bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of pretreatment lung immune prognostic index in patients with metastatic hormone-sensitive and castration-resistant prostate cancer.
Authors: Wang Zhipeng , Liu Haoyang , Zhao Jinge , Shen Pengfei , Zeng Hao 
Published: March 2023

198 Background: The aim of this study was to explore the prognostic value of the lung immune prognostic index (LIPI) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Methods: We retrospectively analyzed data of 502 mHSPC patients primarily treated with maximal androgen blockade and 158 mCRPC patients receiving abiraterone. All cases were classified into the LIPI-Good, LIPI-Intermediate, and LIPI-Poor groups based on their LIPI score calculated by the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase. The potential of LIPI in predicting mCRPC-free survival (CFS), PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) were analyzed. A propensity score matching (PSM) methodology was performed to balance the baseline factors of different groups. Results: In the mHSPC cohort, patients of the LIPI-Good (mCFS: 25.7 mo; mOS: 93.3 mo), LIPI-Intermediate (mCFS: 14.8 mo; mOS: 51.9 mo) and LIPI-Poor group (mCFS: 6.8 mo; mOS: 18.5 mo) had sequentially worse clinical outcomes (P<0.001 for all pairwise comparisons). The results remain consistent after PSM. Multivariate Cox regression further confirmed that LIPI was an independent predictor of survival outcomes. Subgroup analysis verified that LIPI was associated with unfavorable prognosis in all subgroups except for cases with visceral metastases or receiving abiraterone/docetaxel. As for patients with CRPC receiving abiraterone, LIPI was also an indicator of poor prognosis. Specifically, cases in the LIPI-Good, LIPI-Intermediate and LIPI-Poor group had a ladder-shaped worse PSA response (71.4% [50/70] vs. 56.5% [39/69] vs. 36.8% [7/12], P=0.015), PSA-PFS (14.9- vs. 9.3 vs. 3.1 mo, P<0.001) and OS (14.6- vs. 32.3- vs. 53.4 mo, P<0.001). The results were robust even after PSM. Multivariate Cox regression confirmed that LIPI was an independent prognosticator of abiraterone. Conclusions: This study demonstrated that baseline LIPI was a significant prognostic biomarker for both mHSPC and mCRPC patients and could potentially facilitate risk classification and treatment-decision making in clinical practice.
Prevalence of HRR gene mutations in patients with metastatic castration-resistant prostate cancer: Germline results from the Latin-American observational study PROSPECT.
Authors: Manneh Kopp Ray , Alaez Verson Carmen , Angel Martin , Delgado Arturo , Isaacsson Velho Pedro H , Manduley Alejandro , Barbieri Melissa , Vargas Carmen , Gonzalez Francisco , Barata Pedro C. 
Published: March 2023

226 Background: Metastatic castration-resistant prostate cancer (mCRPC) is a molecularly heterogeneous disease, and 20% to 30% of patients harbor alterations in homologous recombination repair (HRR) genes. However, data regarding the genetic profile of mCRPC in Latin American populations are scarce. This study determined the prevalence of HRR gene mutations in Latin American patients with mCRPC to better understand this population and guide future policies. The interim analysis herein reports results focused on germline alterations only. Methods: PROSPECT (NCT04962880) is a cross-sectional, non-interventional, multicenter study. Patients were adults (≥18 years) diagnosed with mCRPC from November 2020 to October 2021 at centers in Argentina, Brazil, Colombia, Costa Rica, Mexico, Panama, and Peru. Diagnoses were confirmed by laboratory testing (PSA and/or testosterone levels) or imaging (X-ray, CT, MRI, or PET scan). All patients provided written informed consent. Blood samples were assayed to determine the prevalence of germline mutations in HRR genes in the participating countries using the AmoyDx HANDLE HRR Next Generation Sequence 32 genes Panel (AmoyDx, Xiamen, China). Results: Overall, 388 participants with a median age of 70 years (range: 49‒89) were included in this study, including 184 Hispanic (47.4%), 101 White (26%), 40 Mestizo (10.3%), 11 African American (2.8%), 2 Asian (0.5%), and 50 “other” (12.9%) patients. Over a third of them (n=151, 38.9%) had a family history of cancer. Median time since prostate cancer diagnosis was 3 years (range: 0‒23) and 2 years (range: 0‒22) since mCRPC diagnosis. Metastases were most frequently localized to the bones (59.6%). The patients’ ECOG status was either 0 (173/365; 47.4%) or 1 (192/365; 52.6%). Among the 167 patients that received treatment, most received androgen deprivation therapy alone (43.7%) or with radiotherapy (21.6%). Overall, 25/381 patients (6.56%) had germline HRR mutations. The 5 most frequently mutated HRR genes were BRCA2 (16%), ATM (12%), CHEK2 (12%), BRIP1 (8%) and HOXB13 (8%). Conclusions: The prevalence of germline HRR mutations found in this multinational Latin American population was lower than expected compared to previously reported rates ranging from 8% to 12% from other countries. Additionally, the most frequently mutated HRR genes differed from those from major trials including PROfound (NCT02987543). Clinical trial information: NCT04962880 . [Table: see text]
Association of obesity with tumor differential gene expression and gene set enrichment pathways in advanced prostate adenocarcinoma (PCa).
Authors: Mathew Thomas Vinay , Chigarira Beverly , Gebrael Georges , Sayegh Nicolas , Tripathi Nishita , Jo Yeonjung , Nussenzveig Roberto , Sahu Kamal Kant Kant , Li Haoran , Tandar Clara , Goel Divyam , McFarland Taylor Ryan , Brundage James , Maughan Benjamin L. , Swami Umang , Agarwal Neeraj 
Published: March 2023

231 Background: Increased Body Mass Index (BMI) has been linked to increased prostate cancer incidence, recurrence, and mortality (PMID: 35538398). Herein, we sought to investigate the underlying differences in gene expression profiles based on BMI in patients (pts) with PCa. Methods: In this IRB-approved retrospective study, eligibility criteria included histologically confirmed PCa and available RNA sequencing results from treatment naïve primary prostate tissue by a CLIA-certified lab. Pts were categorized into two cohorts: obese (Ob, BMI≥30) and non-obese (non-Ob, BMI<30). BMI at the time of diagnosis of PCa was used for analysis. 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 software analysis (GSEA) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R v4.2. Results: 60 pts were eligible, of which 22 were Ob and 38 were non-Ob. Tumor tissues from Ob pts had an increased expression of the heme metabolism, androgen-response, protein secretion, fatty acid, and bile metabolism pathways. Non-Ob pts had a significantly higher expression of genes involved in the inflammation pathways (interferon-alpha & TNF alpha pathways). Normalized enrichment scores are reported. Differential individual gene expression profiles will be presented at the meeting. Conclusions: Our study showed upregulation of distinct genomic pathways in Ob pts with prostate cancer which may help personalize medicine and guide further drug development. These hypothesis-generating data require external validation. [Table: see text]
Machine-learning to predict utility of circulating tumor DNA (ctDNA) for somatic genotyping.
Authors: Herberts Cameron , Tu Wilson , Fonseca Nicolette M. , Maurice-Dror Corinne , Khalaf Daniel Joseph , Annala Matti , Chi Kim N. , Wyatt Alexander William 
Published: March 2023

232 Background: ctDNA genotyping is increasingly used to evaluate patient eligibility for genomics-driven treatments ( e.g., PARP inhibitors) in metastatic castration-resistant prostate cancer (mCRPC), but low ctDNA-fraction (ctDNA%) causes false negatives and is unpredictable. We investigated whether a machine-learning model exploiting routine clinical prognostic markers can predict if a mCRPC patient will have sufficient ctDNA% for informative ctDNA testing. Methods: We analysed plasma cell-free DNA (cfDNA) collected at baseline prior to first-line therapy from 463 consecutive mCRPC patients. ctDNA% was quantified using somatic allele frequencies and genome-wide copy number profiles via deep targeted sequencing. We built an XGBoost model (70:30 train-test split) using 18 clinical factors to predict synchronously measured ctDNA% (binary classification >2% or ≤2%, i.e., the conventional ctDNA% limit of detection for mutations employed by commercial tests), with performance evaluated using area under the curve (AUC) of receiver operating characteristics. Results: Median age was 73 (range: 45-98) and 86% of patients had ECOG 0-1. Median ctDNA% was 5% (range: 0-89%) and correlated with serum and radiographic metrics of disease burden, including total cfDNA concentration (ng/mL of plasma, reflecting cfDNA released by both normal and tumor cells; Spearman ρ=0.55), alkaline phosphatase (ALP) per upper limit of normal (ULN) ( ρ=0.46), lactate dehydrogenase (LDH) per ULN ( ρ=0.41), PSA ( ρ=0.3), presence of liver metastases, and ≥10 bone lesions. We trained an XGBoost model incorporating these and 13 additional clinical factors achieving an AUC for ctDNA >2% of 0.83 (F1 score: 0.79). SHAP interpretability scores indicated that cfDNA concentration most strongly informed prediction of ctDNA >2%, followed by ALP/ULN and PSA—consistent with our prior bivariate rank correlations—whereas features associated with initial prostate cancer diagnosis (Gleason Grade Group, de novo versus metachronous M1 disease) were less informative. Recognizing that comprehensive and standardised clinical annotation is not always available in real-world settings, we built a secondary parsimonious ctDNA%-prediction tool restricted to 8 highly informative and clinically practical factors (cfDNA concentration, ALP/ULN, LDH/ULN, PSA, albumin, ECOG, liver metastases, lung metastases) and flexible to incomplete input data, achieving a comparable AUC for ctDNA>2% of 0.76. Conclusions: Our results demonstrate the feasibility of a machine learning framework to estimate ctDNA% in patients with mCRPC. This point-of-care tool would enable prioritisation of mCRPC patients for ctDNA somatic genotyping with a predicted ctDNA >2%, versus tissue or germline-only testing in patients with a predicted ctDNA ≤2%.
Analysis of TP53 gain of function mutations in metastatic castration-resistant prostate cancer.
Authors: Sweeney Patrick L , Lanka Sree M , Jang Albert , Gupta Kanika , Caputo Sydney , Casado Crystal , Huang Minqi , Pocha Olivia , Hawkins Maddie , Lieberman Alexandra , Schwartz Jennifer , Jaeger Ellen B. , Miller Patrick , Barata Pedro C. , Layton Jodi Lyn , Lewis Brian E. , Ledet Elisa M. , Sartor A. Oliver 
Published: March 2023

246 Background: TP53, an oncogene implicated in the development of many malignancies, is commonly altered in mCRPC. Gain-of-function mutations in TP53 confer increased oncogenic properties of this gene and play a role in mCRPC. The goal of this study was to characterize somatic TP53 mutations, specifically gain-of-function mutations, in the ctDNA of mCRPC patients in the context of prior therapies. Methods: A retrospective analysis of mCRPC patients at Tulane Cancer Center between 2015-2022 was performed. All patients had ctDNA testing performed with the Guardant360 multigene panel assay. Clinical annotation including initial diagnosis, staging, treatment history, and family history were obtained. TP53 mutations were classified based on existing published functional studies and/or in silico evaluation. Statistical analyses were performed with Fisher's exact and Chi-squared tests where appropriate. Results: 338 mCRPC patients with ctDNA testing were included in this analysis. 76 patients had no prior treatment with either abiraterone or enzalutamide, while 262 patients had been treated with abiraterone and/or enzalutamide. Somatic TP53 mutations were similar in frequency between those with or without abiraterone/enzalutamide pretreatment; 46% (35/76) of patients in the abiraterone/enzalutamide naïve subset had a somatic TP53 mutation, compared to 41% (108/262) of patients previously treated with abiraterone and/or enzalutamide. Only 9% (7/76) of abiraterone/enzalutamide naïve patients had a TP53 gain-of-function mutation, compared to 19% (49/262) of patients previously treated with one or both drugs ( p = 0.05). The most common type of TP53 mutation was loss-of-function. There were no significant associations between TP 53 mutations and occurrence of other common mutations. Conclusions: mCRPC patients with prior treatment of abiraterone and/or enzalutamide were significantly more likely to have a gain-of-function TP53 mutation. Further studies are needed to investigate therapeutic implications of these findings.
Development and validation of a multigenomic liquid biopsy (PROSTest) for prostate cancer detection.
Authors: Modlin Irvin Mark , Kidd Mark , Drozdov Ignat A. , Boegemann Martin , Bodei Lisa , Kunikowska Jolanta , Malczewska Anna , Bernemann Christof , Rahbar Kambiz 
Published: March 2023

252 Background: A crucial requirement in prostate cancer (PCa) management is an accurate, easily measurable, liquid biopsy that can define the molecular pathology of an individual PCa. We report the development and clinical validation of a novel PCa-specific, multi-genomic biomarker. Methods: We identified candidate mRNA biomarkers in PCa-Adeno transcriptomes ( n=1,159) using several strategies: co-expression networks, differential expression, and functional enrichment. mRNA transcripts were screened in an independent tumor tissue ( n=50) set and validated as biomarkers in the TCGA-PRAD ( n=500) dataset. An amalgam of Random Forest, Gradient Boosted Machines and Support Vector Machines, all standard machine learning classifiers, was used to develop a classification algorithm and probability score in a peripheral blood gene expression test cohort ( n=430). This multigene biomarker was validated in two independent clinical blood sample sets (Set I: PCa n=77, controls n=54; Set II: PCa n=132, controls/BPH n=99) to determine as PCa-specificity and diagnostic efficacy Clinical utility was evaluated versus Gleason scores, T-staging and PSA ( n=209) and in a prostatectomy cohort ( n=47). Results: The pipeline identified 27 of PCa gene markers in the tumor tissue set and TCGA-PRAD dataset. Gene expression was significantly correlated ( r=0.72, p<0.0001) in matched tissue/blood samples. The PROSTest (scale: 0-100) ensemble algorithm (developed in blood) had a sensitivity for PCa of 92.2% (95% CI: 83.8-97.1%; Set I) and 95.0% (95% CI: 89.9-98%. Set II). The specificity was 100% for Set I (95% CI: 93.4-100%) and 100% for Set II (95% CI: 96.3-100%). PCa scores were significantly ( p<0.0001) lower for controls (Set I: 17±4; Set II: 18±4) and BPH (19±6) to PCa; 82±19 (Set I) and 80±19 (Set II). The AUROC was 0.98±0.01. PROSTest scores were elevated ( p<0.05) in T2-4 and were significantly correlated with Gleason ( r=0.93, p<0.02). In contrast, PSA from matched samples was not associated ( p=NS) with clinically significant disease (Gleason 7-10 or T2-4 tumors). In head-to-head comparisons, the PROSTest was considerably more accurate than PSA for detecting significant disease (z-statistic: 2.43, p=0.015). In the R0 prostatectomy cohort, all scores were elevated (72±7) and significantly decreased post-surgery (26±8, p<0.0001, n=37). Individuals with residual disease ( n=10) exhibited elevated (60±4) post-surgical scores. Conclusions: The PROSTEst is a multigenomic blood-based PCR tool that accurately (>90%) identifies prostate cancer. It is significantly more accurate than PSA for the detection and stratification of clinically significant prostate disease. A multigenomic liquid biopsy for PCA provides a real-time, non-invasive method for detection of a PCa and may facilitate the early identification of residual/recurrent disease.
Evaluation of ctDNA in patients with CRPC with pathogenic germline mutations in BRCA2.
Authors: Huang Minqi , Jaeger Ellen B. , Caputo Sydney , Casado Crystal , Jang Albert , Sweeney Patrick L , Lanka Sree M , Gupta Kanika , Lieberman Alexandra , Schwartz Jennifer , Pocha Olivia , Hawkins Maddie , Miller Patrick , Layton Jodi Lyn , Lewis Brian E. , Barata Pedro C. , Ledet Elisa M. , Sartor A. Oliver 
Published: March 2023

253 Background: Approximately 3-5% of advanced prostate cancer patients have pathogenic BRCA2 mutations in germline tests. In this study, we examine the relationship between pathogenic germline BRCA2 mutation and somatic changes in ctDNA. Methods: Germline screenings were performed by Invitae multi-cancer gene panel which includes 50-84 genes. ctDNA alterations were detected by Guardant 360 assays which report somatic changes in 70-83 genes. All ctDNA samples were collected in post-abiraterone and/or enzalutamide (in CRPC patients). Any pathogenic/likely pathogenic somatic alterations in the ctDNAs with more than 0.1% of allelic fraction were included in this cohort. The type of mutation detected in ctDNA was also assessed (truncating, point, etc.). Statistical significance for comparison is calculated with Fischer Exact Probablity Test and Chi-Square Test. Results: A total of 11 patients had germline BRCA2 pathogenic mutations and ctDNA assays; 267 patients had no germline DNA pathogenic alterations and ctDNA assays. Compared to germline normal patients, the germline BRCA2 mutations were less likely to have AR alterations on ctDNA (OR=0.2133, 95% C.I. [0.087, 0.525], p-value = 0.0003). BRCA2 germline positive patients were also more likely to have a mutated BRCA1, BRCA2, and TP53 ctDNA (OR=7.899, 95% C.I. [1.2745, 48.9548], p=0.055), (OR=7.899, 95% C.I. [1.7529, 16.059], p=0.008), and (OR=6.442, 95% C.I. [2.449, 16.946], p=0.00001), respectively. All other ctDNA assessed genes were mutated at a similar frequency between germline BRCA2 mutated and “normal” germline patients. BRCA2 germline mutations patients are less likely to have copy number alterations (CNVs) (OR=0.3992, 95% C.I. [0.2168, 0.7352], p=0.0031) and more likely to have frameshift mutations (OR=2.3182, 95% C.I. [1.169, 4.5972], p=0.0183). Conclusions: The ctDNA testing in this CRPC population (after abiraterone and/or enzalutamide) was less likely to find AR alterations and more likely to find pathogenic mutations for BRCA1, BRCA2, and TP53 in BRCA2 germline positive patients. In addition, BRCA2 germline positive CRPC patients were more likely to have frameshift mutations and less likely to have CNVs than those with an intact germline. Characterizing the mutational landscape in BRCA2 germline mutated patients may help to better define underlying disease biology. Those with BRCA mutated germline may be less likely to have AR driven tumors. More study is needed to better understand patients with underlying DNA repair defects.
Natural killer cell activity in patients with metastatic castration-resistant prostate cancer treated with enzalutamide.
Authors: Zedan Ahmed , Nederby Line , Volmer Lone , Madsen Christine Vestergaard , Sørensen Bente E. , Hansen Torben 
Published: March 2023

255 Background: Metastatic castration resistant prostate cancer (mCRPC) is the lethal stage for most patients with prostate cancer (PCa). The need for more reliable prognostic and predictive markers for the management of mCRPC is still unmet. The aim of this study was to elucidate the correlation between Natural Killer cell activity (NKA) and treatment outcome in mCRPC patients. Methods: Blood samples were collected prospectively from 87 patients with mCRPC who were treated by enzalutamide as first line treatment. Samples were collected, in NK Vue tubes, at baseline, and prior to each treatment cycle until treatment change. Tubes were placed in an incubator at 37°C within 15 minutes of sampling. Following 20-24 hours of stimulation the level of interferon-gamma (IFNγ) in the plasma was measured, by ELISA (NK Vue) as a surrogate for NKA. Outcomes data were included as endpoints. Results: At the time of biochemical response, plasma IFNγ decreased significantly compared to levels detected at baseline (z-score= 2.334, p=0.019). Additionally, the level of IFNγ was significantly lower at radiological response compared to values at biochemical progression (z-score=2.168, p=0.030). Regarding outcome data, the whole cohort was divided into four groups. In group 1 (n=41) the IFNγ level remained within a normal range (>250 pg/mL), while in group 2 (n=8) it increased from an abnormal (<250 pg/mL) to a normal level. In group 3 (n=13) it dropped to an abnormal level, and it remained at an abnormal level during treatment in group 4 (n=17). There was a significant difference between patients in group 2 and patients in the other three groups regarding both overall survival, radiological free survival and time to next treatment (HR= 3.98, p= 0.012, HR= 6.10, p=< 0.001 and HR= 6.521, p= < 0.001, compared to group 1 respectively). Conclusions: An inverse correlation between NKA and both treatment response and outcome was observed, suggesting a unique role of NK cells in late stage PCa treated with enzalutamide.
Single and multi-hit PIK3CA short variant (SV) genomic alterations (GA) in clinically advanced prostate cancer (CAPC): A genomic landscape study.
Authors: Miguel Carla , Bratslavsky Gennady , Jacob Joseph M , Grivas Petros , Spiess Philippe E. , Necchi Andrea , Pavlick Dean C. , Huang Richard S.P. , Lin Douglas I. , Danziger Natalie , Sokol Ethan , Sivakumar Smruthy , Graf Ryon , Vasan Neil , Ross Jeffrey S. 
Published: March 2023

258 Background: Tumors harboring 2 or more PIK3CA Short variants (SV) (“Multi-hit”) have been described in breast cancer as linked to enhanced clinical outcome from anti-PIK3CA targeted therapies including alpelisib and investigational agents in clinical trials. The landscape and clinical implications of multi-hit PIK3CA alterations in other tumors, including in CAPC, are underexplored. Methods: 19,978 CAPC samples underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of GA and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, signature and loss of heterozygosity (gLOH). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: 18,741 (93.8%) CAPC were PIK3CA wild type (WT), 1,155 (5.8%) featured a single PIK3CA SV and 82 (0.4%) featured multi-hit PIK3CA SVs. The median ages of CAPC patients with single hit (69.1 yrs) or multi-hit (68.7 yrs) PIK3CA SV were older than the PIK3CA WT (67.6 yrs) CAPC (p<.0001 for both). At 14.0%, African ancestry was more frequent in PIK3CA WT CAPC than in single-hit (10.4%; p=.001) and multi-hit (10.2%; not significant). Single-hit (81.4%; p<.0001) and multi-hit (85.2% p=.05) PIK3CA SV CAPC featured significantly more MMR trinucleotide genomic signatures than PIK3CA WT (64.8%). Single-hit (2.7%; p=.02) and multi-hit (5.8% p=.05) PIK3CA SV CAPC featured significantly more POLE trinucleotide genomic signatures than PIK3CA WT (0.4%). MSI high status was significantly more common in both PIK3CA single-hit (12.4% vs 2.5%; p<.0001) and multi-hit (35.4% vs 2.5%; p<.0001). Mean TMB was also significantly higher in single-hit PIK3CA (11.1 vs 3.5 mut/Mb; p<.0001) and multi-hit (42.9 vs 3.5 mut/Mb; p<.0001). Noteworthy differences in GA of potential importance for CAPC pts included significantly higher frequencies of GA in BRCA2 in multi-hit vs WT (18.3% vs 8.5%; p=.019), ATM in multi-hit vs WT (13.4% vs 5.6%; p=.02) and PTEN in single-hit vs WT (40.2% vs 30.1%; p<.0001) and lower frequencies of GA in CDK12 (3.6% vs 5.6%; p=.009) and SPOP (7.4% vs 9.8%; p=.012) in single-hit vs WT. There were no differences in gLOH or PD-L1 expression among the 3 groups. Conclusions: Although uncommon, the identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique subtype of this disease that may be associated with enhanced responsiveness to anti-PIK3CA targeted therapy strategies.