Prostate Cancer Relapse Research Articles

AR (CAG)n Microsatellite and APEX1 c.444T>G (p.Asp148Glu) Polymorphisms as Independent Prognostic Biomarkers in Prostate Cancer: Insights from an Argentinian Cohort.

Prostate cancer (PCa) is the leading malignancy and the third most common cause of cancer-related death in Argentinian men. Predicting outcomes in localized PCa remains difficult due to tumor heterogeneity. In this study, we assessed the impact of AR (CAG)n and APEX1 c.444T>G polymorphisms on biochemical relapse in Argentine patients with localized PCa. We genotyped blood samples from 123 PCa patients for AR (CAG)n and APEX1 p.Asp148Glu (c.444T>G) polymorphisms. Associations with clinicopathological parameters and biochemical relapse-free survival (BRFS) were assessed. AR (CAG)20-23 was associated with a family history of breast/ovarian cancer (p = 0.0469). The combination of AR (CAG)20-23 and APEX1 c.444TT/GG correlated with a 2.89 times higher risk of biochemical relapse (log-rank p = 0.006). Multivariable analysis confirmed AR and APEX1 polymorphisms as independent predictors of biochemical relapse (HR = 3.95, p = 0.002). In patients with PSA levels <10 ng/mL, combined AR (CAG)20-23 and APEX1 c.444TT/GG genotypes were significantly associated with an increased risk of biochemical relapse (HR = 2.61, p = 0.044). Multivariable analysis confirmed the prognostic significance of these genotypes (HR = 3.44, p = 0.02). This study has identified AR (CAG)n and APEX1 c.444T>G polymorphisms as independent predictors of PCa relapse in Argentinian patients, suggesting their potential use in improving prognostic models.

Predictive factors for biochemical relapse in non-metastatic prostate cancer following primary radiotherapy

&amp;lt;p&amp;gt;&amp;lt;strong&amp;gt;Aim&amp;lt;/strong&amp;gt; To investigate the predictors of biochemical relapse (BCR) among patients with non-metastatic prostate cancer treated with radiotherapy as the first-line therapy.&amp;amp;nbsp;&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Methods&amp;lt;/strong&amp;gt; The study included 91 patients diagnosed with prostate cancer at the University Clinical Centre in Tuzla, Bosnia and Herzegovina. After the radiation treatment as the first line of treatment, the patients were monitored for the next 36 months. If patients were classified in medium and high-risk groups, hormone therapy was administered. The occurrence of BCR was determined based on prostate-specific antigen (PSA) values. Potential prognostic parameters, including Gleason score (GS), PSA, tumour size (TNM), and standardised risk classification (RC), were monitored.&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Results&amp;lt;/strong&amp;gt; A total of 46 (50.5%) patients were aged 66-75, with a median PSA of 14.50 ng/mL. A Gleason score &amp;amp;lt;6 was found in 72 (79.1%) of patients, and 31 (34.1%) had T2c tumours. The BCR occurred in 32 (35.2%) patients, with a median relapse time of 18 months. Significant predictors of BCR were Gleason score &amp;amp;ge;6 (OR:4.46; p=0.006) and tumour stage &amp;amp;gt;T2b (OR:3.59; p=0.021). The RC showed an Area Under Curve (AUC) of 0.634 (p=0.050), indicating its potential diagnostic accuracy.&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Conclusion&amp;lt;/strong&amp;gt; Gleason score &amp;amp;ge;6 and TNM&amp;amp;gt;T2b are significant predictors of biochemical relapse in prostate cancer patients treated with radiotherapy. These results emphasize the need for additional monitoring and timely treatment of clinical disease progression in patients with Gleason score &amp;amp;ge;6 and tumour stage &amp;amp;gt;T2b.&amp;lt;/p&amp;gt;

Imaging assessment of prostate cancer recurrence: advances in detection of local and systemic relapse.

Prostate cancer (PCa) relapse, defined either by persistent PSA levels (after RP) or biochemical recurrence (BCR), is a common occurrence. The imaging evaluation of patients experiencing PCa relapse has undergone significant advancements in the past decade, notably with the introduction of new Positron Emission Tomography (PET) tracers such as Prostate-specific membrane antigen (PSMA), and the progress in functional Magnetic Resonance Imaging (MRI). This article will explore the role of traditional imaging, the evolution of MRI towards the development of the Prostate Magnetic Resonance Imaging for Local Recurrence Reporting (PI-RR) scoring system, and how next-generation imaging is enhancing diagnostic accuracy in the setting of PCa relapse, which is essential for adopting personalized strategies that may ultimately impact outcomes.

Targeting PLOD2 suppresses invasion and metastatic potential in radiorecurrent prostate cancer

BackgroundMetastatic relapse of prostate cancer after radiotherapy is a significant cause of prostate cancer-related morbidity and mortality. PLOD2 is a mediator of invasion and metastasis that we identified as being upregulated in our highly aggressive radiorecurrent prostate cancer cell line.MethodsPatient dataset analysis was conducted using a variety of prostate cancer cohorts. Prostate cancer cell lines were treated with siRNA, or the drug PX-478 prior to in vitro invasion, migration, or in vivo chick embryo (CAM) extravasation assay. Protein levels were detected by western blot. For RNA analysis, RNA sequencing was conducted on PLOD2 knockdown cells and validated by qRT-PCR.ResultsPLOD2 is a negative prognostic factor associated with biochemical relapse, driving invasion, migration, and extravasation in radiorecurrent prostate cancer. Mechanistically, HIF1α upregulation drives PLOD2 expression in our radiorecurrent prostate cancer cells, which is effectively inhibited by HIF1α inhibitor PX-478 to reduce invasion, migration, and extravasation. Finally, the long non-coding RNA LNCSRLR acts as a promoter of invasion downstream of PLOD2.ConclusionsTogether, our results demonstrate for the first time the role of PLOD2 in radiorecurrent prostate cancer invasiveness, and point towards its potential as a therapeutic target to reduce metastasis and improve survival outcomes in prostate cancer patients.

Correlation of PSA blood levels with standard uptake value maximum (SUV max ) and total metabolic tumor volume (TMTV) in 18F-PSMA-1007 and 18F-choline PET/CT in patients with biochemically recurrent prostate cancer.

In this prospective study, we investigated the correlation between prostate-specific antigen (PSA) levels in the blood of patients with prostate cancer in biochemical recurrence after radical treatment with the semiquantitative parameters standard uptake value maximum (SUV max ) and the total metabolic tumor volume (TMTV) in the metastatic foci depicted in 18F-prostate-specific membrane antigen (PSMA)-1007 and 18F-choline PET/computed tomography (CT) imaging. We prospectively examined 104 patients with biochemical relapse of prostate cancer after primary definitive treatment. All patients underwent one 18F-PSMA-1007 and one 18F-choline PET/CT examination in randomized order within a time frame of 10 days and were followed for at least 6 months (182 ± 10 days). The semiquantitative parameters of SUV max and metabolic tumor volume (MTV) of each neoplastic lesion in PET/CT imaging were calculated, and further summation of each MTV value was done to calculate the TMTV. According to the Spearman correlation analysis, a positive correlation was found between PSA levels and SUV max and TMTV scores in the metastatic foci of 18F-PSMA-1007 PET/CT ( r = 0.24 and 0.35, respectively; P < 0.05) and SUV max in the lesions of 18F-choline PET/CT ( r = 0.28; P < 0.0239). However, a positive but NS correlation was demonstrated between values of PSA and TMTV for each lesion in the 18F-choline PET/CT study ( r = 0.22; P = 0.0795). The detection rate of the different PSA levels with a cutoff of 1 ng/ml was higher for 18F-PSMA-1007 than 18F-choline. In biochemical relapse patients there is a positive correlation between PSA levels in the blood and the semiquantitative parameters SUV max and TMTV of the metastatic foci in the 18F-PSMA-1007 and 18F-Choline PET/CT imaging.

Glomerulonephritis as a paraneoplastic event from prostate cancer relapse

Abstract Objective We wish to investigate whether there is a known connection between prostate cancer and glomerulonephritis. Methods We present a case report of a patient whom we diagnosed with rapidly progressive glomerulonephritis as a result of prostate cancer relapse. Results In rare cases, prostate cancer is associated with crescentic glomerulonephritis. Conclusion Every patient with cryptic glomerulonephritis should be screened for cancer.

Risk Factors for Relapse of Prostate Cancerafter Radical Prostatectomy in Chinese Population.

To analyze the risk factors for the relapse of prostate cancer (PC) after radical prostatectomy (RP) and build a nomogram as a predictive model. Materials andMethods: The patients who underwent PR from March 2019 to February 2022 were retrospectively enrolled in our hospital's case system. During the follow-up process, two consecutive prostate-specific antigens (PSA) ≥0.2 μg/L were performed. And needle biopsy was performed to further determine whether the patient had prostate cancer recurrence. According to the follow-up results, the patients were divided into non-relapsed and relapsed groups.The related parameters of the two groups were collected. Independent risk factors for postoperative recurrence were determined using a Cox proportional hazards regression model. Statistical software, R, was used to build nomograms. R software was used to construct a nomogram, and the prediction effect of the nomogram was evaluated by the calibration curve and the area under the ROC curve (AUC). Among the 367 patients who underwent RP, 112 (30.52%) had, and 255 (69.48%) did not have relapses after surgery. Cox multivariableregression analysis revealed that preoperative Gleason score, preoperative PSA, pathological staging, positive margin, and seminal vesicle invasion, were the risk factors for postoperative recurrence after RP (all P < 0.05). Verification of the predictive model by ROC curve demonstrated that the AUC of the ROC curves for patients' relapses 3 and 5 years after RP was 0.986 (95%CI0.975-0.998) and 0.974 (95%CI0.961-0.987), respectively. This model validation showed that the results of the predictive model were basically consistent with the actual results, suggesting that the nomogram was able to accurately predict a patient's relapse. The nomogram of this study was a good predictor of postoperative recurrence of PC after RP, which will help doctors provide personalized treatment and follow-up strategies for patients.

Texture Analysis in [18F]-Fluciclovine PET/CT Aids to Detect Prostate Cancer Biochemical Relapse: Report of a Preliminary Experience

Background. As artificial intelligence is expanding its applications in medicine, metabolic imaging is gaining the ability to retrieve data otherwise missed by even an experienced naked eye. Also, new radiopharmaceuticals and peptides aim to increase the specificity of positron emission tomography (PET) scans. Herein, a preliminary experience is reported regarding searching for a texture signature in routinely performed [F18]Fluciclovine imaging in prostate cancer. Materials and methods. Twenty-nine patients who underwent a PET/computed tomography (CT) scan with [18F]Fluciclovine because of biochemical prostate cancer relapse were retrospectively enrolled. First- and second-order radiomic features were manually extracted in lesions visually considered pathologic from the Local Image Features Extraction (LIFEx) platform. Statistical analysis was performed on a database of 29 lesions, one1 per patient. The dataset was split to have 20 lesions for the model training set and 9 lesions for the validation set. The Wilcoxon–Mann–Whitney test was used on the training set to select the most significant features (p-value &lt; 0.05) predicting the dichotomous outcome in a univariate analysis. Results. The best model for predicting the outcome was found to be a multiple logistic linear regression model with two features as variables: an intensity histogram type and a gray-level size zone-based type. Conclusions. Texture analysis of [F18]Fluciclovine PET scans helps in defining prostate cancer relapse in a daily clinical setting.

Salvage Radiotherapy for Relapsed Prostate Cancer after Radical Prostatectomy Is Associated with Normal Life Expectancy

In patients with prostate cancer (PCa), salvage radiotherapy (SRT) for biochemical progression (BP) after radical prostatectomy (RP) improves PCa-specific survival. However, no prospective randomized trials have compared the effect of SRT with untreated patients. In this analysis of 151 patients who received SRT for post-RP BP, we compared their overall survival (OS) with virtual, age-matched controls (n = 151,000) retrieved from government life tables. We also investigated the risk factors associated with BP and OS and compared the prostate-specific antigen (PSA) doubling times (DTs) before and after SRT for patients with BP. The median follow-up was 9.3 years for BP and 17.4 years for OS. The risk factors significantly affecting BP were Gleason score (p &lt; 0.001), pre-SRT PSA (p = 0.003), and negative surgical margins (p = 0.003). None of these risk factors were associated with OS. In 93 patients with BP after SRT, the median PSADT was significantly prolonged compared with pre-SRT values (3.7 vs. 8.3 months, p &lt; 0.001). The OS did not differ between patients and controls (p = 0.112), and life expectancy was similar, likely due to the survival benefit of SRT. The prolonged PSADT after SRT further supports the beneficial role of SRT in this patient population. However, subsequent treatments were not systematically recorded, which may have affected the results.

Understanding the Biological Basis of Polygenic Risk Scores and Disparities in Prostate Cancer: A Comprehensive Genomic Analysis.

For prostate cancer (PCa), hundreds of risk variants have been identified. It remains unknown whether the polygenic risk score (PRS) that combines the effects of these variants is also a sufficiently informative metric with relevance to the molecular mechanisms of carcinogenesis in prostate. We aimed to understand the biological basis of PRS and racial disparities in the cancer. We performed a comprehensive analysis of the data generated (deposited in) by several genomic and/or transcriptomic projects (databases), including the GTEx, TCGA, 1000 Genomes, GEO and dbGap. PRS was constructed from 260 PCa risk variants that were identified by a recent trans-ancestry meta-analysis and contained in the GTEx dataset. The dosages of risk variants and the multi-ancestry effects on PCa incidence estimated by the meta-analysis were used in calculating individual PRS values. The following novel results were obtained from our analyses. (1) In normal prostate samples from healthy European Americans (EAs), the expression levels of 540 genes (termed PRS genes) were associated with the PRS (P < .01). (2) Ubiquitin-proteasome system in high-PRS individuals' prostates was more active than that in low-PRS individuals' prostates. (3) Nine PRS genes play roles in the cancer progression-relevant parts, which are frequently hit by somatic mutations in PCa, of PI3K-Akt/RAS-MAPK/mTOR signaling pathways. (4) The expression profiles of the top significant PRS genes in tumor samples were capable of predicting malignant PCa relapse after prostatectomy. (5) The transcriptomic differences between African American and EA samples were incompatible with the patterns of the aforementioned associations between PRS and gene expression levels. This study provided unique insights into the relationship between PRS and the molecular mechanisms of carcinogenesis in prostate. The new findings, alongside the moderate but significant heritability of PCa susceptibility contributed by the risk variants, suggest the aptness and inaptness of PRS for explaining PCa and disparities.

28S rRNA-Derived Fragments Represent an Independent Molecular Predictor of Short-Term Relapse in Prostate Cancer.

Prostate cancer (PCa) is a global health concern, being a leading cause of cancer-related mortality among males. Early detection and accurate prognosis are crucial for effective management. This study delves into the diagnostic and prognostic potential of 28S rRNA-derived fragments (rRFs) in PCa. Total RNA extracted from 89 PCa and 53 benign prostate hyperplasia (BPH) tissue specimens. After 3'-end polyadenylation, we performed reverse transcription to create first-strand cDNA. Using an in-house quantitative real-time PCR (qPCR) assay, we quantified 28S rRF levels. Post-treatment biochemical relapse served as the clinical endpoint event for survival analysis, which we validated internally through bootstrap analysis. Our results revealed downregulated 28S rRF levels in PCa compared to BPH patients. Additionally, we observed a significant positive correlation between 28S rRF levels and higher Gleason scores and tumor stages. Furthermore, PCa patients with elevated 28S rRF expression had a significantly higher risk of post-treatment disease relapse independently of clinicopathological data. In conclusion, our study demonstrates, for the first time, the prognostic value of 28S rRF in prostate adenocarcinoma. Elevated 28S rRF levels independently predict short-term PCa relapse and enhance risk stratification. This establishes 28S rRF as a potential novel molecular marker for PCa prognosis.

Tumor removal limits prostate cancer cell dissemination in bone and osteoblasts induce cancer cell dormancy through focal adhesion kinase

BackgroundDisseminated tumor cells (DTCs) can enter a dormant state and cause no symptoms in cancer patients. On the other hand, the dormant DTCs can reactivate and cause metastases progression and lethal relapses. In prostate cancer (PCa), relapse can happen after curative treatments such as primary tumor removal. The impact of surgical removal on PCa dissemination and dormancy remains elusive. Furthermore, as dormant DTCs are asymptomatic, dormancy-induction can be an operational cure for preventing metastases and relapse of PCa patients.MethodsWe used a PCa subcutaneous xenograft model and species-specific PCR to survey the DTCs in various organs at different time points of tumor growth and in response to tumor removal. We developed in vitro 2D and 3D co-culture models to recapitulate the dormant DTCs in the bone microenvironment. Proliferation assays, fluorescent cell cycle reporter, qRT-PCR, and Western Blot were used to characterize the dormancy phenotype. We performed RNA sequencing to determine the dormancy signature of PCa. A drug repurposing algorithm was applied to predict dormancy-inducing drugs and a top candidate was validated for the efficacy and the mechanism of dormancy induction.ResultsWe found DTCs in almost all mouse organs examined, including bones, at week 2 post-tumor cell injections. Surgical removal of the primary tumor reduced the overall DTC abundance, but the DTCs were enriched only in the bones. We found that osteoblasts, but not other cells of the bones, induced PCa cell dormancy. RNA-Seq revealed the suppression of mitochondrial-related biological processes in osteoblast-induced dormant PCa cells. Importantly, the mitochondrial-related biological processes were found up-regulated in both circulating tumor cells and bone metastases from PCa patients’ data. We predicted and validated the dormancy-mimicking effect of PF-562,271 (PF-271), an inhibitor of focal adhesion kinase (FAK) in vitro. Decreased FAK phosphorylation and increased nuclear translocation were found in both co-cultured and PF-271-treated C4-2B cells, suggesting that FAK plays a key role in osteoblast-induced PCa dormancy.ConclusionsOur study provides the first insights into how primary tumor removal enriches PCa cell dissemination in the bones, defines a unique osteoblast-induced PCa dormancy signature, and identifies FAK as a PCa cell dormancy gatekeeper.

Extended nodal radiotherapy for prostate cancer relapse guided with [11C]-choline PET/CT: ten-year results in patients enrolled in a prospective trial.

To report long-term outcomes of relapsed prostate cancer (PC) patients treated in a prospective single-arm study with extended-nodal radiotherapy (ENRT) and [11C]-choline positron emission tomography (PET)/computed tomography (CT)-guided simultaneous integrated boost (SIB) to positive lymph nodes (LNs). From 12/2009 to 04/2015, 60 PC patients with biochemical relapse and positive LNs only were treated in this study. ENRT at a median total dose (TD) = 51.8Gy/28 fr and PET/CT-guided SIB to positive LNs at a median TD = 65.5Gy was prescribed. Median PSA at relapse was 2.3 (interquartile range, IQR:1.3-4.0) ng/ml. Median number of positive LNs: 2 (range: 1-18). Androgen deprivation therapy (ADT) was prescribed for 48 patients for a median of 30.7 (IQR: 18.5-43.1) months. Median follow-up from the end of salvage treatment was 121.8 (IQR: 116.1, 130.9) months; 3-, 5-, and 10-year BRFS were 45.0%, 36.0%, and 24.0%, respectively; DMFS: 67.9%, 57.2%, and 45.2%; CRFS: 62.9%, 53.9%, and 42.0%; and OS: 88.2%, 76.3%, and 47.9%, respectively. Castration resistance (p < 0.0001) and ≥ 6 positive LN (p = 0.0024) significantly influenced OS at multivariate analysis. Castration resistance (p < 0.0001 for both) influenced DMFS and CRFS in multivariate analysis. In PC relapsed patients treated with ENRT and [11C]-choline-PET/CT-guided SIB for positive LNs, with 10-year follow-up, a median Kaplan-Meier estimate CRFS of 67months and OS of 110months were obtained. These highly favorable results should be confirmed in a prospective, randomized trial.

46 Patterns of Relapse and Biochemical Control in Intermediate Risk Prostate Cancer Treated with High Dose Rate Brachytherapy (HDRB) Monotherapy

46 Patterns of Relapse and Biochemical Control in Intermediate Risk Prostate Cancer Treated with High Dose Rate Brachytherapy (HDRB) Monotherapy

Genomic Evolution and Transcriptional Changes in the Evolution of Prostate Cancer into Neuroendocrine and Ductal Carcinoma Types.

Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuroendocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease, and the former often arises on a background of androgen deprivation therapy, although it can also arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tissue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with three longitudinal samples over 5 years. Case 2 was a single time point after the development of treatment-related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all samples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, and 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small-cell neuroendocrine and ductal prostatic carcinoma can have a common ancestry. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

Patterns of practice regarding use of radiation therapy following radical prostatectomy: A survey of Radiation Oncologists and Urologists in Australia and New Zealand.

This study aimed to investigate the patterns of practices of radiation oncologists (ROs) and urologists in Australia and New Zealand with respect to the utilisation of post-prostatectomy radiation therapy (RT) and help guide the development of an update to the existing Faculty of Radiation Oncology Genito-Urinary Group post-prostatectomy guidelines. ROs and urologists with subspecialty practice in prostate cancer from Australia and New Zealand were invited to participate in an online survey comprised of clinical scenarios regarding post-prostatectomy RT. Sixty-five ROs and 28 urologists responded to the survey. In the setting of low-risk biochemical relapse, the threshold for initiating RT was lower for ROs than urologists. ROs were more likely than urologists to recommend adjuvant RT for node-positive disease. When salvage RT was advised for a pT3N0R1 recurrence, there was no consensus amongst ROs on whether to add either ADT or nodal treatment over prostate bed RT alone. For a solitary PSMA-avid pelvic lymph node recurrence, whole pelvis RT with androgen deprivation therapy was the preferred treatment option (72% ROs, 43% urologists). Most ROs (92%) recommended conventionally fractionated RT to 66-70 Gy, with a boost to any PSMA PET avid recurrent disease. This survey highlights the marked discordance in practice for the management of prostate cancer relapse post-prostatectomy. This is seen not only between specialties but also within the radiation oncology community. This emphasises the need for an updated evidence-based guideline to be produced.

Depth of PSA nadir and subsequent PSA progression-free survival in patients (pts) with high-risk biochemically relapsed prostate cancer: Results from the phase 3 PRESTO study (AFT-19).

5077 Background: In the phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (Apa) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated the association between PSA nadir within 3 months of treatment initiation with subsequent PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months, without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + Apa, or ADT + Apa + AAP, stratified by PSADT (&lt; 3 vs 3–9 months), with post-treatment follow-up. The association between PSA nadir within the first three months on treatment with subsequent PSA PFS was analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + Apa (N = 168) or ADT + Apa + AAP (N = 169). 463 pts were evaluable for PSA nadir at 3 months. Across the three treatment arms, a PSA nadir of less than 0.1, between 0.1 – 0.2, and ≥ 0.2 ng/mL within the first three months of treatment was observed in 86.3%, 4.4%, and 9.3% of patients, respectively. A PSA nadir of &lt; 0.2 ng/mL was reached within 3 months of treatment initiation in 79.8%, 96.9%, and 95.0% of pts randomized to the ADT, ADT + Apa, and ADT + Apa + AAP arms, respectively. The association between time to PSA nadir and subsequent PSA PFS was -0.30 (standard error = 0.03, Kendall’s tau modified for bivariate censoring), and median time to PSA nadir was 2.0 months (interquartile range 1.12 – 4.76 months). Failure to reach a PSA nadir &lt; 0.2 ng/mL within the first three months of treatment was associated with a significantly shorter PSA PFS compared to pts with a PSA nadir ≤ 0.1 ng/mL (median PSA PFS of 13.9 vs. 22.8 months from 3 months post-treatment initiation; hazard ratio = 5.60, 95% CI: 3.58 – 8.75, p &lt; 0.0001). There was also a significant difference in PSA PFS in those with a three-month PSA nadir between 0.1 – 0.2 vs ≤ 0.1 ng/mL (median PSA PFS 17.4 vs 22.8 months, HR = 2.63, 95:CI: 1.49 – 4.63, p = 0.0008). Conclusions: Using a landmark analysis at 3 months, a failure to reach PSA nadir less than 0.1 ng/mL within three months following initiation of ADT in BRPC is associated with shorter time to subsequent progression following treatment discontinuation. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissues and whole blood RNA in pts with suboptimal PSA nadir to identify potential markers of relative androgen pathway inhibitor resistance. Clinical trial information: NCT03009981 .

NKX3.1 immunohistochemistry and methylome profiling in mesenchymal chondrosarcoma: additional diagnostic value for a well-defined disease?

Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript involving HEY1 and NCOA2. Histologically, the tumours show a biphasic appearance consisting of an undifferentiated blue and round cell component as well as islands of highly differentiated cartilage. Particularly in core needle biopsies, the chondromatous component can be missed and the non-specific morphology and immunophenotype of the round cell component can cause diagnostic challenges. We applied NKX3.1 immunohistochemistry which was recently reported as a highly specific marker as well as methylome and copy number profiling to a set of 45 well characterised MCS cases to evaluate their potential diagnostic value. Methylome profiling revealed a highly distinct cluster for MCS. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. NKX3.1 immunohistochemistry showed positivity in 36% of tumours, the majority of which was rather focal and weak. Taken together, NKX3.1 expression showed a low sensitivity but a high specificity in our analysis. Methylome profiling on the other hand represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. Furthermore, it can aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.

Multiparametric imaging guided HDR interventional radiotherapy (brachytherapy) boost in localized prostate cancer: a multidisciplinary experience.

The aim of this study was to report a monoinstitutional multidisciplinary experience about the use of multiparametric imaging to identify the areas with higher risk of relapse in localized prostate cancer, with the purpose of allowing a biologically planned target dose escalation. We performed a retrospective evaluation of patients diagnosed with prostate cancer who received treatments at our Interventional Oncology Center with interstitial interventional radiotherapy from 2014 to 2022. Inclusion criteria were histologically confirmed localized prostate cancer; and National Comprehensive Cancer Network (NCCN) risk class unfavorable intermediate or high/very high risk. The diagnostic work-up included multiparametric Magnetic resonance imaging (MRI), multiparametric Transrectal ultrasound (TRUS), Positron Emission Tomography Computed Tomography (PET-CT) with choline or PSMA (or alternatively bone scan). All patients were assessed and received one treatment with interstitial high-dose-rate interventional radiotherapy (brachytherapy) delivering external beam radiotherapy (46 Gy). All procedures were performed using transrectal ultrasound guidance under general anesthesia and the prescribed doses were 10 Gy to the whole prostate, 12 Gy to the peripheral zone and 15 Gy to the areas at risk. We report the data of 21 patients who were considered for the statistical analysis with a mean age of 62.5 years. The mean PSA nadir was 0.03 ng/ml (range 0-0.09). So far, no biochemical nor radiological recurrences have been recorded in our series. Regarding acute toxicity, the most commonly reported side effects were G1 urinary in 28.5% of patients and G2 urinary in 9.5%; all recorded acute toxicities resolved spontaneously. We present a real-life experience of biologically planned local dose escalation by interventional radiotherapy (brachytherapy) boost, followed by external beam radiotherapy in patients with intermediate unfavorable- or high/very high risk. The local control and the biochemical control rates are proved to be excellent and the toxicity profile tolerable.