV, highest tumor SUVmax, and total tumor SUVmean between cycles 1 and 2 were calculated and grouped into a) stable or decrease and b) increase. Serum PSA levels were assessed at each therapy cycle and at follow-up until progression or death. Changes in TTV, PSA, SUVmax, and SUVmean were correlated with PSA-progression-free survival (PSA-PFS) and the overall survival (OS) using the Kaplan-Meier methodology (log-rank test). RESULTS: Between 07/2020 and 04/2022, 111 patients were screened and 73 finally included in the data analysis. The median follow-up was 8.9 months (range 1.4-26.6 months). Stable or decreased TTV at cycle 2 was associated with longer OS (hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.09-0.86, p < 0.01). Similar, stable, or decreased PSA was associated with longer OS (HR 0.21; CI 0.07-0.62, p < 0.01) and PSA-PFS (HR 0.34; 95% CI 0.16-0.72, p < 0.01). Combining TTV and PSA will result in an augmented prognostic value for OS (HR 0.09; CI 0.01-0.63; p < 0.01) and for PSA-PFS (HR 0.11; CI 0.02-0.68; p < 0.01). A reduction of SUVmax or SUVmean was not prognostically relevant, neither for OS (p 0.88 and 0.7) nor for PSA-PFS (p 0.73 and 0.62, respectively). CONCLUSION: Six weeks after initiating [177Lu]Lu-PSMA I&T, TTV and serum PSA appear to be good prognosticators for OS. Combined together, TTV + PSA change demonstrates augmented prognostic value and can better predict PSA-PFS. Larger studies using TTV change prospectively as an early-response biomarker are warranted for implementing management change towards a more personalized clinical practice.

Creatine supplementation and resistance training to preserve muscle mass and attenuate cancer progression (CREATINE-52): a protocol for a double-blind randomized controlled trial.

BACKGROUND: Muscle mass is important for metastatic prostate cancer survival and quality of life (QoL). The backbone of treatment for men with metastatic castration sensitive prostate cancer (mCSPC) is androgen deprivation therapy (ADT) with an androgen signaling inhibitor. ADT is an effective cancer treatment, but it facilitates significant declines in muscle mass and adverse health outcomes important to mCSPC survivors, such as fatigue, and reductions in physical function, independence, insulin sensitivity, and QoL. In non-metastatic CSPC survivors, resistance training (RT) preserves muscle mass and improves these related health outcomes, but the biggest barrier to RT in CSPC survivors of all stages is fatigue. Creatine monohydrate supplementation coupled with RT (Cr + RT) may address this barrier since creatine plays a critical role in energy metabolism. Cr + RT in cancer-free older adults and other clinical populations improves muscle mass and related health outcomes. Evidence also suggests that creatine supplementation can complement cancer treatment. Thus, Cr + RT is a strategy that addresses gaps in survivorship needs of people with mCSPC. The purpose of this parallel, double-blind randomized controlled trial is to test the effects of 52-weeks of Cr + RT compared with placebo (PLA) and RT (PLA + RT) on muscle mass, other related health outcomes, and markers of cancer progression. METHODS: We will carry out this trial with our team's established, effective, home-based, telehealth RT program in 200 mCSPC survivors receiving ADT, and evaluate outcomes at baseline, 24-, and 52-weeks. RT will occur twice weekly with elastic resistance bands, and an established creatine supplementation protocol will be used for supplementation delivery. Our approach addresses a major facilitator to RT in mCSPC survivors, a home-based RT program, while utilizing a supervised model for safety. DISCUSSION: Findings will improve delivery of comprehensive survivorship care by providing a multicomponent, patient-centered lifestyle strategy to preserve muscle mass, improve health outcomes, and complement cancer treatment (NCT06112990).

Impact of homologous recombination repair/BReast CAncer (BRCA) gene alterations on survival in a real-world setting of metastatic prostate cancer.

OBJECTIVE: To investigate alterations of homologous recombination repair (HRR) and especially BReast CAncer 1/2 (BRCA1/2) gene on overall survival (OS). Moreover, to explore the effect of inhibition of poly(ADP-ribose)-polymerase (PARPi) as systemic therapy for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Of all HRR-screened patients with metastatic prostate cancer, baseline characteristics were sampled. Kaplan-Meier estimates and multivariable Cox regression models predicted the effect of HRR/BRCA1/2 alterations on OS. RESULTS: Of 196 eligible patients, 61 (31%) harboured any HRR and 40 (20%) BRCA1/2 alterations. Of HRR alterations, 40 (66%) vs six (10%) vs five (8.2%) vs four (6.6%) vs two (3.3%) vs four (6.6%) were BRCA1/2 vs Ataxia-telangiectasia mutated kinase (ATM) vs checkpoint kinase 2 (CHEK2) vs cyclin-dependent kinase 12 (CDK12) vs Fanconi anaemia complementation Group A (FANCA) vs positive for other mutations. Of these, 30% received a PARPi. OS differed significantly between HRR-positive vs -negative patients. Specifically in hormone-sensitive prostate cancer, the median OS was 63 (HRR positive) vs 57 (BRCA1/2 positive) vs 113 months (HRR negative) (P ≤ 0.01). In mCRPC, OS was 42 (HRR positive) vs 41 (BRCA1/2 positive) vs 70 months (HRR negative) (P ≤ 0.01). HRR and BRCA1/2 alterations were associated with worse OS after multivariable adjustment. Finally, patients with mCRPC with BRCA1/2 mutation treated without PARPi harboured worse OS than patients with BRCA1/2 mutation and PARPi therapy (median OS: 33 vs 48 months, P < 0.03). CONCLUSION: Incidence of HRR alteration in a clinical real-world setting is high when using blood- and tissue-based tests. Patients with HRR/BRCA alterations have worse outcomes resulting in significant OS differences between HRR/BRCA-positive patients with mCRPC with and without PARPi usage vs HRR/BRCA-negative patients.

Prediction of undetectable circulating tumor DNA by comprehensive genomic profiling assay in metastatic prostate cancer: the SCRUM-Japan MONSTAR SCREEN project.

BACKGROUND: Undetectable circulating tumor DNA (ctDNA) is an obstacle to performing comprehensive genomic profiling in daily practice to identify genomic alterations. We investigated the associations between clinicopathological factors and undetectable ctDNA using a commercially available comprehensive genomic profiling assay in metastatic prostate cancer. PATIENTS AND METHODS: Patients treated with systemic treatment for metastatic prostate cancer were included. ctDNA was analyzed by FoundationOne®Liquid CDx at enrollment. The associations between clinicopathological characteristics and ctDNA detection were analyzed. RESULTS: The number of bone metastasis was associated with ctDNA detection (odds ratio [95% confidence interval], 13.6 [1.71-108], P = 0.014). An algorithm predicting ctDNA detection using clinicopathological parameters was created. If ≥ 4 bone metastases were observed, ctDNA detection was estimated to be 98.9%. Among the patients with < 4 bone metastases, if two or three features among ISUP grade group 5, PSA level ≥ 10 ng/ml, and castration resistance were present, the ctDNA detection rate was 96.7% while the ctDNA detection rate was 86.3% if no or only one feature was present. CONCLUSIONS: An algorithm created in this study is helpful in determining when to undertake comprehensive genomic profiling assay using blood.

The Cost-Effectiveness of Germline BReast CAncer Gene Testing in Metastatic Prostate Cancer Followed by Cascade Testing of First-Degree Relatives of Mutation Carriers.

OBJECTIVES: Patients with metastatic prostate cancer (mPCa) with BReast CAncer gene (BRCA) mutations benefit from targeted treatments (eg, olaparib). In addition, family members of affected patients have increased risk of hereditary cancers and benefit from early detection and prevention. International guidelines recommend genetic testing in mPCa; however, the value for money of testing patients with mPCa and cascade testing of blood-related family members has not been assessed. In this context, we evaluated the cost-effectiveness of germline BRCA testing in patients with mPCa followed by cascade testing of first-degree relatives (FDRs) of mutation carriers. METHODS: We conducted a cost-utility analysis of germline BRCA testing using 2 scenarios: (1) testing patients with mPCa only and (2) testing patients with mPCa and FDRs of those who test positive. A semi-Markov multi-health-state transition model was constructed using a lifetime time horizon. The analyses were performed from an Australian payer perspective. Decision uncertainty was characterized using probabilistic analyses. RESULTS: Compared with no testing, BRCA testing in mPCa was associated with an incremental cost of AU$3731 and a gain of 0.014 quality-adjusted life-years (QALYs), resulting in an incremental cost-effectiveness ratio of AU$265 942/QALY. Extending testing to FDRs of variant-positive patients resulted in an incremental cost-effectiveness ratio of AU$16 392/QALY. Probability of cost-effectiveness at a willingness-to-pay of AU$75 000/QALY was 0% in the standalone mPCa analysis and 100% in the cascade testing analysis. CONCLUSION: BRCA testing when performed as a standalone strategy in patients with mPCa may not be cost-effective but demonstrates significant value for money after the inclusion of cascade testing of FDRs of mutation carriers.

Real-world clinical outcomes among patients with metastatic castration-sensitive prostate cancer initiating apalutamide.

Aim: To describe overall survival, time to castration resistance and castration resistance-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) initiating apalutamide in a US oncology network. Patients & methods: Patients with mCSPC initiating apalutamide on or after 17 September 2019 from an electronic health record-derived deidentified database were included. Patients were followed from apalutamide initiation and were censored at the earlier of end of clinical activity or data availability (31 October 2022). Results: At 12 and 24 months, overall survival rates were 91.0 and 88.3%, rates of castration sensitivity were 85.7 and 72.1%, and castration resistance-free survival rates were 80.2 and 65.9%, respectively. Conclusion: Real-world clinical outcomes of patients with mCSPC treated with apalutamide were comparable to results from the phase III TITAN trial.

This study looked at health outcomes among 176 patients receiving a prostate cancer medication, apalutamide. The average age of patients was 72 years, and approximately two-thirds of patients were White. Two years after starting apalutamide, most patients remained alive and their cancer did not progress.

Psoas mass index at the level of the third lumbar vertebra on computed tomography is a prognostic predictor for metastatic castration-sensitive prostate cancer.

BACKGROUND: Computed tomography-defined low skeletal muscle mass is associated with oncological outcomes in patients with prostate cancer. However, its association with the outcomes of hormone-treated metastatic castration-sensitive prostate cancer remains unclear. We aimed to determine the association between metastatic castration-sensitive prostate cancer and psoas muscle parameters. METHODS: We retrospectively reviewed 121 patients with N1 and/or M1 metastatic castration-sensitive prostate cancer who underwent primary androgen deprivation therapy between 2005 and 2021, either by administration of luteinizing hormone-releasing hormone agonist/antagonist or by surgical castration accompanied by bicalutamide, a first-generation antiandrogen. Before treatment administration, the psoas muscle index at the level of the third lumbar vertebra (psoas muscle area [cm2]/height2 [m2]) and the mean Hounsfield units of the psoas muscle were evaluated using non-contrast computed tomography and in relation to oncological outcomes. RESULTS: The median follow-up was 56.9 months. Furthermore, during follow-up, 82 (67.7%) and 53 (43.8%) patients progressed to castration-resistant prostate cancer and died, respectively. Multivariate analysis of castration-resistant prostate cancer-free survival and overall survival showed significant differences in the Gleason score, clinical N-stage, and psoas muscle index (median cutoff: 3.044 cm2/m2). CONCLUSIONS: Pretreatment psoas muscle index is an independent predictor of poor castration-resistant prostate cancer-free survival and overall survival in patients with N1 and/or M1 metastatic castration-sensitive prostate cancer.

Evaluating limited biopsy templates for men with markedly elevated PSAs.

INTRODUCTION: To define the smallest prostate needle biopsy (PNB) template necessary for accurate tissue diagnosis in men with markedly elevated PSA while decreasing procedural morbidity. MATERIALS AND METHODS: We performed a chart review of 80 men presenting with a newly elevated PSA > 100 ng/mL who underwent biopsy (PNB or metastatic site). For patients who underwent a full 12-core biopsy, simulated templates of 2- to 10-cores were generated by randomly drawing subsets of biopsies from their full-template findings. Templates were iterated to randomize core location and generate theoretical smaller template outcomes. Simulated biopsy results were compared to full-template findings to determine accuracy to maximal Grade Group (GG) diagnosis. RESULTS: Amongst those that underwent PNB, 93% had GG 4 or 5 disease. Twenty-two (40%) underwent a full 12-core biopsy, 20 (37%) a 6-core biopsy, and only 8 (15%) had fewer than six biopsy cores sampled at our hospital. Simulated templates with 2-, 4-, 6-, and 8-cores correctly diagnosed prostate cancer in all patients, and accurately identified the maximal GG in 82%, 91%, 95%, and 97% of patients, respectively. The biopsy locations most likely to detect maximal GG were medial mid and base sites bilaterally. A 4-core template of these sites would have accurately detected the maximal GG in 95% of patients relative to a full 12-core template. CONCLUSIONS: In men presenting with PSA > 100 ng/mL, decreasing from a 12-core to a 4-core prostate biopsy template results in universal cancer detection and minimal under-grading while theoretically decreasing procedural morbidity and cost.

The trend of dental check-up and prevalence of dental complications following the use of bone modifying agents in patients with metastatic breast and prostate cancer: analysis of data from the Korean National Health Insurance Service.

BACKGROUND: Bone-modifying agents (BMA) are key components in the management of cancer patients with bone metastasis. Despite their clinical benefits, the use of BMA is associated with dental adverse events (AEs) including medication-related osteonecrosis of the jaw (MRONJ). This study investigated the frequency of dental surveillance before BMA treatment and the prevalence of dental AEs including MRONJ, after BMA treatment in patients with bone metastasis from breast and prostate cancer using data from the national health insurance system. METHODS: Data, including age, cancer diagnosis, administered BMA, and dental AEs during cancer treatment, of patients with bone metastasis from breast and prostate cancer who received at least one infusion of BMA between 2007 and 2019 were extracted from the Korean National Health Insurance Service (KNHIS) dataset. RESULTS: Of the 15,357 patients who received BMA, 1,706 patients (11.1%) underwent dental check-ups before BMA treatment. The proportion of patients receiving dental check-up increased from 4.4% in 2007 to 16.7% in 2019. Referral to dentists for a dental check-up was more active in clinics/primary hospitals than general/tertiary hospitals, and medical doctors and urologists actively consulted to dentists than general surgeons, regardless of the patient's health insurance status. After BMA treatment, 508 patients (3.8%) developed dental AEs, including abscess (42.9%), acute periodontitis (29.7%), acute pericoronitis (14.9%), and MRONJ (12.5% of dental AEs cases, 0.5% of total BMA treated patients). CONCLUSIONS: Considering the long treatment period in patients with metastatic cancer, coordination between dentists and oncologists is necessary to ensure appropriate dental management before the initiation of BMA.

Homologous Recombination Repair Deficiency in Metastatic Prostate Cancer: New Therapeutic Opportunities.

More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of BRCA1 or BRCA2 pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript.

Distinguishing spheno-orbital metastatic prostate cancer mimicking a meningioma using novel 18F-PSMA PET/CT imaging.

A 78-year-old man presented with acute-onset left temporal pain, eyelid swelling, and double vision. Computed tomography (CT) demonstrated a left sphenoid wing mass with extra-osseous intra-orbital and intracranial extension, thought to be a typical sphenoid wing meningioma by the primary team. The patient was admitted for an urgent craniotomy, which was planned for the following day. However, upon consultation with ophthalmic plastic surgery, concern was raised for an alternative diagnosis given the atypical timeline, inflammatory changes, and uncharacteristic imaging findings of mixed lytic and sclerotic bony changes without hyperostosis on CT and extensive peri-lesional dural thickening and enhancement on magnetic resonance imaging. A serum prostate-specific antigen was elevated to 206 ng/mL. Subsequent positron emission tomography (PET)/CT using 18F-fluorodeoxyglucose radiotracer was negative for metastatic disease. A prostate-specific membrane antigen (PSMA) PET/CT was then obtained and demonstrated extensive metastases. An orbital biopsy revealed poorly differentiated prostatic adenocarcinoma. The significant incongruence between the standard PET/CT and PSMA PET/CT highlights the value of this novel advanced radiographic modality in narrowing the differential diagnosis and determining the extent of disease. Findings of widespread metastasis on the PSMA PET/CT ultimately helped to avoid a large, morbid neurosurgical intervention in this patient, allowing for a minimally invasive orbital biopsy to characterize the tumor for therapeutic targeting.

Spatial whole transcriptome profiling of primary tumor from patients with metastatic prostate cancer.

Prostate cancer (PCa) is a highly heterogeneous disease in terms of its molecular makeup and clinical prognosis. The prostate tumor microenvironment (TME) is hypothesized to play an important role in driving disease aggressiveness, but precise mechanisms remain elusive. In our study, we used spatial transcriptomics to explore for the first time the spatial gene expression heterogeneity within primary prostate tumors from patients with metastatic disease. In total, we analyzed 5459 tissue spots from three PCa patients comprising castration-resistant (CRPC) and neuroendocrine (NEPC) disease stages. Within CRPC, we identified a T cell cluster whose activity might be impaired by nearby regulatory T cells, potentially mediating the aggressive disease phenotype. Moreover, we identified Hallmark signatures of epithelial-mesenchymal transition in a cancer-associated fibroblast (CAF) cluster, indicating the aggressive characteristic of the primary TME leading to metastatic dissemination. Within NEPC, we identified active immune-stroma cross-talk exemplified by significant ligand-receptor interactions between CAFs and M2 macrophages. Further, we identified a malignant cell population that was associated with the down-regulation of an immune-related gene signature. Lower expression of this signature was associated with higher levels of genomic instability in advanced PCa patients (SU2C cohort, n = 99) and poor recurrence free survival in early-stage PCa patients (TCGA cohort, n = 395), suggesting prognostic biomarker potential. Taken together, our study reveals the importance of whole transcriptome profiling at spatial resolution for biomarker discovery and for advancing our understanding of tumor biology.

18 F-sodium fluoride positron emission tomography quantitation of bone metastases in African American and non-African American men with metastatic prostate cancer.

BACKGROUND: Bone is the most common site of metastases in men with prostate cancer. The objective of this study was to explore potential racial differences in the distribution of tumor metastases in the axial and appendicular skeleton. METHODS: We conducted a retrospective review of patients with metastatic prostate cancer to the bone as detected by 18 F-sodium fluoride positron emission tomography/computed tomography (18 F-NaF PET/CT) scans. In addition to describing patients' demographics and clinical characteristics, the metastatic bone lesions, and healthy bone regions were detected and quantified volumetrically using a quantitative imaging platform (TRAQinform IQ, AIQ Solutions). RESULTS: Forty men met the inclusion criteria with 17 (42%) identifying as African Americans and 23 (58%) identifying as non-African Americans. Most of the patients had axial (skull, ribcage, and spine) disease. The location and the number of lesions in the skeleton of metastatic prostate cancer patients with low disease burden were not different by race. CONCLUSIONS: In low-disease burden patients with metastatic prostate cancer, there were no overall differences by race in the location and number of lesions in axial or appendicular skeleton. Therefore, given equal access to molecular imaging, African Americans might derive similar benefits. Whether this holds true for patients with a higher disease burden or for other molecular imaging techniques is a topic for further study.

Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer.

BACKGROUND: We performed a secondary analysis of ACIS study to determine if synchronous versus metachronous metastatic presentation has any association with survival and treatment response to dual androgen receptor axis-targeted therapy (ARAT) in docetaxel naïve metastatic castrate resistant prostate cancer (mCRPC). METHODOLOGY: In this phase III randomized controlled trial, docetaxel naïve mCRPC patients were randomized to either apalutamide or placebo combined with abiraterone and prednisone. Multivariable Cox regression models were applied to determine the adjusted association of M-stage with radiographic progression-free survival (rPFS) and overall survival (OS). To determine the heterogeneity of treatment effect based on metastatic stage (M-stage) at presentation, Cox regression was applied with interaction terms between M-stage and treatment. RESULTS: Among 972 patients, 432 had M0, 334 had M1, while M-stage at presentation was unknown in 206. There was no association of M-stage at presentation with rPFS in patients with prior local therapy (LT) (hazard ratio for M1-stage: 1.22 [95% confidence interval: 0.82-1.82]; unknown: 1.03 [0.77-1.38]) or without prior LT (M1-stage: 0.87 [0.64-1.19]; unknown: 1.15 [0.77-1.72]) with no significant heterogeneity. Similarly, there was no association of M-stage with OS in patients with prior LT (M1-stage: 1.04 [0.81-1.33]; unknown: 0.98 [0.79-1.21]) or without prior LT (M1-stage: 0.95 [0.70-1.29]; unknown: 1.17 [0.80-1.71]) with no significant heterogeneity. Based on M-stage at presentation, we did not find any significant heterogeneity in treatment effect on rPFS (interaction p = 0.13), and OS (interaction p = 0.87). CONCLUSION: M-stage at presentation had no association with survival in chemotherapy-naïve mCRPC. We did not find any statistically significant heterogeneity in efficacy of dual ARAT based on synchronous versus metachronous presentation.