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NGS-based molecular panel analysis of metastatic prostate cancer for daily routine: How often do we detect druggable mutations?
203 Background: Guidelines recommend molecular analysis to identify druggable mutations after failure of the first-line systemic therapy for metastatic prostate cancer (mPCA). We report our results of molecular diagnostics in mCRPC patients. Methods: From 2018 to 2023, 311 mCRPC patients underwent molecular panel analysis of archived prostatectomy samples (n=96) or CT-guided biopsies of progressive metastases (n=215) using standardized NGS procedures after the failure of first- or second-line systemic therapy. Mutation analysis was initially performed using NGS with a custom "Prostate Cancer Panel" of 18 multiplex PCR amplicons (AR, ATM, AURKA/MYC, BRCA1/2, CDK12, CTNNB1, DLL3, ETS family, FOXA1, FOXO1, MED12, PIK3CA, PTEN, RAD51C, TP53, Wnt-Pathway), generated using a GeneRead DNAseq Custom Panel V2 (Qiagen). Since 2023, we perform apply the TSO500 panel in selected cases. Analysis of HRD was performed by combining BRCA1 and BRCA2 mutations with the HRD score (Genomic ScarScore GSS) using the HANDLE HRD Focus Panel (Halo-shape Annealing and Defer-Ligation Enrichment, AmoyDx). The data were evaluated using the following thresholds: tumor cell content ≥ 30%, GScore positive at ≥ 50, HRD positive: GScore at ≥ 50 or BRCA1/2 category 4/5 mutation. In addition MSI-high and mutations of MSH2, MSH6, PMS2, and MLH1 were analysed. The following databases were reviewed to identify druggable mutations: OncoKB, ClinVar, JAX-CKB, COSMIC, and My Cancer Genome. Results: Out of 311 biopsies, 299 (96%) had sufficient DNA content for NGS. NGS was performed from prostate (31%), lymph node (30%), visceral (15%), and bone (24%) metastases with informative DNA retrival in 95%, 95%, 92%, and 85%, respectively. Overall, 157 patients (50.5%) had no or non druggable mutations, while 154 patients (49.5%) exhibited druggable mutations. HRD gene mutations (BRCA1/2, ATM, CDK12, CHEK2, FANCA, Rad51C) and inactivating p53 mutations were observed in 66 patients (22%). 3 patients had p53 mutations with gain-of-function resulting in ATM inactivation. 50% HRD gene mutations including a positive HRD score were pathogen and treated with PARPi resulting in a progression-free survival of 3-28 months. Activating androgen receptor mutations and inactivating PTEN/activating PIK3Ca mutations were found in 42 (14%) and 24 (8%) patients, resp. Switch of treatment for AR mutation resulted in PFS of 6-9 months. Mismatch repair deficiency/MSI high mutations were identified in 3 cases who received pembrolizumab with a PFS of 4-8 months. Conclusions: NGS analysis in mCRPC reveals mutations in two-thirds of patients, of which 41% are already druggable. Only 50% of druggable mutations are based on BRCA1/2 or ATM. NGS analysis should be integrated into the diagnostic armamentarium following failure of first-line systemic therapy for mCRPC.
Enzymatic conversion of blood group B kidney prevents hyperacute antibody-mediated injuries in ABO-incompatible transplantation
Machine learning prediction of glaucoma by heavy metal exposure: results from the National Health and Nutrition Examination Survey 2005 to 2008
Site-specific disease progression in patients with metastatic renal cell carcinoma treated with first-line nivolumab plus ipilimumab or axitinib-based immunotargeted combinations.
478 Background: Data on site-specific progression patterns in metastatic renal cell carcinoma (mRCC) treated with immuno-oncology agents are limited. This study aimed to characterize sites of progression in patients receiving nivolumab plus ipilimumab (Nivo-Ipi) or axitinib-based immunotargeted combinations in the first-line setting. Methods: A retrospective, observational cohort study included patients with clear-cell mRCC who received either Nivo-Ipi (Cohort A) or pembrolizumab-axitinib and avelumab-axitinib (Cohort B) from 2018 to 2024. The primary objective was to assess the occurrence of new lesions in different organs. Secondary analysis evaluated disease progression by an increase of more than 20% in target lesion size. Results: A total of 334 patients were identified, with radiographic progression observed in 86.3% (107/124) of Cohort A and 60% (126/210) of Cohort B. In the ITT population (n=233), the median age at mRCC diagnosis was 59.7 years (range 31–84), 79% were male, 74% had undergone nephrectomy, 61% had intermediate IMDC risk, and 64% had two or more metastatic sites. Cohort B had a younger median age (60.2 vs. 65.4 years), a higher incidence of bone metastases (28.6% vs. 13.1%), and more favorable risk (15.1% vs. 0.9%) compared to Cohort A. The site-specific rate of new lesions differed between cohorts (Table). Progression due to increased target lesions occurred in 60.7% (65/107) of Cohort A and 77.8% (98/126) of Cohort B patients. Conclusions: New lesion development was more frequent with Nivo-Ipi, with lymph nodes being the most common site of new lesions of mRCC across both cohorts. Cohort An=107 Cohort Bn=126 Baseline At the time of progression Baseline At the time of progression Patients with new lesions, n (%) - 42 (39.3) - 28 (22.2) Sites of metastases, n (%) Lung 73 (68) 81 (76) 76 (60) 79 (63) Lymph node 55 (51) 94 (88) 68 (54) 81 (64) Liver 27 (25) 28 (26) 39 (31) 47 (37) Bone 14 (13) 26 (24) 36 (29) 41 (33) Adrenal gland 19 (18) 20 (19) 20 (16) 28 (22) Contralateral kidney 5 (5) 5 (5) 1 (0.8) 2 (1.6) Brain 1 (1) 2 (2) 4 (3) 4 (3) Soft tissues 4 (4) 4 (4) 1 (0.8) 1 (0.8) Pancreas 2 (2) 3 (3) 0 (0) 2 (1.6) Other* 5 (5) 7 (7) 9 (7) 9 (7) *Thyroid gland, pleura, peritoneum, ovary, breast.
Optyx study: Clinical characteristics and preferences for initiating relugolix in a cohort of US patients in real-world care settings.
67 Background: Relugolix is the only oral androgen deprivation therapy indicated for advanced prostate cancer (PC). The OPTYX study is the first prospective study to collect evidence on the long-term safety, effectiveness, treatment patterns, disease course, and patient outcomes with relugolix in real-world care. Enrollment is completed and this analysis assessed key baseline variables, reasons for starting relugolix, and treatment patterns. Methods: The multi-center observational OPTYX study enrolled men with PC starting relugolix across various disease stages and treatment regimens (e.g., mono or combination therapy). Enrollment occurred in diverse clinical settings including urology, oncology, and radiation oncology. Eligibility required intent to treat with relugolix for more than 4 months. Data collected included baseline demographics, clinical characteristics, reasons for initiating treatment, treatment patterns, and quality of life (FACT-P) questionnaires from Oct 2022 to Sept 2024. Results: By September 2024, 999 men were enrolled and received relugolix with a median treatment duration of 242 days. The median age was 71 years; 77.4% self-identified as White, 16.4% as Black. Over 80% submitted FACT-P questionnaires at baseline. Disease states included localized (42.0%), locally advanced (16.7%), biochemical recurrence (11.2%), metastatic castration sensitive PC (18.7%), non-metastatic (1.5%), metastatic castration resistant PC (4.8%), and unknown (5.0%). Of these, 476 men (47.7%) received relugolix in combination with other PC therapies including radiation and systemic therapies. Prior ADT was reported in 21.0% of patients. Mean (SD) baseline testosterone and PSA were 293.1 (227.8) ng/dL and 61.3 (342.4) ng/mL, respectively. The top reasons physicians prescribed relugolix were preference for oral over injection administration (41.5%), rapid testosterone suppression (34.6%), and safety (29.0%), while patients reported physician recommendation (72.3%), oral over injection (36.4%), and rapid testosterone recovery (10.2%). Conclusions: The OPTYX study enrolled 999 patients to assess real-world experience with relugolix. Nearly half started relugolix with other therapies. Many patients and physicians preferred the oral formulation, and other top reasons for initiation included safety and rapid testosterone suppression and recovery. Clinical trial information: NCT05467176 . Relugolix Initiation Preference n (%) By Physician By Patient Oral Instead of Injection 415 (41.5) 364 (36.4) Rapid Testosterone Suppression 346 (34.6) 98 (9.8) Safety Profile 290 (29.0) 95 (9.5) Efficacy Data 255 (25.5) 66 (6.6) Rapid Testosterone Recovery 209 (20.9) 102 (10.2) Tolerability 119 (11.9) 55 (5.5) Co-morbid Disease 76 (7.6) 17 (1.7) Physician Recommended 60 (6.0) 722 (72.3) Other/Unknown 45 (4.5) 22 (2.2)
First-line therapies analysis in advanced/metastatic urothelial carcinoma: Prognostic insights with propensity score analysis and RNA-seq.
713 Background: The combination of antibody-drug conjugates (ADCs) and immunotherapy has great prospects for first-line treatment of advanced urothelial carcinoma (UC). This study aimed to explore the efficacy, safety, and prognostic biomarkers of disitamab vedotin (DV) combined with a PD-1 inhibitor and compared them with other first-line regimens without DV. Methods: Patients with advanced UC received first-line treatment and were enrolled retrospectively from July 2021 to December 2023 in two cancer centers. Propensity score (PS) matching analysis was used to compare the DV group and the non-DV group. In the DV group, RNA-seq was used to analyze differential expressed genes. Results: A total of 97 patients were included. The 1-year overall survival (OS) and progression-free survival (PFS) rates were 74.4% and 49.7%, respectively. PS score and first-line treatment regimen were independent prognostic factors for both OS and PFS. Survival analysis showed that DV combined with PD-1 inhibitor significantly improved PFS compared with other 3 regimens, including chemotherapy alone (P≤0.01), PD-1 inhibitor plus chemotherapy (P≤0.01), and PD-1 inhibitor alone (P≤0.01). DV combined with PD-1 inhibitor also led to better OS compared to chemotherapy (P≤0.01) or PD-1 inhibitor alone(P≤0.01), with a trend toward improved OS versus PD-1 inhibitor plus chemotherapy (P＝0.129). After PS matching, there were 40 patients, each in the DV group and Non-DV group. There were significant differences between the DV group and Non-DV group in terms of objective response rate (77.5% vs.37.5%, p=0.001), 1-year PFS rate (72% vs.22.2%, p=0.000), and 1-year OS rate (84% vs. 62%, p=0.003). Additionally, differentially expressed genes were identified between patients using DV with PFS >1 year and PFS <1 year and RNA-Seq analysis highlighted enriched pathways such as cytosolic and metabolic pathways, offering potential insights into DV resistance mechanisms. Conclusions: The first-line regimen of DV plus immunotherapy for patients with advanced UC was more effective and safer than the regimen without DV.
Evaluating survival in aggressive variant prostate cancer patients undergoing PSMA radioligand therapy.
259 Background: Aggressive variant prostate cancer (AVPC) is a subtype of metastatic castrate-resistant prostate cancer (mCRPC) characterized by several high-risk features. AVPC is associated with poorer overall survival and has limited response to androgen receptor targeted therapy, although it often shows some responsiveness to chemotherapy. In this study, we evaluated the outcomes of AVPC patients who received Prostate-Specific Membrane Antigen (PSMA) radioligand therapy (RLT). Methods: This retrospective study included 201 mCRPC patients who received Lutetium-177, [ 177 Lu]-PSMA RLT at two academic centers. Patients were classified as having AVPC based on the presence of at least one of the following eight criteria: exclusive visceral metastases (n=1), predominantly lytic bone metastasis (n=1), bulky lymphadenopathy or pelvic mass (≥5 cm) (n=4), low PSA (≤10 ng/mL) at initial presentation plus high-volume (≥20) bone metastases (n=0), serum CEA and/or LDH levels twice the upper limit of normal at the time of treatment (n=5), a short interval (≤6 months) to CRPC (n=7), small cell/neuroendocrine carcinoma morphology (n=5), and the presence of two or more genomic defects among TP53, RB1, and PTEN (n=13). Results: Of the 201 patients, 34 (16.9%) were classified as having AVPC (Table). The PSA50 response rate was 55% in the AVPC group and 60% in the non-AVPC group. The median overall survival (OS) (median time from the start of therapy to the last follow-up or death) was 171 days for the AVPC group and 282 days for the non-AVPC group. Although, the Kaplan-Meier plot only suggested a trend toward worse survival in AVPC patients compared to non-AVPC patients, the difference did not reach statistical significance (log-rank test p-value = 0.179). Conclusions: Our study suggests patients with AVPC may benefit from PSMA RLT and should be considered for this treatment if they are eligibly. Further studies are needed for a better understanding of this patient population. Details of patients. AVPC Non AVPC N=201 34 167 Age 1 (mean, year) 64.38 64.09 PSA 2 (mean, ng/mL) 331 251 PSA 3 (mean, ng/mL) 717 504 PSA50 (%) 55 60 OS/FU (median, day) 171 282 1 Age at the time of therapy. 2 Baseline PSA at diagnosis. 3 Most recent PSA prior to therapy.
Rare earth stibolyl and bismolyl sandwich complexes
Abstract The design of molecular rare earth complexes to achieve unique magnetic and bonding properties is a growing area of research with possible applications in advanced materials and molecular magnetics. Recent efforts focus on developing ligand frameworks that can enhance magnetic characteristics. Here we show the synthesis and characterization of a class of rare earth complexes, [(η5-C4R4Sb)Ln(η8-C8H8)] and [(η5-C4R4Bi)Ln(η8-C8H8)], featuring η5-coordinated stibolyl and bismolyl ligands. The ligand aromaticity and bonding situation within these complexes are investigated by quantum chemical calculations. Magnetic studies of the ErIII analogues reveal large barriers and intriguing properties, including waist-restricted hysteresis and slow relaxation of the magnetization, making them single-molecule magnets. Comparison between the experimental barrier and CASSCF-SO calculations indicates that relaxation in all systems occurs through high-energy excited states. These findings suggest that stibolyl and bismolyl ligands can be promising candidates for achieving high-energy barriers in Er-based SMMs, offering a pathway to molecular designs with enhanced magnetic properties.
Pharmacological and toxicological effects of Jiangfangbaoxin and determination of its components in the blood of spontaneously hypertensive rats
Homologous recombination deficiency signature (HRDsig+) and the genomic landscape of clinically advanced prostate carcinoma (CAPC).
196 Background: CAPC is very challenging with significant need for improvement in systemic therapy, including for patients (pts) with incurable disease. Recently a novel HRDsig biomarker has been linked to clinical outcomes after PARP inhibitor-based treatments. We aimed to explore HRD sig status and related biomarkers, including other GA, to generate hypothesis and inform clinical trial designs for pts with CAPC. Methods: 22,061 cases of CAPC underwent comprehensive genomic profiling (CGP) to examine all classes of genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and trinucleotide mutational signatures were determined from sequencing data. HRDsig status was calculated using a broad set of genome-wide copy number features.PD-L1 was determined by IHC using the Dako 22C3 tumor proportional score (TPS) system. Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery. Results: Overall, 2,244 (10.2%) of CAPC cases were HRDsig+. There were slightly more MSI-high cases in the HRDsig- vs HRDsig+ CAPC (3.1% vs 0.5%; P<.0001). Both TMB and PD-L1 levels were low and varied in both groups. HRD associated GA included BRCA2 and RAD21 were more frequent in the CAPC HRDsig+ cases. BRCA1 GA were extremely rare in both groups. In the HRDsig- group, 90%/49% of BRCA1 / BRCA2 mutated CAPC were mono-allelic, likely non-driver GA, respectively Higher frequencies of GA in CDK12 and SPOP (11.1% vs 5.9%; P<.0001) were found in HRDsig- cases and a higher frequency of AR GA in HRDsig+ cases. MTOR pathway related GA in PTEN were similar, although homozygous deletions of PTEN were more frequent in the HRDsig- cases (22.2% vs 19.2%; P=.0009; Table). Conclusions: With a 10.2% frequency, HRDsig+ status is a relatively common biomarker in CAPC. HRDsig+ status was associated with a higher frequency of BRCA2 GA, including homozygous deletions in >20% of these pts, which has been associated with prolonged benefit from PARPi in selected pts. Given that likely non-driver mono-allelic BRCA1/2 GA are frequently identified in HRDsig- CAPC, mono-allelic GA may not be associated with HRDsig status and might not yield similar clinical benefit from PARPi. Limitations include the retrospective nature, potential selection bias and lack of clinical outcomes annotation. Main differences in GA classes between HRDSig- and HRDSig+. HRDSig- HRDSig+ P value Age (yrs) 68 70 <.0001 AFR ancestry 15.4% 13.1% 0.0110 AR 10.8% 17.3% <.0001 BRCA2 mutation 3.3% 52.3% <.0001 BRCA2 homozygous deletion 0.6% 21.4% <.0001 CDK12 5.5% 1.2% <.0001 RAD21 7.2% 16.3% <.0001 MMR sig 4.0% 2.0% <.0001 TMB≥10 mut/Mb 4.4% 3.7% NS
A prognostic model for survival of patients with metastatic upper tract urothelial carcinoma with first-line systemic therapy.
868 Background: Upper tract urothelial carcinoma (UTUC) presents distinct clinicopathological, molecular features, and biological behaviors compared to urothelial bladder carcinoma (UBC). Currently, no prognostic model exists for metastatic UTUC (mUTUC). This study aimed to develop a prognostic model for mUTUC patients receiving first-line systemic therapy. Methods: A total of 476 patients with mUTUC who received first-line systemic therapy at Peking University Cancer Hospital from January 2005 to March 2024 were included in the analysis. Patients were randomly assigned to development and validation cohorts in a 3:1 ratio, with potential prognostic factors recorded prospectively. Univariate Cox regression analysis identified clinical and laboratory factors significantly associated with median overall survival (mOS) in the development cohort, followed by multivariate Cox regression analysis to determine independent prognostic factors. These factors were utilized to develop a prognostic model. Internal validation was conducted using the validation cohort. Results: After a median follow-up of 51.8 months, 321 patients (67.4%) had died, with a mOS of 26.6 months. The median age at diagnosis was 63 years, with 58.4% males. Common visceral metastatic organs included lung (37.8%), liver (17.9%), and adrenal gland (7.4%). The most frequent first-line treatment option was platinum-containing chemotherapy (63.7%). The number of metastatic organs ≥ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) > 1, time to distant metastasis (TTDM) < 12 months, white blood cell (WBC) count > upper limit of normal (ULN), and alkaline phosphatase (ALP) level > ULN were identified as independent prognostic risk factors for mUTUC (Table). A prognostic model for mUTUC was developed, in which the patients were stratified into three risk categories: favorable (0 risk factors, mOS 65.0 months [95% CI 35.5–94.6]), intermediate (1 risk factor, mOS 32.0 months [95% CI 25.8–38.2]), and poor (2+ risk factors, mOS 16.0 months [95% CI 12.1–19.9]) ( p < 0.05). The model's concordance statistic (c-statistic) was 0.71 in the development cohort and 0.72 in the validation cohort. Conclusions: We developed and validated a prognostic model for mUTUC patients receiving first-line systemic therapy, which can inform future clinical practice and trial designs. Results of multivariate analysis. Variables P Hazard Ratio (95% CI) Reference Category TTDM <0.01 3.01 (2.13 ~ 4.26) ≥ 12 months ECOG PS <0.01 2.28 (1.30 ~ 3.97) ≤ 1 Number of Metastatic Organs 0.01 1.41 (1.04 ~ 1.91) < 3 WBC <0.01 1.89 (1.21 ~ 2.95) ≤ ULN ALP 0.02 1.71 (1.10 ~ 2.64) ≤ ULN
Final oncological outcomes of the randomized phase II trial ARNEO: Neoadjuvant degarelix with or without apalutamide prior to radical prostatectomy for high-risk prostate cancer.
394 Background: High-risk prostate cancer (PCa) patients have a high risk of biochemical recurrence (BCR) and metastatic progression following local therapy. The ARNEO trial is a double-blind, placebo-controlled trial, evaluating the role of neoadjuvant degarelix with or without apalutamide before radical prostatectomy (RP) in men with high-risk PCa. Previously, we demonstrated that patients receiving neoadjuvant degarelix + apalutamide (n=45) had significantly better pathological response in terms of pT2 disease (51% vs. 27%; p=0.022) and minimal residual disease (MRD) (37.8% vs. 9.1%, p=0.002) compared to patients receiving degarelix alone (n=44). However, it was yet unclear if these improved pathological outcomes were also associated with improved oncological outcomes. Methods: High-risk PCa patients were randomly assigned 1:1 to degarelix + apalutamide versus degarelix + placebo for 12 weeks followed by radical prostatectomy. Follow-up of patients included PSA and testosterone testing every 6 months. No adjuvant radiotherapy was given. However, at time of PSA relapse (PSA >0.2 ng/ml) patients received a PSMA PET/CT. In case of negative imaging at time of BCR, patients received salvage radiotherapy to the prostate bed (+/- pelvic region). Results: All patients had a minimum follow-up of 36 months. Median follow-up was 46.5 months (IQR 42-53.5) in the degarelix + placebo arm and 46 months (IQR 42-53) in the degarelix + apalutamide arm. Median time to testosterone recovery (>50 ng/dl) was 6 and 7 months, respectively ( p = 0.15 ). In total, 14 (31%) patients in the degarelix + apalutamide arm developed BCR compared to 18 (41%) patients in the placebo arm (p=0.3). No statistically significant difference in BCR was observed between patients who achieved MRD and patients without MRD at final pathology (35% vs 38%; p = 1 ). However, ypT2 disease at final pathology was highly associated with improved BCR-free survival (11% vs 52%; p < 0.0001 ). Finally, we also looked at the prognostic value of achieving specimen-confined disease (SCD; defined as ypT2-3a AND negative surgical margins AND pN0). Patients with SCD at final pathology also had a significantly better BCR-free survival, compared to those patients without SCD (18% vs 65%; p < 0.0001 ). Conclusions: At 3 years follow-up, no statistically significant difference in terms of BCR was observed between patients treated with neoadjuvant degarelix + apalutamide or degarelix alone. MRD was not associated with improved BCR-free survival. However, ypT2 and SCD disease following neoadjuvant hormonal therapy was highly associated with improved BCR-free survival, suggesting that ypT2 and SCD disease might be used as a surrogate endpoints for improved BCR-free survival. Clinical trial information: NCT03080116 .
Darolutamide monotherapy in patients with castration-sensitive prostate cancer (CSPC) after biochemical recurrence (BCR): ARAMON lead-in phase results.
150 Background: Treatment of a BCR typically starts with androgen-deprivation therapy (ADT), which is limited by treatment-emergent adverse events (TEAEs) that adversely impact patients’ quality of life. The second-generation androgen receptor inhibitors (ARIs), enzalutamide and apalutamide, were explored in patients with BCR, demonstrating a reduction in prostate-specific antigen (PSA) but an increase in testosterone levels from baseline at week 25 of 114% and 134% (1,2). Given the strong efficacy and favorable tolerability of darolutamide, the open-label, phase 2 ARAMON study (NCT05526248) was conducted to investigate the reactive testosterone increase associated with darolutamide monotherapy in patients with CSPC after BCR. Here, we report lead-in phase results. Methods: Eligible patients had confirmed CSPC and a prior radical prostatectomy or radiotherapy, with a rising PSA doubling time ≤20 months, <5 asymptomatic metastatic lesions, serum testosterone >150 ng/dL, and ECOG performance status (PS) of 0/1. Patients received darolutamide 600 mg twice daily for 52 weeks. ADT was not allowed. The primary endpoint was the change in testosterone from baseline to week 12 and secondary endpoints of PSA response and TEAEs up to January 17, 2024 are also reported. Results: Of 23 evaluable patients, the median age was 74 (range, 54–84) years, the majority were white (n=14), had an ECOG PS of 0 (n=21), and Gleason score <8 (n=20). At study entry, the median PSA was 6.0 (range, 2.1–27.4) ng/mL, and most patients had nonmetastatic CSPC (n=15), 5 patients had oligometastatic disease (bone metastatic lesions <5), and 3 patients had soft tissue metastases (all <2 cm). At week 12, the mean percent increase in testosterone from baseline was 53% (95% CI, 33–76). Deep PSA responses to <0.2 ng/mL were observed in 15 patients at week 12. Feminizing TEAEs (gynecomastia, breast pain, breast tenderness, nipple pain, breast enlargement, breast mass, breast swelling, and hot flush) occurred in 18 patients and were grade 1 or 2 in 17 patients; 4 patients had dose modifications due to feminizing TEAEs and 2 patients received tamoxifen for gynecomastia. At week 12, none of the patients had discontinued darolutamide due to TEAEs. One patient discontinued darolutamide due to gynecomastia after week 12. Fatigue and hypertension occurred in 5 and 4 patients, all of which all events were grade 1/2 in severity. Conclusions: In patients with CSPC, darolutamide monotherapy increased baseline testosterone levels to a lesser degree than previously reported for other ARI agents administered as monotherapy and provided deep PSA responses at week 12. Darolutamide was well tolerated, with a low rate and severity of TEAEs. The ARAMON lead-in phase is limited by its single-arm, open-label design, and small sample size. 1. Tombal et al 2014. 2. Maluf et al 2021. Clinical trial information: NCT05526248 .
Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis
Longitudinal evaluation of the oral conditions of individuals with intellectual disabilities attending special Olympics events in Italy
Machine learning model integrating CT radiomics and circulating microRNAs to predict residual disease histology in metastatic non-seminoma testicular cancer (mNSTC).
647 Background: The primary treatment of most mNSTC is chemotherapy followed by surgery if the residual disease (RD) is >1 cm. However, conventional imaging lacks the specificity to characterize the tissue, often leading to overtreatment. This study hypothesizes that integrating CT-driven radiomics features with plasma miR371 and miR375 will enhance the predictive accuracy of Machine Learning (ML) models to predict teratoma, viable germ cell (vGCT) and fibrosis/necrosis (F/N) in mNSTC patients with RD. Methods: 111 lesions from52 patients, including residual teratoma (n=57), F/N (n=33), vGCT (n=10), and additional seminoma (n=11) for training purposes were included, split into training (N=78) and test cohorts (N=33). Lesions were lymph nodes (n=87), lung (n=21), and brain (n=3) with a median size of 1.6 cm (Q1-Q3 interval=1.2-2.73 cm). 3D Slicer version 5.6.1 was used to segment the RD > 1 cm (short axis) and extract radiomics features. Plasma miRNA levels before resection were measured by RT-PCR. Random Forest (RF), Support Vector Machine (SVM), Gradient Boosting (GB), and CatBoost (CB) ML models were evaluated to define the operating characteristics of radiomics alone (R-only) and in combination with miR371 (371) and/or miR375 (375) levels in predicting teratoma, vGCT and F/N. Results: For predicting teratoma, the best models were RF (R+375 and R+371+375), CB (R+371+375), and GB (R+371 and R+371+375). While adding miR371 or miR375 to R-only slightly improved AUC across models, the best results were achieved with the R+375+371 dataset. CB achieved AUCs ranging from 0.94 to 0.97 in training and 0.81 to 0.93 in test sets, with its highest AUC of 0.93 (95% CI: 0.78-0.97) on the R+375+371 dataset to differentiate all three classes. Similarly, GB demonstrated strong performance, achieving its highest AUC of 0.93 (95% CI: 0.79-0.96) on the R+375+371 dataset (Table). Conclusions: Integration of plasma miR371, miR375 and radiomics improved accuracy of predicting histologies across all ML models. These methods could be used to characterize the histology of RD in mNSTC patients to better inform treatment decisions. Further refinement, including incorporation of histological findings of the primary tumor, will be reported. AUC values of different ML algorithms on training and test sets. TRAINING SET TEST SET Model ±SD R R+375 R+371 R+375+371 Model (95% CI) R R+375 R+371 R+375+371 RF 0.93±0.05 0.95±0.04 0.95±0.03 0.96±0.04 RF 0.8(0.59-0.89) 0.85(0.72-0.93) 0.87(0.76-0.95) 0.91(0.78-0.95) SVM 0.84±0.06 0.84±0.09 0.89±0.11 0.89±0.09 SVM 0.72(0.54-0.80) 0.74(0.56-0.82) 0.83(0.69-0.92) 0.84(0.76-0.94) GB 0.94±0.04 0.91±0.08 0.95±0.05 0.97±0.03 GB 0.84(0.61-0.96) 0.89(0.77-0.97) 0.89(0.79-0.96) 0.93(0.79-0.96) CB 0.95±0.03 0.94±0.03 0.94±0.04 0.97±0.03 CB 0.81(0.6-0.93) 0.86(0.73-0.94) 0.89(0.78-0.97) 0.93(0.78-0.97)
Evaluation of MIR-371A-3P for clinical implementation in a CLIA-certified laboratory.
648 Background: MicroRNAs (mi-RNAs) have emerged as promising biomarkers for the detection of viable germ cell tumors (GCT). Our previous work in a research lab demonstrated optimal performance with positive results that had Cq values less than 28, an indeterminate range between 28-35 and negative results greater than 35. In this study, we assessed performance characteristics of miR-371a-3p in a CLIA certified lab at UCSD. Methods: Due to workflows, equipment and scaling, several modifications were required from our original research protocol. Ultimately, serum samples from 53 cases and 139 controls were analyzed using qPCR for miR-371a-3p in the CLIA lab. Initial runs and re-runs were conducted for the indeterminate samples. Metrics used for calculation of performance were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the curve (AUC) and Youden’s index. Results: We used two analytic pipelines for classifying positive and negative Cq values: 1) a binary cutoff of 26.9 and, 2) an indeterminate range of 25.6 to 31.5. Using the binary cutoff, a sensitivity of 86%, specificity of 98%, PPV of 94%, NPV of 95%, AUC of 0.94 and Youden index of 0.85 was observed. In contrast, initial runs on the indeterminate ranges yielded a sensitivity of 95%, specificity of 99%, PPV of 97%, NPV of 98%, AUC of 0.97 and Youden index of 0.94. However, 36% (51 of 139) controls fell into the indeterminate range. Re-runs on these samples demonstrated similar findings. Conclusions: Our data demonstrated that there are likely lab specific, protocol specific and disease-state specific analytics and thresholding for circulating miR-371a-3p testing. These factors will need to be carefully considered while moving towards clinical implementation.
Androgen suppression with abiraterone acetate, leuprolide, PARP inhibition, and stereotactic body radiotherapy (ASCLEPIuS) in high-risk and node positive prostate cancer (PCa): Phase I multicenter results.
387 Background: Level 1 evidence supports treatment of high-risk and node positive PCa using 4-9 weeks of radiotherapy (RT) combined with 18-36 months of androgen deprivation therapy (ADT) with or without abiraterone acetate plus prednisone (AAP). While effective, some cancers recur, and this prolonged treatment is associated with inconvenience and variable morbidity. We aimed to determine whether the biological synergy of stereotactic body radiotherapy (SBRT) with a 6-month combination of ADT, AAP, and the PARP inhibitor niraparib, could enable a shorter intensified, yet safe and effective, therapeutic alternative. Methods: ASCLEPIuS (NCT04194554) is a multicenter investigator-initiated phase I/II trial in high-risk or node positive, homologous recombination unselected, PCa. Patients received 6 months of ADT, AAP, niraparib and SBRT to the prostate (37.5-40 Gy) +/- pelvic lymph nodes (25 Gy). Focal prostate/nodal boosting was permitted. The phase I primary endpoint was the maximum tolerated dose (MTD) of niraparib using the time-to-event continuous reassessment method (3 dose levels: 100 mg and 200 mg held during SBRT, or 200 mg concurrent with SBRT). Dose limiting toxicities (DLT) were any persistent grade 4+ hematologic toxicity or any grade 3+ rectal/urinary toxicity at least possibly related to treatment as assessed by CTCAE v5.0. Patient reported quality of life (QOL) was assessed with the EPIC-26 short form. Linear mixed models were used to compare scores over time. Results: Accrual began in Nov. 2020 with a transition from phase I to phase II in May 2023 after enrolling 54 men. Median follow-up of the phase I cohort is 12.1 months (IQR 9.4-18.9), 80% (n=43) had Grade Group 4-5, median PSA was 17 ng/mL (range, 1-73), 15% (n=8) had cN+ disease, and 76% (n=41) received nodal RT. There were 0 DLTs to date, no grade 3+ rectal or urinary toxicities, and 5 serious adverse events at least possibly attributable to study treatment (anemia, non-rectal gastrointestinal, syncope, infection, musculoskeletal). The most common grade 3 toxicities were hypertension (n = 11, 21%) and leukopenia (n=6, 11%). Transient dose reductions or holds of AAP or niraparib occurred in 10 and 11 patients, respectively. There were no statistically significant declines in patient reported urinary QOL at 6- or 12-months post-treatment compared to baseline (all p >0.15). A transient decline in bowel QOL at 6-months occurred (p<0.01), which improved by 12-months (p=0.16). Conclusions: Our phase I findings support the short-term safety and tolerability of the combination of SBRT to the prostate and nodes, ADT, AAP, and niraparib at an MTD of 200 mg in men with high-risk or node positive PCa. Our trial completed phase II enrollment in May 2024, and longer-term safety, efficacy, and genomic correlations will be presented in the future. Clinical trial information: NCT04194554 .
The impact of pelvic radiotherapy on hematological outcomes in pediatric genitourinary rhabdomyosarcoma.
379 Background: Hematological toxicities are common with radiation therapy (RT), particularly pelvic RT, which affects nearly 50% of total body hematopoiesis. This study evaluates the impact of pelvic RT on hematological toxicities in pediatric patients with pelvic genitourinary rhabdomyosarcoma (GU-RMS). Methods: Following permission, a secondary analysis was conducted on 488 pediatric subjects with intermediate-risk RMS from the ARST0531 (NCT00354835) trial. This trial compared Vincristine, Dactinomycin, and Cyclophosphamide (VAC) to VAC alternating with Vincristine and Irinotecan (VI). Both arms received RT starting in week 4. Of these, 65 patients had pelvic GU-RMS (bladder/prostate = 60 [92.3%]; female-organ = 2 [3.1%]; paratesticular = 3 [4.6%]) and received pelvic RT, while 423 received non-pelvic RT. Multivariable logistic regression models assessed hematological toxicities (anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia) during weeks 1–43, adjusting for age, race, tumor size, and chemotherapy. Primary outcomes included any hematological toxicity, and secondary outcomes focused on febrile neutropenia (FN), infectious complications (IC), and the timing of toxicity at T1 (weeks 1–15), T2 (weeks 16–30), and T3 (weeks 31–43). Results: Subjects with GU-RMS receiving pelvic RT did not have a significantly higher risk of cytopenias compared to non-GU RMS patients. Neutropenia affected 79.4% of patients, with no significant difference between GU (73.8%) and non-GU (80.4%) (OR 0.64, p=0.16). Thrombocytopenia was significantly more common in GU-RMS patients during the first 15 weeks (OR 2.79, p=0.01). FN and IC were comparable across groups. Conclusions: Hematological toxicities were similar in pediatric GU and non-GU RMS patients. Pelvic RT was linked to an early rise in thrombocytopenia, though the difference diminished over time. Understanding these toxicities is key to improving management of pediatric RMS patients. Patient characteristics and hematological toxicities outcomes: pelvic GU vs. non-GU primary. Parameter Overall Cohort, N (%)N = 488 GU, N (%)N= 65 (14.51) Non-GU, N (%)N = 383 (85.49) p-value < 10 y.o. 306 (68.30) 56 (86.15) 250 (65.27) 0.001 Male 241 (53.79) 48 (73.85) 193 (50.39) <0.001 White Race 319 (71.21) 48 (73.85) 271 (70.76) 0.487 Cytopenia OR (95% CI, p ) Anemia 159 (35.5) 24 (36.9) 135 (35.2) 0.96(0.54-1.70, 0.89) Thrombocytopenia 131(29.2) 22 (33.8) 109 (28.4) 1.49 (0.81-2.73, 0.20) Leukopenia 196 (43.75) 26 (40) 170 (44.4) 0.73 (0.42-1.27, 0.27) Neutropenia 356 (79.4) 48 (73.8) 308 (80.4) 0.64 (0.34-1.19, 0.16) Lymphopenia 105 (23.4) 15 (23.1) 90 (23.5) 0.85 (0.45-1.61, 0.61) GU – Genitourinary; OR – Odds Ratios.