PD44-03 MOLECULAR ASSOCIATIONS WITH PLASMA CELL CONTENT IN PROSTATE CANCER

5047 Background: We identified plasma cell free DNA (cfDNA) based copy number variations (CNV); single nucleotide variants (SNVs) & TMPRSS-ERG fusion in four sub states of metastatic prostate cancer (mPCa) and determined the impact on survival. Two mHSPC cohorts included treatment naïve, gp-1 and mHSPC patients (pts) responding to chronic androgen ablation (AA) (gp-2). Two mCRPC cohorts included mHSPC pts with PSA relapse on chronic AA (gp-3) and a clinically progressive mCRPC cohort post AA (gp-4). Methods: Enrollment of mPCa pts was performed from 2009-14 who were followed until 2018. Plasma from collected blood was used for extracting cfDNA. NGS was performed using Illumina HiSeq X for a preselected target panel of 129 genes including DNA damage repair genes. Statistical analyses of genomic aberrations were performed in R 3.5.1 and Cox proportional-hazard models were used for survival analyses. Results: A total of 255 pts were enrolled with 215 having adequate cfDNA that passed NGS QC. Median study follow up was 90.2 (Range:73;99) months. The table highlights pts in each gp with CNV, SNV, fusion events. ARamplification was higher in mCRPC gps3&4 (20/103 pts) compared to 3/106 pts in mHSPC gps1&2 (p < 0.001) and was prognostic for poor survival in mCRPC (p < 0.001;HR:3.34; 95%CI: 1.9-5.76). 54/103 pts in gp3&4 had SNVs in TP53 compared to 34/106 pts in mHSPC gps1&2 (P < 0.01). SNVs in APC, AR, CDK12 and BRIP1 were also increased in gps3&4 (p < 0.01). Gp1 mHSPC pts with SNVs in ATM/ CHEK2 had shorter response to AA (p < 0.001; HR:3.66; 95%: CI:1.81-7.39). Conclusions: Plasma cfDNA based somatic aberrations are detected with increased prevalence in mHSPC to mCRPC states. The ease of specimen collection and the need for molecular profiling in mPCa increases its potential for clinical applications in pt care. [Table: see text]

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Re: Niven Mehra, David Dolling, Semini Sumanasuriya, et al. Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA). Eur Urol 2018;74:283–91

European Urology ◽

10.1016/j.eururo.2018.05.015 ◽

2018 ◽

Vol 74 (3) ◽

pp. e67-e68 ◽

Cited By ~ 1

Author(s):

Vincenza Conteduca ◽

Giorgia Gurioli ◽

Ugo De Giorgi

Keyword(s):

Prostate Cancer ◽

Plasma Cell ◽

Phase Iii ◽

Castration Resistant Prostate Cancer ◽

Two Phase ◽

Cell Free Dna ◽

Dna Concentration ◽

Castration Resistant ◽

Free Dna ◽

Phase Iii Trials

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Tumor Immune Microenvironment Clusters in Localized Prostate Adenocarcinoma: Prognostic Impact of Macrophage Enriched/Plasma Cell Non-enriched Subtypes

10.20944/preprints202005.0462.v1 ◽

2020 ◽

Author(s):

Neil K. Jairath ◽

Mark W. Farha ◽

Sudharsan Srinivasan ◽

Ruple Jairath ◽

Michael D. Green ◽

...

Keyword(s):

Prostate Cancer ◽

Plasma Cell ◽

Immune Cell ◽

Cox Regression ◽

M2 Macrophage ◽

Significant Heterogeneity ◽

Prognostic Impact ◽

Cell Type ◽

Immune Microenvironment ◽

Immune Cell Type

Background: Prostate cancer (PCa) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of prostate adenocarcinomas (n=496) was utilized. The immune microenvironment was characterized using the CIBERSORTX tool to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Analyses of progression-free survival (PFS), distant metastases, and overall survival (OS) were performed using Kaplan-Meier estimates and Cox-regression multivariable analyses. Results: Four immune clusters were identified, largely defined by plasma cell, CD4+ Memory Resting T Cells (CD4 MR), M0 and M2 macrophage content (CD4 MRHighPlasma CellHighM0LowM2Low, CD4 MRLowPlasma CellHighM0LowM2Low, CD4 MRHighPlasma CellLowM0HighM2Low, and CD4 MRHighPlasma CellLowM0LowM2High). The two macrophage-enriched/plasma cell non-enriched clusters (3&4) demonstrated worse PFS (HR 2.24, 95% CI 1.46–3.45, p=0.0002) than the clusters 1&2. No metastatic events occurred in the non-macrophage-enriched clusters. Comparing clusters 3 vs 4, in patients treated by surgery alone, cluster 3 had zero progression events (p<0.0001). However, cluster 3 patients had worse outcomes after post-operative radiotherapy (p=0.018). Conclusion: Distinct tumor immune clusters with a macrophage-enriched phenotype and reduced plasma cell enrichment independently characterize an aggressive phenotype in localized prostate cancer that may differentially respond to treatment.

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Plasma cell-free DNA-based predictors of response to abiraterone acetate/prednisone and prognostic factors in metastatic castration-resistant prostate cancer

Prostate Cancer and Prostatic Diseases ◽

10.1038/s41391-020-0224-4 ◽

2020 ◽

Vol 23 (4) ◽

pp. 705-713 ◽

Cited By ~ 1

Author(s):

Meijun Du ◽

Yijun Tian ◽

Winston Tan ◽

Liewei Wang ◽

Liguo Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Prognostic Factors ◽

Plasma Cell ◽

Abiraterone Acetate ◽

Castration Resistant Prostate Cancer ◽

Cell Free Dna ◽

Castration Resistant ◽

Free Dna ◽

Predictors Of Response

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Plasma cell-free DNA-based prognosis in metastatic hormone sensitive prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.242 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 242-242

Author(s):

Manish Kohli ◽

Siddhartha Yadav ◽

Winston Tan ◽

Irbaz Bin Riaz ◽

Tiantian Zheng ◽

...

Keyword(s):

Prostate Cancer ◽

Plasma Cell ◽

Univariate Analysis ◽

Newly Diagnosed ◽

Illumina Hiseq ◽

Cell Free Dna ◽

Free Dna ◽

Genomic Aberrations ◽

Hormone Sensitive ◽

Ngs Data

242 Background: We evaluated plasma cell free based genomic aberrations for prognosticating survival of newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) patients (pts). Methods: Plasma was collected from mHSPC pts enrolled between 2009-2014. Platelet poor plasma (PPP) fractions were processed uniformly and cell free DNA (cfDNA) extracted using Qiagen kits. Pts were followed after initiating hormonal therapy until death. Next Gen Sequencing (NGS) of cfDNA was performed using Illumina HiSeq X for a preselected panel of 128 genes (PredicineDDR-77 cancer driver genes; 29 genes in BRCA-FA homologous recombination deficiency (HRD) pathway; 22 DNA damage repair pathway genes). Statistical analyses of plasma genome based aberrations with overall survival (OS) were performed in R 3.5.1. Cox proportional-hazard models were used for survival analysis. Results: An average of 2.5 ml PPP from 99 pts yielded a median of 10.5 ng (range: 2.8-702) cfDNA per sample. 15/99 pt samples with a yield < 5 ng were excluded from sequencing; 9/99 samples failed NGS. Median follow-up time was 80.2 months (mths) (Range: 74.7, 87]); median OS was 69.1 mths (range: 54,NR). 29 pts with full NGS data had high volume metastatic disease. cfDNA yield correlated with metastatic volume (P = 0.01). Univariate analysis revealed both variables prognostic for OS (Metastatic volume: log-rank P=0.01, HR=2.1, 95% CI: 1.1-3.8; cfDNA yield: P =0.04, HR = 1.3, 95% CI: 1.03-1.7). Multivariate regression showed prognostic value of cfDNA yield remained independent of metastatic volume (P = 0.03, HR = 1.34, 95% CI: 1.02-1.76). 54/67 samples with NGS data had at least one mutation/copy number variation detected. Top mutated genes included TP53 (N=18), ATM (N=9), CHEK2 (N=7), FANCM (N=6), RB1 (N=6), BRCA2 (N=5), PIK3CA (N=4) and 37/67 pts harbored 1≥ variant in HDR pathways. These pts had a shorter survival (median: 58.6 mths) (P=0.04, HR= 2.28, 95% CI: 1.01-5.18) and pts with ATM mutations did significantly worse (median survival: 47.4 mths) (HR=4.03, P=0.0005, 95% CI: 1.73-9.37). Conclusions: Plasma cfDNA yield is prognostic for survival in newly diagnosed mHSPC state and presence of HRD pathway genomic aberrations in plasma cfDNA are associated with poor survival.

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