bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of epigenetic regulator KMT2C mutation detected by liquid biopsy in survival in patients with prostate cancer.
Authors: Xu Nanwei , Zhu Sha , Shen Pengfei , Zeng Hao
Published: March 2023

222

Background: KMT2 (lysine methyltransferase) family enzymes exert epigenetic regulation to active gene transcription. KMT2C is mainly involved in enhancer-associated H3K4me1 and is also the top mutated gene in cancer (6.6% in pan-cancer). Currently, the clinical significance of KMT2C mutations in prostate cancer is understudied. Methods: We included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cfDNA-based liquid biopsy test results in this study. We explored the association of KMT2C mutations with other mutations and investigates the prognostic significance of KMT2C mutation measured by overall survival (OS) and castration-resistance free survival (CFS). In addition, we explored the prognostic value of KMT2C mutation in different patient subgroups. Results: The KMT2C mutation rate in this cohort is 7.24% (16/221). KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CFS and OS (CFS: mutated 9.9 vs. WT 22.0 months, p=0.015; OS: mutated 71.9 vs. WT 137.4 months, p=0.012). KMT2C mutation was also an independent risk factor in OS [HR: 3.815 (1.461, 9.96), P=0.006] in multivariate analyses. Besides, we also explored the association of KMT2C mutations and other genes, and the results showed that KMT2C mutation was related to Serine/Threonine-Protein Kinase 11 ( STK11, p=0.004) and Catenin Beta 1 ( CTNNB1, p=0.008) mutations. For OS, KMT2C mutation was significantly associated with survival in patient subgroups with PI3K pathway mutation (HR: 6.64, p=0.009) or WNT pathway mutation (HR: 2.44, p=0.043). Conclusions: KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CFS and OS, and KMT2C mutation was associated with STK11 and CTNNB1 mutations. Furthermore, KMT2C mutation was significantly associated with survival in certain patient subgroups, such as patients with PI3K and WNT pathway mutation, etc.
Inherited mutations in DNA damage gene repair (gDDR) in Italian men with metastatic prostate cancer.
Authors: De Giorgi Ugo , Casadei Chiara , Conteduca Vincenza , Gurioli Giorgia , Scarpi Emanuela , Cursano Maria Concetta , Brighi Nicole , Lolli Cristian , Schepisi Giuseppe , Basso Umberto , Fornarini Giuseppe , Bleve Sara , Farolfi Alberto , Altavilla Amelia , Olmos David , Castro Elena
Published: March 2023

223

Background: The need for genetic prognostic and predictive markers is urgent in order to identify potential target therapies or personalized therapeutic sequences for men with metastatic prostate cancer (mPC). The prevalence of pathogenic germline mutations in DNA damage repair (gDDR) such as germline mutations in BRCA2 (gBRCA) is well established: in the Anglo-American population with mPC was 5.3%, while in the Chinese population was 4.3% and in Spanish population 3.3%. This prospective multicenter cohort study evaluated the prevalence of gDDR alterations in the Italian population affected by mPC. Methods: In an observational prospective trial, 300 consecutive Italian patients affected by mPC were recruited between 2015 and 2019 and were screened for gDDR mutations in 107 genes. The primary aim was to assess the frequency of ATM/BRCA1/BRCA2/PALB2 germline mutations in the Italian population of patients with mPC. Secondary aims included the association of gDDR subgroups with metastatic onset, Gleason Score ≥8, and time to castration resistance. Results: We analyzed 300 patients and we identified 297 valuable patients. 46 patients had a pathogenic/likely pathogenic variants (15.4%): the more frequent is gBRCA2 in ten cases, gATM in five (1.7%), gMUTYH in four cases (1.3%), gCHEK2 in three cases (1%) and one case in PALB2 (0.3%). No mutations in BRCA1 were identified. We also highlighted six patients (2%) with clonal hematopoiesis of indeterminate potential (CHIP) interference in ATR (n=2), ATM (n=2), CHEK1 (n=1) and BRIP1 (n=1). Finally, we identified 117 alterations of variants of unknown significance (VUS) in 98 patients. In a univariate analysis, the median time to castration resistance in gBRCA2 patients was 11.6 months versus 22.3 months in patients with other mutation versus 23.4 months in no mutated patients. There were no associations of gDDR subgroups with metastatic onset and Gleason Score ≥8. Conclusions: The prevalence of gBRCA2 in the Italian population is 3%, which is similar to those of Spanish population, identifying interesting similarities between people of the Western Mediterranean area. The presence of gBRCA2 mutations correlates with lower time to the onset of castration resistant disease, according to a more aggressive phenotype.
Effect of Janus kinase (JAK) signaling inhibition on lineage plasticity and drug sensitivity in castrate resistant prostate cancer.
Authors: Zaidi Samir , Chan Joseph Minhow , Love Jillian , Zhao Jimmy , Setty Manu , Lawrence Kayla , Gopalan Anuradha , Goodrich David , Morris Michael J. , Chen Yu , Karthaus Wouter , Pe'er Dana , Sawyers Charles L.
Published: March 2023

227

Background: Despite the remarkable successes of targeted cancer therapies, certain cancers, including lung, breast, and prostate cancer and melanoma, invariably become resistant to therapy. One mechanism of secondary resistance—lineage plasticity—arises when cells alter their identity and transition into aggressive states. In the case of prostate cancer, cells can acquire a neuroendocrine histology. This is often associated with a loss of tumor suppressor genes, such as TP53, RB1, and PTEN. However, while these genomic events initiate plasticity, tumor progression is not always associated with successive genomic alterations. This, in essence, not only poses a clinical challenge, but also confronts us with a wide-open biological question—what are the molecular underpinnings of lineage plasticity, and importantly, can the process be reversed? Methods: To study the temporal evolution of lineage plasticity and its relationship to androgen receptor signaling inhibitor (ARSI) resistance, we utilized genetically engineered mouse models (GEMMs) and murine organoids that were deleted for Tp53, Rb1, and/or Pten. Single cell RNA analyses were utilized to dissect which genes and pathways were up-regulated and most associated with the progression of plasticity. Plasticity-associated genes and pathways were perturbed using FDA-approved inhibitors or genetic editing tools. The presence of these pathways was confirmed in a subset of metastatic index lesions obtained by radiologically guided biopsies and as visualized by metabolic imaging. Furthermore, relevant findings were functionally validated in human tumor derived organoids (“tumoroids”). Results: Using GEMMs and organoid models, we found the lineage plasticity depended on increased Janus Kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Pharmacologic inhibition using FDA–approved inhibitors of JAK/STAT (ruxolitinib) and FGFR (erdafinitib), or through genetic knockdown, demonstrated increased androgen receptor (AR) signaling and restored ARSI sensitivity. These findings were further validated in a subset of ARSI-insensitive human tumoroids. By performing single cell RNA sequencing on mCRPC tumors biopsies, the presence of highly plastic JAK/STAT- and FGFR-high cells were confirmed, with implications for stratifying patients for clinical trials. Conclusions: JAK/STAT and FGFR signaling pathways promote lineage plasticity and result in complete insensitivity to androgen receptor signaling inhibitors (ARSIs). FDA-approved inhibitors of JAK/STAT (ruxolitinib) and FGFR (erdafitinib) synergize to reverse lineage plasticity and restore ARSI sensitivity.
Correlation of age and the tumor transcriptomic profile in patients (pts) with advanced prostate cancer (PCa).
Authors: Sahu Kamal Kant Kant , Jo Yeonjung , Chigarira Beverly , Kim Jong Taek , Sayegh Nicolas , Gebrael Georges , Tripathi Nishita , Kumar Shruti Adidam , Mathew Thomas Vinay , Li Haoran , Nussenzveig Roberto , Kohli Manish , Gupta Sumati , Maughan Benjamin L. , Agarwal Neeraj , Swami Umang
Published: March 2023

233

Background: In general, older pts are likely to have an advanced stage PCa, hence poor overall survival (PMID: 18660852). Owing to increased awareness and better diagnostics, the incidence of PCa has steadily increased amongst older adolescents and young adult pts (PMID: 31553489). Recent reports suggest that younger pts often are staged less adequately, present with more advanced stages, and could have worse outcomes than older pts (PMID: 33575208). Hence, elucidating the underlying molecular biology of PCa by age may unravel specific biologic features and distinct genomic expressions specific to young-age PCa, and help investigate new therapeutic targets. Methods: In this IRB-approved retrospective study, eligibility criteria included pts diagnosed with advanced PCa with available tumor-based comprehensive transcriptomic profiling from a CLIA-certified lab. DeSeq2 analysis was implemented in Bioconductor software to analyze differentially expressed genes based on the cohort's age cut-off points (< 65 vs. ≥65 years). DeSeq2 results included the Log2 Fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were then subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways upregulated or downregulated in each cohort. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. The statistical significance level was predetermined at 0.05. Results: 80 pts were eligible: < 65 (n=44) vs ≥65 years (n=36). No differences in Gleason score (<8/≥8), baseline PSA levels, and disease volume (high/low) between the cohorts (Table). As compared to pts ≥65 years; in young pts, (1) the three most upregulated significant pathways were oxidative phosphorylation (OXPHOS), bile acid, and fatty acid metabolism pathways, and (2) the three most downregulated significant pathways were tumor necrosis factor-alpha (TNFα) via NF-Κb, transforming growth factor-β (TGF β), and inflammatory response pathways. Differential individual gene expression profiles will be presented at the meeting. Conclusions: These hypothesis-generating data show distinct genomic pathways to be upregulated in younger pts vs. older pts with advanced PCa and may guide further drug development, e.g., OXPHOS inhibitors in younger pts vs. drugs targeting inflammatory response in older pts. These hypothesis-generating results, upon external validation, may provide the rationale for personalized therapy in pts with PCa. [Table: see text]
Tumor transcriptomic profiling of patients (pts) with metastatic castration sensitive prostate cancer (mCSPC) who do versus who do not achieve an optimal PSA response to intensiﬁed androgen deprivation therapy (i-ADT).
Authors: Mathew Thomas Vinay , Sayegh Nicolas , Chigarira Beverly , Gebrael Georges , Jo Yeonjung , Tripathi Nishita , Nussenzveig Roberto , Li Haoran , Sahu Kamal Kant Kant , Tandar Clara , Goel Divyam , Iyer Puja , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj
Published: March 2023

234

Background: Pts with mCSPC receiving i-ADT and achieving a PSA nadir ≤0.2 ng/mL (PSA-L) demonstrate significantly better overall survival (OS) as compared to those with a PSA nadir > 0.2 ng/mL (PSA-H) (Chi AUA 2021, Saad ASCO 2022). We hypothesized that tumor gene expression proﬁle would differ between PSA-L and PSA-H. Methods: In this IRB-approved retrospective study, eligibility criteria included conﬁrmed mCSPC receiving i-ADT with androgen receptor-axis-targeted therapy (ARAT) and availability of RNAseq proﬁling performed by a CLIA-certiﬁed lab of primary prostate biopsies collected before treatment. Pts were divided into 2 groups: PSA-L and PSA-H based on achieving a PSA nadir ≤0.2 ng/mL at any time during treatment course. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p values (q values) for each differentially expressed gene. These results were subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R studio v4.2. Results: 78 pts were eligible: 55 were PSA-L, and 23 were PSA-H. The most significantly upregulated pathways in PSA-L were the TNFA signaling, androgen response (AR), estrogen response, and interferon-alpha response pathways. The most upregulated pathways in PSA-H were epithelial-mesenchymal transition, coagulation, and bile acid metabolism pathways. Normalized enrichment scores are reported in the table. Differential individual gene expression profiles will be presented at the meeting. Conclusions: These hypothesis-generating data show that mCSPC pts on i-ADT with PSA-L have distinct baseline tumor gene expression profiles, such as upregulation of AR signaling, compared to pts with PSA-H. After external validation, these findings may help personalize medicine prior to initiation of therapy in pts not expected to achieve PSA-L. [Table: see text]
Correlation of tumor gene expression profile and gleason score (GS) in patients (pts) with metastatic prostate cancer.
Authors: Sayegh Nicolas , Tripathi Nishita , Chigarira Beverly , Jo Yeonjung , Mathew Thomas Vinay , Nussenzveig Roberto , Sahu Kamal Kant Kant , Li Haoran , Gebrael Georges , Tandar Clara , Goel Divyam , Rathi Nityam , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj
Published: March 2023

235

Background: GS is the most powerful prognostic predictor in prostate adenocarcinoma. However, the underlying reasons of disease aggressiveness as a function of GS are currently unknown. Herein we sought to investigate the corresponding differences in gene expression profiles of pts with prostate adenocarcinoma with respect to GS. Methods: In this IRB approved retrospective study, eligibility criteria included histologically confirmed prostate adenocarcinoma and available RNA sequencing results from treatment naïve primary prostate tissue by a CLIA certified lab. Pts were categorized into two cohorts: low GS (GS <8) and high GS (GS ≥ 8). The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) in order to identify pathways enriched in each cohort. All bioinformatic analyses were undertaken using R v4.2. Results: Fifty-seven pts were eligible, of which 13 had a GS <8 and 44 had a GS ≥8. Tumor tissues with high GS had a significantly higher expression of genes involved in the immune pathways (e.g., inflammatory response, interferon-γ, allograft rejection, and interferon-α), epithelial-mesenchymal transition, KRAS signaling, E2F targets and G2M checkpoint (q for all <0.01). The genes involved in the androgen response pathway were significantly more expressed in biopsies with a low GS (q<0.01). Normalized enrichment scores are reported in the table. Differential individual gene expression profiles will be presented at the meeting. Conclusions: Pts with prostatic adenocarcinoma with a GS ≥8 demonstrated a different transcriptomic profile than those with a GS <8. Higher GS tumor tissues had upregulated of inflammatory, proliferation, and KRAS signaling. Lower GS tumor tissues had upregulated androgen signaling pathway. These hypothesis-generating results upon external validation may provide the rationale for personalized therapy in men with prostatic cancer. [Table: see text]
Use of prostate cancer subtyping by gene expression to predict response to radiation and chemohormonal therapies.
Authors: Weiner Adam B , Liu Yang , Hakansson Alexander K. , Zhao Xin , Proudfoot James Alexander , Zhang JJ Haijing , Karnes R. Jeffrey , Den Robert Benjamin , Kishan Amar Upadhyaya , Reiter Robert Evan , Hamid Anis , Ross Ashley , Tran Phuoc T. , Chua Melvin L.K. Lee Kiang , Spratt Daniel Eidelberg , Attard Gerhardt , Lotan Tamara L. , Sweeney Christopher J , Davicioni Elai , Schaeffer Edward M.
Published: March 2023

241

Background: We previously reported on the use of gene expression profiling to characterize four primary subtypes in an analysis of over 100,000 prostate cancer primary tumors. Here we examine these subtypes and response to radiation (RT) after prostatectomy or chemotherapy in addition to androgen deprivation therapy (ADT) in hormone-sensitive metastatic prostate cancer (mHSPC). Methods: We examined a 215-gene prostate subtyping classifier (PSC) which groups luminal and basal gene expression profiles into one of four subtypes; luminal differentiated (LD), luminal proliferating (LP), basal immune (BI) and basal neuroendocrine-like (BN). The log-rank method was used to compare (i) metastasis-free survival between patients who did and did not receive salvage RT in the META855 cohort of localized disease patients treated with radical prostatectomy (n=855) and the (ii) overall survival of patients on the Phase III mHSPC EA3805 CHAARTED trial of ADT or ADT + docetaxel chemotherapy (n=160). Results: After radical prostatectomy, patients with BI tumors derived benefit from RT in terms of metastasis-free survival ( P=9.23e-4) while those with other subtype tumors did not (Each Log-rank P≥0.5). Patients with metastatic disease and LP tumors derived benefit from docetaxel (Log-rank P=0.002) while those with other subtypes tumors did not (Log-rank P=0.2). Conclusions: Basal-luminal subtyping segments tumors by relevant biological processes with potential implications for identifying patients who benefit from salvage radiation post prostatectomy and addition of docetaxel to ADT in mHSPC.
Differences in the tumor transcriptomic profile of patients (pts) with advanced prostate cancer (PCa) with and without diabetes mellitus (DM).
Authors: Tripathi Nishita , Li Haoran , Chigarira Beverly , Kumar Shruti Adidam , JongTaek Kim , Sayegh Nicolas , Gebrael Georges , Jo Yeonjung , Sahu Kamal Kant Kant , Mathew Thomas Vinay , Nussenzveig Roberto , Goel Divyam , Tandar Clara , Rathi Nityam , Swami Umang , Agarwal Neeraj , Maughan Benjamin L.
Published: March 2023

244

Background: Pre-existing DM is associated with increased PCa specific and all-cause mortality in men with prostate cancer (PMID: 27652121). However, the underlying reasons are unclear. We hypothesized that transcriptomic profile of metastatic PCa pts with diagnosis of DM prior to the diagnosis of metastatic disease and start of systemic therapy will be different from those without DM. Methods: In this IRB-approved retrospective study, advanced PCa pts with available RNA profiling of treatment naïve tumor tissue through a CLIA-certified laboratory were included. Based on pre-existing DM prior to onset of metastatic disease, pts was grouped into DM and non-DM. Differential gene expression analysis between the two groups was performed using DeSeq2. These results were subjected to Gene Set Enrichment software analysis (GSEA) to identify pathways enriched in each cohort. Gene ontology analysis using TopGO software was done to identify the biological process occurring at the molecular level of these differentially expressed genes. All bioinformatic analysis was conducted in R studio, version 4.1.1. Results: 75 pts were eligible and included: 20 DM vs 55 non-DM. Baseline characteristics (DM vs non-DM): median age 63.5 vs 64 years; median PSA at diagnosis 20 vs 18.85ng/mL; de novo disease: 55% vs 43.6%; Gleason score ≥8: 60% vs 74.5%. DM pts had upregulation of the following pathways: TNF alpha signaling, inflammatory response, IL-6 JAK STAT3 signaling, heme metabolism, and the p53 pathway vs non-DM pts. Gene ontology analysis and individual differential gene expression profiles will be reported at the meeting. Conclusions: Our study found that pre-existing DM is associated with upregulation of inflammatory pathways in pts with PCa These hypothesis-generating results need external validation. Identification of transcriptomic biomarkers in these subsets of pts may help with further drug development. [Table: see text]
Social determinants of health (SDOH) and survival among patients with metastatic prostate cancer (mPC): A systematic literature review (SLR).
Authors: Freedland Stephen J. , Niyazov Alexander , Nazari Jonathan , Worthington Evelyn , Lansing Austin , Rosta Emily , Samjoo Imtiaz
Published: March 2023

25

Background: Population level data show strong associations between race and other SDOH including income, education, and geographic region of residence. The relationship between SDOH and clinical outcomes has become increasingly recognized. This review examines the impact of SDOH on survival in patients with mPC in real-world (RW) settings. Methods: A systematic literature search in accordance with Cochrane guidelines was conducted on July 7, 2022, searching for RW studies published as full-text (Jan 2012-July 2022) and conferences (Jan 2019-July 2022) using Ovid MEDLINE, Embase, and Cochrane. A manual search of key congress websites for conference abstracts was also conducted. Studies which assessed the impact of SDOHs on survival, treatment access, and other clinical outcomes in patients with mPC were included in the overall SLR. Here, we present results from studies which assessed the impact of SDOH on overall survival (OS) and prostate cancer specific mortality (PCSM). Clinical trials were excluded. Results: Of 3,228 records screened, 86 studies were included, with findings reported in 67 full-text publications (60 US and 7 ex-US) and 28 conference abstracts (22 US and 6 ex-US). The impact of race on survival was reported in 54 studies. While most studies showed no difference between Black vs White for both OS (n=22) and PCSM (n=8), for patients on specific mPC treatments, there was an association between Black race and improved OS (n=5). Asian patients had improved OS vs White patients (n=4), and reduced PCSM vs White (n=6) and Black patients (n=1). Higher income was generally associated with improved OS (n=7), but no difference in PCSM (n=3). Although the regions compared differed, most studies found disparities in OS among US geographic regions (n=5). Education level was generally not associated with OS (n=2) or PCSM (n=3). Most studies showed that married patients had improved OS (n=4) and reduced PCSM (n=3) compared to unmarried patients. Conclusions: This SLR demonstrated that various SDOH are associated with disparities in survival among mPC patients. Asian race, which is generally associated with higher frequency of better SDOH risk factors, was linked with better OS. In contrast, Black race, which is generally associated with higher frequency of worse SDOH risk factors, was associated with similar or better OS. Having lower income and being unmarried were both associated with reduced OS, while disparities in OS were reported across geographic regions of the US. More studies are needed to understand why SDOH are linked with poor outcomes, including their connection with access to care.
Evaluation of the aggressive variant prostate cancer molecular profile (AVPCm) in CLIA environments.
Authors: Viscuse Paul Vincent , Zhang Miao , Rohra Prih , Slack Tidwell Rebecca , Pritchard Colin C. , Subudhi Sumit Kumar , Pilié Patrick Glen , Logothetis Christopher , Corn Paul Gettys , Aparicio Ana
Published: March 2023

250

Background: 20-30% of prostate cancers respond poorly to androgen receptor (AR)-directed therapies and have an atypical, virulent course. The aggressive variant prostate cancers ( AVPC) encompass virulent androgen indifferent tumors and are characterized by combined defects in ≥ 2/3 of TP53, RB1, and PTEN (AVPC-m). Post-hoc analysis in a phase I/II trial indicated a benefit of carboplatin+cabazitaxel in men with AVPCm+ metastatic castrate resistant prostate cancer (mCRPC). We assess the feasibility of detecting the AVPCm in CLIA-certified environments. Methods: Men with progression of mCRPC undergoing biopsies for standard molecular profiling at MD Anderson Cancer Center (MDACC) were eligible. TP53, RB1, and PTEN expression was assessed by immunohistochemistry (IHC) and read by 2 pathologists independently. Next generation sequencing of solid tumor DNA (stDNA) and circulating tumor DNA (ctDNA) was performed on the MDACC Molecular Diagnostics Laboratory and the University of Washington OncoPlex ctDNA platforms respectively . Results: Of 64 eligible patients, 49 (77%), 37 (58%), and 54 (84%) had results reported for IHC, stDNA, and ctDNA respectively. Concordance of IHC reads between pathologists was variable: Kappa 0.78, 0.67, and 0.91 for TP53, RB1, and PTEN respectively. 36 (66.7%) ctDNA samples had low tumor content, such that false negatives could not be excluded. AVPC-m was detected in 14 (29%) of patients by IHC per the original reading pathologist, 2 (5%) by stDNA NGS, and 7 (39%) by ctDNA NGS. Median turnaround times for IHC, stDNA and ctDNA were 12 (2-35), 28 (12-56) and 16 (11-56) days respectively. Conclusions: We show the operational characteristics of the AVPCm detection using CLIA certified assays. IHC detected a greater proportion of patients with AVPCm+ tumors than stDNA, likely due, partly, to the challenges of copy number loss detection. ctDNA detected the greatest proportion of AVPCm+ tumors but was not evaluable in two thirds of patients. These data serve to inform the design of clinical trials using AVPCm as a criterion for patient selection or stratification. [Table: see text]
Long-term taxane exposure and transdifferentiation of prostate cancer in vitro.
Authors: Von Amsberg Gunhild , Dyshlovoy Sergey , Hauschild Jessica , Sailer Verena , Perner Sven , Offermann Anne , Merkens Lina , Krisp Christoph , Werner Stefan , Pantel Klaus , Kaune Moritz , Tilki Derya , Schlüter Hartmut , Graefen Markus , Bokemeyer Carsten
Published: March 2023

254

Background: Development of aggressive variants of metastatic castration-resistant prostate cancer (AVPC) is a major challenge in the course of therapy but the underlying mechanisms of aggressive transdifferentiation are not completely understood and appropriate tumor models are missing. Here, we investigated the consequences of long-term taxane exposure on hormone-independent, BRCA2-mutated, AR-V7-positive 22Rv1 cells. Methods: 22Rv1 cells were treated with stepwise increased taxane concentrations for 10 months. Individual clones were picked and further cultured in media containing either docetaxel (Doce) or cabazitaxel (Caba). Passage-matched cells were maintained in culture without treatment. Further characterization was carried out using proliferation, migration, metabolic, and colony formation assays as well as proteomics, RNAseq analyses and xenotransplantation in immunodeficient mice. Results: In total, three single cell 22Rv1-DR clones (50-100-fold resistance to Doce) and three 22Rv1-CR clones (80-150-fold resistance to Caba) were successfully established. All clones showed cross-resistance to either drug. Expectedly, treatment-induced overexpression of ABCB1 was detected and validated. Moreover, alteration of drug resistance related SLC7A5, SLC3A2, and SLC25A24 genes was observed. Additionally, an enrichment analyses identified, among others, neuroendocrine transdifferentiation (GO-term “Neuroendocrine tumors”, p=4.46e-5) to be stimulated in prostate 22Rv1 cells under long-term treatment with Doce or Caba. In line with this, the neuroendocrine features were validated in vitro as well as in xenotransplanted tumors in vivo with upregulation of synaptophysin, chromogranin and neuron specific enolase accompanied by downregulation of the androgen receptor (AR) and upregulation of AR spice variants. Additionally, neuritic morphology, shift to higher nuclear-plasma ratio, partial loss of adherent properties and growth slowdown, along with higher migratory activity were detected. Conclusions: Long-term taxane exposure of 22Rv1 cells resulted in the development of neuroendocrine traits in individual cell clones that have successfully been translated into stable cell lines. Thus, we provide a new cell line model for secondary therapy-induced neuroendocrine transdifferentiation. Further in-depth analysis to identify individual alterations in the course of therapy is currently ongoing.
Homologous recombination repair (HRR) mutation concordance between liquid biopsy (LB) and tumor tissue by NGS in a real-world prostate cancer (PC) database.
Authors: Shen John , Wang Liang , Khaki Ali Raza , Jimenez Rafael E , Mauer Elizabeth , Stoppler Melissa Conrad , Chao Calvin Y. , Kohli Manish
Published: March 2023

260

Background: NGS to identify HRR mutations (mut) is indicated in advanced prostate cancer (aPC); samples for testing may be tissue or plasma. In a large real-world (RW) database, we determined concordance between plasma ctDNA and primary tumor tissue (PT) and/or metastatic tissue (MT) for BRCA1, BRCA2, and ATM mut in PC patients (pts) who received both LB and tissue NGS any time during standard of care (SOC) management. The study objective was to assess the utility of LB to detect actionable mut in these HRR genes and demonstrate the utility of combined LB and tissue testing. Methods: We examined de-identified data from pts who had NGS using both Tempus xF (105 genes-LB) and Tempus xT (648 genes-tissue) during SOC for aPC. Analyses included 1) PT and LB and 2) MT and LB. The results from the pts’ earliest PT or MT and earliest LB were used for paired analyses. The prevalence of a pathogenic/likely pathogenic germline and/or somatic mut in BRCA1, BRCA2, or ATM was reported as N (%), 95% CI. The sensitivity of the LB to identify observed HRR mut in tissue was also reported as N (%), 95% CI. Concordance between pairs was evaluated by Cohen’s kappa statistic with 95% CI. Results: HRR results are show for 1074 PC pts who had NGS performed on PT and LB and 451 PC pts with NGS on both MT and LB. In the PT and LB analysis, HRR mut were found in 6.2% (95% CI: 4.9%-7.9%) of LB and 8.8% (95% CI: 7.2%-11%) of PT. The sensitivity of LB to detect HRR mut in the PT was 53% (95% CI: 43%-64%). Cohen’s kappa statistic was 0.59, 95% CI=0.50-0.68, between PT and LB. In the MT and LB analysis, HRR mut were found in 10% (95% CI 7.8%-14%) of LB and 10% (7.6%-13%) of MT. The sensitivity of LB to detect HRR mut in the MT was 70% (95% CI: 54%-82%). Cohen’s kappa statistic was 0.65, 95% CI=0.54-0.77, between MT and LB. Conclusions: In this large RW dataset, plasma ctDNA-based analysis of BRCA1, BRCA2, and ATM mut showed greater concordance between LB and MT than LB and PT, and may be used as an initial tool for HRR mut detection. When LB results are negative, further exploration with tissue-based testing may identify HRR mut to guide clinical decisions. [Table: see text]
Cost-effectiveness analysis of seven treatment regimens in metastatic hormone-sensitive prostate cancer (mHSPC): A public payer perspective using network meta-analysis.
Authors: Kohli Manish , Dougherty Maura , Cutshall Zachary , Beckstead Rylee , Kohli Rhea , Haaland Benjamin , Nelson Richard , Yoo Minkyoung
Published: March 2023

268

Background: Recently several new treatment regimens have been approved for treating mHSPC, building on the previous standard of care using androgen deprivation therapy (ADT) alone. These include docetaxel+ADT (DA), Abiraterone Acetate+Prednisone+ADT (AAP), Apalutamide+ADT (AAT), Enzalutamide+ADT (ET), Darolutamide+Docetaxel+ADT (DAD) and Abiraterone+Prednisone+ADT+Docetaxel (AAD). There are no current predictive biomarkers for choosing any specific regimen. The goal of this study was to determine the cost-effectiveness of these new treatments from the US public sector perspective with a lifetime horizon. Methods: We developed a partitioned survival model in which mHSPC patients transitioned between three health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a network meta-analysis. A Bayesian network meta-analysis of seven clinical trials included 7,208 patients. The effectiveness outcome in our model was quality-adjusted life-years (QALYs) with utility values obtained from published literature. Costs in our model included those associated with treatment regimens and subsequent therapies, terminal care, and for managing grade 3-4 drug related adverse events, and were obtained from the Federal Supply Schedule and published literature. Results: Average lifetime costs ranged from $154,139 (AAP) to $770,848 (DAD) and mean QALYs ranged from 3.33 (ADT) to 5.08 (ET). All treatment strategies other than AAP and ET were eliminated due to dominance. Compared to AAP, the incremental cost-effectiveness ratio for ET was $484,943/QALY. Results from our analysis including all regimens are shown. Conclusions: Our simulation model found that ET in mHSPC state yielded the most QALYs and would be the most cost-effective option with a WTP threshold as high as $500,000/QALY. However, for a WTP threshold of $150,000/QALY, AAP was the most cost-effective treatment strategy. [Table: see text]
Ability of STAR-CAP staging system to prognosticate risk of subsequent therapies after initial treatment of M0 prostate cancer.
Authors: Sung Daeun , Tward Jonathan David
Published: March 2023

310

Background: Given lower mortality rates and life expectancy loss in prostate cancer, treatment regimens must consider long-term outcomes with quality of life. Aggressiveness of treatment impacts severity of side effects and depends on the highly heterogeneous staging of the disease at onset. Staging and risk-classification systems have been developed, including STAR-CAP staging system which informs prognosis and could help with treatment intensification decisions. Compared with existing models such as the AJCC, STAR-CAP had superior performance and prognostic power for disease mortality prediction. However the risk of requiring subsequent therapies (ie salvage radiation therapy or androgen deprivation therapies after initial treatment) has not been described in STAR-CAP cohorts. Quantifying risk of subsequent therapies after initial therapies is clinically useful to help patients decide between various management strategies and whether monotherapies or multi-modality therapies may be sufficient. Methods: Patients who could be stratified by STAR-CAP system and underwent surgery or radiation therapy were identified from an institutional observational registry. Patients treated before 2010 were gathered retrospectively (n=835) and prospectively thereafter (n=2588). The primary endpoint was progression to additional therapy after primary treatment (radiation, surgery, or systemic therapy). Risk of progression accounting for STAR-CAP group was estimated using the Fine and Gray Competing risk model, with death as the competing risk. P<0.05 was considered statistically significant. Results: 3424 men diagnosed with prostate cancer underwent curative-intent treatment with surgery or radiation therapy (RT) between 1995 – 2022. The median age at diagnosis was 64.9 years (IQR 59.4 to 70.0); median follow-up time was 5.4 years. Patients with STAR-CAP 1A-1C had a statistically similar risk of requiring additional therapies, whereas those with 2A to 3B disease had a significantly and incrementally higher risk of requiring additional therapies (by group, hazard ratios and 95% CI: 2A, 1.8 (1.2 to 2.5); 2B, 2.9 (2.1 to 4.2); 2C, 3.4 (2.4 to 4.9); 3A, 5.7 (3.9 to 8.3); 3B, 7.0 (4.4 to 11.1), all p<0.001). The 5-year risks of requiring additional therapy after surgery for a Stage 1A, 2A, and 3A patient is 9.7%, 16.2%, and 38%, respectively. The 5-year risks of requiring additional therapy after radiation with or without ADT for a Stage 1A, 2A, and 3A patient are 7.3%, 10.4% and 27.9%, respectively. Conclusions: The STAR-CAP grouping system can prognosticate risk of requiring additional therapies after primary treatment of localized prostate cancer. The lower risk of subsequent therapy seen in RT patients is likely due to use of ADT with RT. Using STAR-CAP to prognosticate risk of subsequent therapies after primary treatment can help guide treatment intensification decisions upfront.
Prediction of significant prostate cancer in equivocal MRI lesions: A high-volume international multicenter study.
Authors: Sigle August , Borkowetz Angelika , von Hardenberg Jost , Drerup Martin , Kornienko Kira , Gratzke Christian , Mahjoub Samy
Published: March 2023

311

Background: The decision of performing prostate biopsy in men with equivocal findings in prostate magnetic resonance imaging (MRI) is challenging as they have a low but still relevant risk of harboring significant prostate cancer (sPC). Objective: To identify clinical predictors of sPC in men with equivocal findings in prostate MRI. Secondly, we aimed to analyze the hypothetical effect of incorporating prostate-specific antigen density (PSAD) into biopsy decision. Methods: We analysed a retrospective multinational cohort from 10 academic centers comprising 1476 men who underwent combined prostate biopsy (MRI-targeted plus systematic) between 02/2012 – 04/2021 due to an equivocal lesion found in prostate MRI (Prostate Imaging Reporting and Data System 3). Primary outcome was the detection of sPC (ISUP ≥ 2) in combined biopsy. Regression analysis was performed to identify predictors for this outcome. Descriptive statistics were applied to evaluate the hypothetical effect of involving PSAD into biopsy decision. Results: 273/1476 (18.5%) men were diagnosed with sPC by combined biopsy. MRI-targeted biopsy diagnosed less sPC as compared to combined strategy: 183/1476 (12.4%) vs. 273/1476 (18.5%), p<0.01. Regression analysis confirmed age (OR 1.10 [95% CI: 1.05 – 1.15]; p < 0.001), prior negative biopsy (OR 0.46 [0.24 – 0.89]; p = 0.022) and PSAD (p<0.001) as independent predictors for sPC. Applying a PSAD cut-off of 0.15 for biopsy decision, 817/1398 (58.4%) of the biopsy procedures would have been avoided at the cost of missing sPC in 91 (6.5%) men. Limitations were the retrospective design, heterogeneity of the study cohort due to the long inclusion period and a missing central revision of MRI. Conclusions: Age, previous biopsy status and PSAD were found independent predictors of sPC in men with equivocal prostate MRI. Implementation of PSAD into biopsy decision can avoid a large proportion of unnecessary biopsies. Clinical parameters such as PSAD need validation in a prospective setting.
Detection of true positive M1 lesions by 18F-rhPSMA-7.3 PET in newly diagnosed prostate cancer: Results from the phase 3 prospective LIGHTHOUSE study.
Authors: Koontz Bridget F. ,   LIGHTHOUSE Study Group
Published: March 2023

315

Background: Radiohybrid (rh) 18F-rhPSMA-7.3 is a novel high affinity prostate specific membrane antigen (PSMA)-targeting positron emission tomography (PET) radiopharmaceutical. The LIGHTHOUSE study (NCT04186819) evaluated the diagnostic performance of 18F-rhPSMA-7.3 in newly diagnosed prostate cancer. Here we report the 18F-rhPSMA-7.3 verified detection rate (VDR), defined as the proportion of patients with M1 lesions identified by blinded image evaluation (BIE) and subsequently confirmed true positive (TP) by biopsy or confirmatory imaging. Methods: Men with treatment-naïve, unfavorable intermediate to very high-risk prostate cancer who were scheduled to undergo radical prostatectomy underwent PET 50-70 min after IV administration of 296 MBq 18F-rhPSMA-7.3. Onsite readers interpreted the images before submission for BIE by 3 central readers.Ifthe onsite read indicated M1 disease, verification (by biopsy, surgery or additional imaging) of PET-positive M1 lesions was attempted prior to treatment. 18F-rhPSMA-7.3 M1 VDR was evaluated amongall study patients without major protocol deviations. Results: Of the 335 men analyzed (median [range] PSA, 8.89 [1.15-120] ng/mL), 58 (17%) had M1 lesions by majority read. In total, 34 (10%) had verified M1 lesions with individual readers’ M1 VDR ranging from 10-15%. By region, verified M1 lesions were most common in bone, ranging from 6.0-11% across readers (majority read, 6.6%). Similar data were shown among a subgroup who had negative baseline conventional imaging. In these patients, the VDR ranged from 8.9-13% across readers (majority read, 8.6%). Again, bone showed the highest regional VDR, ranging from 4.8-9.2% (majority read, 5.1%). Conclusions: Further to its clinically meaningful sensitivity and specificity for pelvic lymph node metastases (reported separately), here we show 18F-rhPSMA-7.3 PET to be a useful staging tool, as distant metastatic lesions were verified in 10-15% of newly diagnosed patients with unfavorable intermediate to very high-risk prostate cancer. Determining the presence of M1 disease prior to surgery may help guide treatment planning by identifying patients for whom surgery is the optimal approach, or those for whom alternatives such as radiation therapy and/or androgen deprivation may be more suitable. Clinical trial information: NCT04186819 . [Table: see text]
Positron emission tomography of patients with confirmed prostate cancer using 64Cu-SAR-bisPSMA.
Authors: Emmett Louise , Wong Veronica , Lenzo Nat , Lengyelova Eva , Biggin Colin
Published: March 2023

318

Background: Prostate cancer (PC) is the second most frequent malignancy in men worldwide. 68Ga-PSMA-11 is one of the most widely used radiotracers for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with PC and is part of standard clinical practice at many centres. Due to the longer half-life and shorter positron range of copper-64 (t1/2=12.7 hours; mean positron range=0.56 mm), a novel PSMA-targeting radiotracer labelled with this radionuclide, 64Cu-SAR-bisPSMA, has the potential to provide advantages over 68Ga-PSMA-11 (t1/2=68 minutes; mean positron range=3.5 mm). The 12.7 hour half-life of Cu-64 allows the central manufacturing of 64Cu-SAR-bisPSMA with a product shelf-life of up to 2 days. The longer half-life enables PET imaging from 1 to 72 hours after administration which offers greater flexibility in terms of scheduling of patients and may translate into detection of additional lesions due to increased Standardized Uptake Values (SUV) in the lesions relative to background following biological clearance of the tracer from organs over time. The shorter positron range may lead to improved resolution on the scan and thus, better detection of small lesions, including those that are in close proximity to each other, or to organs involved in clearance of the product such as the bladder and kidneys. In addition to the potential imaging and supply benefits of Cu-64, current generation PSMA targeting agents such as 68Ga-PSMA-11 have only a single targeting functional group. 64Cu-SAR-bisPSMA has two PSMA-targeting functional groups, which can lead to improved tumor uptake and retention. This was shown in a preclinical study, where 64Cu-SAR-bisPSMA outperformed the monomeric 64Cu-SAR-PSMA with respect to both tumor uptake and retention (Zia et al, 2019). Methods: Patients with untreated, histopathology-proven, intermediate- to high-risk PC, planned for radical prostatectomy underwent 68Ga-PSMA-11 PET/CT per institutional practice and were subsequently allocated to 1 out of 3 dose cohorts (1:1:3) to receive either 100 MBq, 150 MBq or 200 MBq of 64Cu-SAR-bisPSMA, respectively. A PET/CT was acquired at 3-hours (±1 hour) post-injection of 64Cu-SAR-bisPSMA. Two independent, blinded, central readers assessed the detection of primary PC on the 200 MBq 64Cu-SAR-bisPSMA PET/CTs as the primary endpoint. To compare the intensity of lesions on 68Ga-PSMA-11 and 64Cu-SAR-bisPSMA PET, both readers determined the SUVs (SUVmax, SUVmean) and tumour-to-background ratio (ratio of lesion SUVmax and background SUVmean) in up to 5 concordant lesions between 68Ga-PSMA-11 and 64Cu-SAR-bisPSMA PET/CT as an exploratory endpoint. Clinical trial information: NCT04839367 .
BPH-related false positive of 68Ga-PSMA PET/CT in the diagnosis of prostate cancer: The Achilles heel of biopsy-free radical prostatectomy?
Authors: Tang Wei , Tang Yongxiang , Qi Lin , Zhang Ye , Tang Guyu , Gao Xiaomei , Hu Shuo , Cai Yi
Published: March 2023

319

Background: Radical prostatectomy (RP) is the primary treatment for localized clinically significant prostate cancer (csPCa). However, its application is generally based on prior pathological diagnosis. 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) has recently been found to have high diagnostic efficacy and is considered promising in biopsy-free RP. Notably, inadequate specific or positive predictive value of imaging diagnosis strategy could become the Achilles’ Heel of biopsy-free RP. For 68Ga-PSMA PET/CT, the expression of PSMA in benign prostatic hyperplasia (BPH) tissue and its related positive reaction, which can reduce the specificity of diagnosis, are important concerns affecting the imaging diagnosis of PCa as well as the feasibility of biopsy-free RP. Currently, no study has explored the BPH-related false positive rate of 68Ga-PSMA PET/CT in the detection of PCa. Furthermore, the influence of maximum standardized uptake value (SUVmax) on biopsy-free RP is also poorly characterized. Methods: To investigate BPH-related false positive rate of 68Ga-PSMA PET/CT in detecting PCa and the influence of SUVmax on biopsy-free RP, a retrospective descriptive observational study was conducted. Patients who received 68Ga-PSMA PET/CT because of clinical suspicion of PCa based on elevated prostate-specific antigen (> 4ng/ml) or abnormal digital rectal examination and subsequently were confirmed to be BPH or PCa by systematic biopsy or targeted biopsy (TB) were included. The receiver operating characteristic curve was generated for SUVmax values, from which the area under the curve (AUC) and the Youden index was calculated. Sensitivity and specificity were calculated based on the cutoffs. Results: A total of 89 BPH and 94 PCa patients who met the inclusion criteria were included. 27 of the 89 BPH cases were considered 68Ga-PSMA PET/CT positive, all dominant lesions were confirmed to be BPH tissue through TB, and thus, were regarded as BPH-related false positive. The BPH-related false positive rate of 68Ga-PSMA PET/CT in the detection of PCa was 30.3%. SUVmax could effectively distinguish BPH and grade group (GG) one patients with an AUC of 0.8562 and could potentially benefit biopsy-free RP by avoid BPH-related misdiagnosis and GG one-related overtreatment. The optimal SUVmax cutoff value was 9.750 with a sensitivity of 64.71% and a specificity of 97.22%. Given the pivotal role of specificity in biopsy-free RP, we investigated the optimal SUVmax cutoff under when the specificity was 100%. The result was 14.60, with a sensitivity of 41.18% and a specificity of 100%. Conclusions: Our results revealed, for the first time, the BPH-related false positive rate of 68Ga-PSMA PET/CT in the primary diagnosis of PCa. Using SUVmax values in biopsy-free RP can effectively exclude both BPH and GG one patients.