bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disease characteristics, survival outcomes, and tumor molecular landscape in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) harboring CDK12 alterations (CDK12a) receiving intensified androgen deprivation therapy (ADTi).
Authors: Hage Chehade Chadi , Gebrael Georges , Srivastava Ayana , Tripathi Nishita , Sayegh Nicolas , Mathew Thomas Vinay , Galarza Fortuna Gliceida , Chigarira Beverly , Nordblad Blake , Campbell Patrick , Tandar Clara , Li Haoran , Maughan Benjamin L. , Agarwal Neeraj , Swami Umang 
Published: January 2024

189 Background: CDK12 is one of the homologous recombination repair ( HRR) genes involved in genomic stability. The presence of CDK12a has been associated with worse survival outcomes in pts with metastatic prostate cancer [PMID: 32988971; 32462107]. However, the impact of CDK12a on outcomes in pts with mHSPC undergoing ADTi with doublets has never been reported. Herein, we sought to assess this impact while evaluating disease characteristics and tumor molecular landscape. Methods: This was a retrospective IRB-approved study. Eligibility: pts with mHSPC undergoing ADTi with either docetaxel or an androgen receptor pathway inhibitor (ARPI) (i.e., abiraterone, enzalutamide, apalutamide) harboring pathogenic CDK12a on comprehensive genomic profiling (CGP) of primary prostate tissue, metastatic lesion, or on cell-free DNA. Descriptive statistics were used for clinical features and survival outcomes. Optimal PSA response (PSA-R) was defined as PSA ≤ 0.2 ng/ml. Progression-free survival (PFS) was defined from the start of therapy for mHSPC to progression (per PCWG-3) or death from any cause. Overall survival (OS) was defined from treatment initiation for mHSPC to death from any reason or censored at the last follow-up. Concurrent genomic alterations with a frequency ≥ 10% were reported. Results: Of 323 pts with mHSPC receiving ADTi doublet with CGP testing, 19 pts harbored CDK12a and were included. The median age at diagnosis was 66.1 (56 – 77), with 63.2% of pts receiving ADTi with an ARPI. Baseline characteristics are summarized in the Table. Overall, 7 pts (36.8%) achieved an optimal PSA-R by 6 months (mo). The median PFS was 18.8 mo (95% CI 4.2 – 33.4 mo), and the median OS was 33.1 mo (95% CI 9.5 – 56.7 mo). CGP was performed on primary tissue (84.2%), followed by metastatic lesion (10.5%) and blood (5.3%). PIK3CA and TP53 were the most frequent associated genomic alterations (15.8%), followed by ARID1A, CTNNB1, RB1, and TMPRSS2 (10.5%). Conclusions: This is the first real-world study to report outcomes of pts with mHSPC and tumor CDK12a undergoing ADTi with doublets. We show these pts to have inferior outcomes than those enrolled in the registration trials of mHSPC with ADTi. Upon external validation in larger cohorts, these hypothesis-generating data may guide future clinical trial design for these pts, their preferential selection for trials, and counseling and prognostication in the clinic. [Table: see text]
Germline mutations in patients with metastatic prostate cancer: A prospective cohort study in South Korea (KCSG GU20-19).
Authors: Park Joo-Hwan , Park Inkeun , Kim Jinju , Lee Chang Seon , Park Kwonoh , Kim Jin Young , Kim Se Hyun , Kim Il Hwan , Lee Hyo Jin , Bae Woo Kyun , Huh Seok Jae , Kim Miso , Lee Min-Young , Shin Seong Hoon , Kim Ho Young , Sohn Byeong Seok , Kim In-Ho , Lee Jae-Lyun 
Published: January 2024

193 Background: Several clinical guidelines recommend screening for hereditary prostate cancer in high-risk groups for metastatic prostate cancer. However, despite the recent increase in the diagnosis of prostate cancer in Korea, genetic testing for hereditary prostate cancer is not being performed, making it impossible to know the frequency of hereditary prostate cancer. This study aimed to determine the prevalence of germline mutations in unselected Korean patients with metastatic prostate cancer. Methods: Between July 2021 and December 2022, metastatic prostate cancer patients were enrolled prospectively, without any specific selection based on age or family history. Germline mutation analysis was performed on DNA from blood via next generation sequencing using SOLIDaccuTestTM DNA HRD (NgeneBio, Korea). Results: A total of 301 patients were enrolled and the prevalence of germline mutation was analyzed. At diagnosis, the median age was 67 (46-91 years old), and the median PSA was 150 ng/mL (3.07-5000). 250 patients had a Gleason score of 8 or higher. 36 patients (12.0 %) carried a pathogenic (14/301, 4.6 %)/likely pathogenic (22/301, 7.3 %) variant in a germline mutation. Of these patients, 11 patients (3.65 %) had BRCA2 mutations. ATM (6/301, 1.99 %) was the second most frequently mutated gene, followed by FH (4/301, 1.33 %), FANCA, FANCD2, MRE11, SLFN11, SMO (0.66 % of each, 2/301), BLM, CHEK2, ERBB3, MAP2K1, and VHL (0.33 % of each, 1/301). Further analysis will be conducted to evaluate the impact of germline mutations on somatic mutation results, treatment patterns, and clinical outcomes. Conclusions: The prevalence of pathogenic germline mutations among unselected Korean patients with metastatic prostate cancer was 12.0 %. Germline mutation prevalence in this cohort was comparable to previous reported results. This study provides the framework for the development of preventive and treatment strategies based on hereditary genetic factors for prostate cancer in the Korean population. [Table: see text]
Association of BTN2A1+ microvesicles with overall survival and the role of γδ T cells as a potential therapeutic target in patients with hormone-sensitive metastatic prostate cancer.
Authors: Billon Emilien , Imbert Caroline , Gorvel Laurent , Richaud Manon , Ghossoub Rania , Girault Virginie , Fest Thierry , Gravis Gwenaelle , Olive Daniel 
Published: January 2024

194 Background: Despite the recent progress in cancer management, metastatic prostate cancer remains incurable. In the context of immunotherapy failure, we need to identify new immune biomarkers, to improve patient therapy, and explore their potential as therapeutic target. To this end, we screened the prognostic value of soluble immune checkpoints in the plasma of metastatic prostate cancer patients at diagnosis, and depicted their role in anti-tumor activities. Methods: Patients with hormone naive metastatic prostate cancer were prospectively included in the NK-Prostate study (NCT02963155). Blood collection was performed before treatment and patients were followed for 5 years. We determined by ELISA assay plasma levels the soluble form of PD-L1, Pan-BTN3A, BTN3A1, BTN2A1 and BTLA. Large extracellular vesicles (MVs) were pelleted at 10 000g by sequential ultracentrifugation. Results: 66 patients were included in the NK-Prostate with a median follow-up of 42.6 months. Only plasma levels of BTN2A1 were associated with overall survival > 50 months. Patients with enriched sBTN2A1 (soluble form of BTN2A1) presented poorer overall survival (HR for death 2.91 95%CI 1.33 – 6.33, p=0.0072) and progression-free survival than low-level patients (HR for progression 2.73 95%CI 1.48 – 5.05, p=0.0012). Prostate cancer cell line produced sBTN2A1, with 40% associated with extracellular vesicles. High level of BTN2A1+ microvesicles (MVs) were identified by spectral cytometry in patient’ plasma but not in healthy volunteer plasma, and deep phenotyping revealed that B cell-derived BTN2A1+ MVs were associated with shorter overall survival (HR 4.22 95%CI 1.68 – 10.57, p=0.0021). To evaluate the impact of BTN2A1+ MVs on γδ T cells, we generated BTN2A1 KO MVs, BTN2A1 overexpressed MVs, and BTN2A1 mutant overexpressed MVs (that do not interact with γδ TCR). We demonstrated that BTN2A1 overexpressed MVs could specifically interact with γδ T cell; and impaired their proliferation and cytotoxicity against prostate cancer cell lines (LNCaP, DU145 and PC3). Conclusions: Our study shows the negative impact of B cell derived BTN2A1+ MVs in hormone naïve metastatic prostate cancer. Plasma MVs phenotyping is an easy-to-perform test, accessible for all patients. Our results highlight the role of γδ T cell in the anti-tumor immunity in prostate cancer, making them an interesting target for immunotherapy in this pathology. Clinical trial information: NCT02963155 .
Molecular profiling and clinical relevance of low PTEN expression in patients with metastatic hormone-sensitive prostate cancer.
Authors: Garcia de Herreros Marta , Jiménez Natalia , Reig Torras Oscar , Ruiz de Porras Vicente , Pardo Juan Carlos , Font Pous Albert , Aversa Caterina , Ferrer-Mileo Laura , Mazariegos Manuel , Rodriguez-Carunchio Leonardo , Trias Isabel , Jordà Mireia , García-Esteve Samuel , Cros Costa Sara , Fernandez-Mañas Laia , Figols Mariona , Gonzalez-Billalabeitia Enrique , Chirivella Isabel , Rodriguez-Vida Alejo , Mellado-Gonzalez Begoña 
Published: January 2024

198 Background: Genomic alterations in PTEN are associated with an aggressive disease and treatment resistance in patients (pts) with castration-resistant prostate cancer (PC). The aim of the present study is to characterize the molecular alterations associated to tumor PTEN-low mRNA expression in different cohorts of metastatic hormone-sensitive PC (mHSPC) pts and its prognostic value. Methods: This is an ongoing multicenter ambispective study enrolling mHSPC pts receiving different treatment strategies. PTEN status was assessed in FFPE tumor samples by mRNA expression by nCounter and RNA-seq. PTEN expression was correlated with castration resistance-free survival (CRPC-FS) and overall survival (OS) by Kaplan Meier and multivariate Cox analysis. Results: 297 pts were included: 125 treated with ADT + docetaxel (ADT+D), 79 with androgen deprivation therapy (ADT) + abiraterone or enzalutamide (A/E) and 93 with ADT alone. Median follow-up of 46.3 months (m) (6.7-223). Median age was 66.4 years, 75.7% of pts presented de novo stage IV and 67.9% had high-volume disease. RNA-seq analysis was performed to assess differences in gene expression between low vs. high/medium PTEN expression tumors in 66 pts. There was a significant correlation between PTEN expression detected by nCounter and by RNASeq (p=8.7e-11). Differential expression analysis found 13 genes differentially expressed (padj<0.05 &abs(LFC)>0.26) in PTEN-low (25.8%) vs the rest, including PTEN and 2 novel transcripts (Table). In the functional analysis PTEN-low tumors had overexpression of several pathways including cell cycle, DNA repair, metabolism and immune regulatory response, and infraexpression of the androgen-response hallmark. In the whole cohort (n=297 pts), PTEN-low (30.5%) was independently associated with low CRPC-FS (HR 1.8 (95% CI, 1.3 – 2.4), p=8.7e-5) and OS (HR 1.7 (95% CI, 1.2 – 2.2), p=0.0038). Conclusions: Lower expression of PTEN correlates with a distinct molecular profile and a more aggressive disease in pts with mHSPC, supporting the development of new therapeutic strategies in pts. [Table: see text]
Characterizing longitudinal molecular changes in ctDNA in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tran Eli , Jani Chinmay , Zhang Nicole , Tsai Jill , Pan Elizabeth , Panian Justine , McKay Rana R. 
Published: January 2024

205 Background: Next-generation sequencing (NGS) of ctDNA is a novel technology that can complement tumor tissue NGS and has the potential to inform prognosis, treatment (tx) selection, and real time evolution of tumor molecular alterations. While tx options for pts with mCRPC have advanced, tx resistance is inevitable. Our real-world evidence study aims to evaluate longitudinal molecular changes in ctDNA following systemic tx to inform sequential tx strategies for pts with mCRPC. Methods: We interrogated data from GuardantINFORM, a clinical-genomics database with ctDNA molecular information and structured commercial payer-claims data. We conducted genetic mutations analysis in pts diagnosed with prostate cancer both before and after Androgen Receptor Signaling Inhibitors (ARSi), Poly(ADP‐ribose) Polymerase Inhibitors (PARPi), and taxanes. The post-tx analysis was performed on samples collected within 3 months of tx discontinuation prior to initiation of a subsequent tx as a proxy of disease progression. Mann-Whitney test was conducted to assess the differences in mutations observed pre and post tx. We also examined the association between ctDNA burden and overall survival (OS). Results: Overall, from a database of 21,682 patients with prostate cancer, following the above filters, we analyzed 145 pts with paired pre / post-ARSI, 54 with paired pre / post-PARPi, and 115 with paired pre / post-taxane samples. Table highlights the most commonly altered genes prevalent in post-tx samples. The most frequent (%pre/%post) AR alterations post-ARSI included AR amplifications (11%/23%), AR T878A (5%/9%), AR L702H (2%/6%), AR H875Y (0.7%/1.4%), and AR F877L (0%/1.4%). The most frequent HRR alterations post PARPi included ATM (25%/25%), BRCA2 (25%/18%), BRCA1 (3%/5%), CDK12 (6%/5%), and PALB2 (3%/2%). All three tx exhibited a significantly higher prevalence of mutations post-tx (mean increase in alterations 0.3-1.3, p<0.001 for all tx). Pts with higher ctDNA burden in pre-tx samples had worse OS compared to pts with low or undetectable burden. Conclusions: Our study revealed dynamic shifts in genetic mutations in pts with mCRPC following ARSi, PARPi and taxanes. Additionally, we highlight the prognostic significant of ctDNA burden in mCRPC. These data can help inform personalized sequential tx strategies for pts with mCRPC. [Table: see text]
Homologous recombination repair (HRR) alterations may be passenger events in patients with advanced prostate cancer (PC) with high tumor mutational burden (hTMB).
Authors: Bhatlapenumarthi Vineel , De Sarkar Navonil , Patwari Anannya , Antonarakis Emmanuel S. , Nelson Ariel Ann , Kilari Deepak 
Published: January 2024

206 Background: HRR and microsatellite instability-high (MSI-H) alterations (alt) are typically mutually exclusive in pan-cancer cohorts. However, in PC 12.8% of BRCA1 and 3.4% of BRCA2 genomic alteration(alt) (Loss of function mutation or copy loss) co-occurred with MSI-H (PMID: 35772050) but were not associated with elevated genome-wide loss of heterozygosity (gLOH), suggesting that BRCA1/2 alt are likely ‘passenger’ events in the presence of MSI-H. further characterize this potential bystander phenomenon, we hypothesized that patients (pts) with HRR alt occurring in the context of hTMB will lack functional HRD signatures. Methods: We queried the Stand Up to Cancer (SU2C) East Coast Dream Team’s exome dataset (N=429) to identify pts with hTMB and at least monoallelic HRR alterations. Demographics, treatment, and outcome data were also collected. Adopting the approach per PMID: 34877933, we derived CSig3 (a COSMIC single-base-substitution mutational signature indicative of HR dysfunction [HRD]) and iHRD (a functional signature of HR deficiency developed by our group) in this subset to evaluate HRR functional activity. Results: 18 men with hTMB (>10mut/Mb) and concurrent HRR alt were identified in SU2C. Of those, 9 had biallelic, and 9 had monoallelic HRR alt. 22% had biallelic BRCA2, 22% had biallelic RAD and 39% had monoallelic BRCA2 alt. However, only 33% of these HRR-altered tumors were CSig3(+)/iHRD(+) (5 biallelic and 1 monoallelic HRR alt) and 67% were negative for both signatures (4 biallelic, 8 monoallelic HRR alt), indicating that the HRR alt in these instances are likely bystander events. In all of the CSig3(+)/iHRD(+) cases, TMB ranged between 10-20 mut/Mb, whereas when TMB was >20 mut/Mb, those tumors were invariably CSig3(-)/iHRD(-). None of these pts in the SU2C cohort were treated with Immune checkpoint inhibitors or PARPi. Conclusions: In PC pts with hTMB and concurrent HRR mutations, it is more likely that the HRR alteration is a ‘passenger’ event, and the likelihood increases as TMB rises above >20 mut/Mb. HRD signature (-) hTMB pts are unlikely to respond to PARPi monotherapy, even if they have a concurrent HRR alt. HR functional signatures such as CSig3 or iHRD could be utilized in treatment selection and to avoid diagnostic dilemmas.
Building a predictive model for outcomes with [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer using VISION data: Preliminary results.
Authors: Herrmann Ken , Gafita Andrei , De Bono Johann S. , Sartor A. Oliver , Chi Kim N. , Krause Bernd J. , Rahbar Kambiz , Tagawa Scott T. , Czernin Johannes , El-Haddad Ghassan , Wong Connie , Zhang Zhaojie , Wilke Celine , Mirante Osvaldo , Morris Michael J. , Fizazi Karim 
Published: January 2024

208 Background: 177Lu-PSMA-617 is approved in adults with PSMA+ metastatic castration-resistant prostate cancer (mCRPC). This analysis of VISION data sought to build predictive models for clinical outcomes after 177Lu-PSMA-617. Methods: In VISION, adults with PSMA+ mCRPC received 177Lu-PSMA-617 (7.4 GBq every 6 weeks, ≤6 cycles) plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, 29 baseline parameters were assessed for prognostic and predictive value on overall survival (OS), radiographic progression-free survival (rPFS) and PSA response (≥50% reduction; PSA50). Parameters associated with outcome regardless of treatment were prognostic, and those associated with outcome after treatment with 177Lu-PSMA-617+SoC vs SoC were predictive. Cox proportional hazards (OS and rPFS) or logistic regression (PSA50) models were used in univariate analyses for parameter selection and to build statistical models. Here, univariate analyses are presented. Multiplicity was corrected by use of q values (α = 0.05). Results: Data from 831 adults were analyzed. In initial univariate analyses, 76%, 69% and 38% of parameters assessed were prognostic for OS, rPFS and PSA50, respectively; fewer were predictive of better outcomes after 177Lu-PSMA-617+SoC vs SoC (subset shown). Conclusions: Baseline prognostic and predictive parameters were identified for OS, as well as for rPFS and PSA50, in adults with mCRPC in VISION receiving 177Lu-PSMA-617+SoC or SoC alone. For clinical application, select parameters will be reassessed categorically, and multivariate predictive models will be developed using identified parameters and parameter shrinkage. [Table: see text]
Homologous recombination repair gene mutation (HRRm) testing patterns and treatment selection from a real-world cohort of patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Shore Neal D. , Craver Christopher , Blanc Simon , Sathyan Pratheesh , Aton Lindsay , Varughese Prateesh , Tierno Marni Brisson 
Published: January 2024

210 Background: Routine germline and somatic testing is recommended by professional guidelines as standard of care for all mCRPC patients since the approvals of poly ADP ribose polymerase inhibitors (PARPi) for treatment in those with tumors harboring select HRRm. Yet, analyses suggest that many mCRPC patients are not offered testing and thus patients with HRRm+ tumors may not have the shared decision-making opportunity to consider PARPi therapy. We reviewed HRR testing and treatment patterns within a real-world cohort of mCRPC patients to identify potential clinical practice gaps. Methods: The IntegraConnect – Precision Q Database that includes electronic, practice management and payer data from 500 US sites of care was utilized to select a de-identified real-world cohort of newly diagnosed and actively treated mCRPC patients (excluding those with lymph node only metastasis) between 1/1/2020 – 12/31/2021. Patient charts were manually reviewed by medical curators to extract data including frequency and timing of germline and somatic testing for HRRm, testing modality (tissue or liquid biopsy), results of HRRm testing, and the use of PARPi in the HRRm+ patient cohort. Results: A total of 996 mCRPC patients met criteria with 93% managed by community oncologists, 6% community urologists, and 1% academic oncologists. 59.2% (n=590) received testing for HRRm (19.8% germline (n=117); 59.8% somatic (n=353); 4.1% (n=24) germline + somatic; 16.3% (n=96) unknown) with testing rates increasing after PARPi approval: 15% between 1/1/2020 – 5/31/2020; 23% between 6/1/2020 – 9/30/2020; 62% between 10/1/2020 – 12/31/2021. The vast majority (64%) were tested after receiving mCRPC treatment, with 48% tested after failure on first line therapy. Somatic tissue testing was the predominant testing modality over liquid biopsy and germline testing. 31.7% (n=187) of tested patients were HRRm+ (11.2% germline (n=21); 73.8% somatic (n=138); 2.1% (n=4) germline + somatic; 12.8% (n=24) unknown), though not all tests utilized included the 14 HRR genes in the olaparib approval. BRCA2, ATM, CHEK2, and CDK12 HRRm were most commonly detected with a higher frequency of ATM and CHEK2 mutations seen in liquid biopsies. Of the mCRPC patients who were HRRm+, 66.8% (n=125) received PARPi. Conclusions: In this real-world analysis, 40.8% of mCRPC patients did not receive germline or somatic testing while 33.2% of HRRm+ patients did not receive PARPi. Optimizing germline and somatic testing for mCRPC is a significant unmet need, which negatively impacts therapeutic offerings.
Effect of variants in the KLK3 gene on prostate cancer survival and time to metastases in a large biobank prostate cancer dataset.
Authors: Pagadala Meghana , Nelson Tyler J. , Lynch Julie Ann , Gao Anthony , Agiri Fatai , Pridgen Kathryn , Seibert Tyler , Lee Kyung Min , Rose Brent S. , Carter Hannah , Teerlink Craig , Hauger Richard 
Published: January 2024

219 Background: Prostate Specific Antigen (PSA), a serine protease, is the most widely used clinical biomarker to detect prostate cancer. It is a product of the KLK3 gene. Several SNPs in KLK3 gene have previously been implicated in prostate cancer aggressiveness and PSA levels, however, the effect of KLK3 SNPs on survival and metastatic disease is not clear. We surveyed common and rare variants within 10-Kb of the KLK3 gene to estimate their effect on prostate cancer survival and time to metastasis in a large biobank data set. Methods: We analyzed a cohort of 5,287 men who developed prostate cancer after enrollment in the Million Veterans Program (MVP), 619 of whom developed metastatic disease. We analyzed 1,583 imputed SNPs (Info-R2 > 0.3) that occurred within 10-Kb of the KLK3 gene, regardless of minor allele frequency. We conducted two separate analyses, the first concerned survival times of prostate cancer specific mortality and the second analysis concerned time to metastatic disease using the Survival R package. For each analysis, variants were collectively assessed for an effect on survival using SKAT-O (metaSeq R package). We also performed a logistic regression to test each SNP for association with Gleason score 8-10 at diagnosis. Results: We identified seven rare SNPs that significantly affected prostate cancer survival (Bonferroni corrected p<3.16e-5) within 10-Kb of KLK3, 3 of which occurred within the gene boundaries (SKAT-O p=1e-4). We also identified 11 other SNPs that significantly affected time to metastasis (SKAT-O p=7e-3). The logistic regression of each SNP on Gleason score 8-10 at diagnosis identified 20 significant SNPs. The SNPs emerging from these analyses were all rare (minor allele frequency < 1e-4), and no SNPs were in linkage disequilibrium with each other, indicating that they comprise independent signals. Conclusions: Understanding the mechanism and role of rare SNPs in the KLK3 gene in prostate cancer detection has important clinical implications, especially in an era when patients’ genetics is being used to inform PSA screening. These finding may identify patients who should undergo prostate biopsy at lower PSA thresholds and/or for whom PSA biochemical recurrence is a less reliable predictor of disease progression. Ongoing prospective and retrospective analyses of Veterans with these variants both prior to and absent any prostate cancer diagnoses and progression.