Plasma cell free DNA (cfDNA) based somatic aberrations detected in treatment naïve metastatic hormone sensitive prostate cancer (mHSPC), hormonally ablated mHSPC and metastatic castration resistant prostate cancer (mCRPC) states and their impact on survival.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5047-5047
Author(s):  
Manish Kohli ◽  
Winston Tan ◽  
Tiantian Zheng ◽  
Amy Wang ◽  
Calvin Wong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Plasma Cell ◽  
Copy Number Variations ◽  
Cell Free Dna ◽  
Androgen Ablation ◽  
Free Dna ◽  
Impact On Survival ◽  
Treatment Naïve ◽  
The Impact ◽  
Somatic Aberrations

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]

Association of plasma cell-free DNA concentration [cfDNA] with outcome from taxane therapy (TT) for castration resistant prostate cancer (CRPC).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 5014-5014 ◽  
Author(s):  
Niven Mehra ◽  
Rossitza Christova ◽  
Lorna Pope ◽  
Suzanne Carreira ◽  
Jane Goodall ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Plasma Cell ◽  
Castration Resistant Prostate Cancer ◽  
Cell Free Dna ◽  
Dna Concentration ◽  
Castration Resistant ◽  
Free Dna

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

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.

scholarly journals Copy number variations in urine cell free DNA as biomarkers in advanced prostate cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (24) ◽  
pp. 35818-35831 ◽  
Author(s):  
Yun Xia ◽  
Chiang-Ching Huang ◽  
Rachel Dittmar ◽  
Meijun Du ◽  
Yuan Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Copy Number ◽  
Advanced Prostate Cancer ◽  
Copy Number Variations ◽  
Cell Free Dna ◽  
Free Dna

Plasma cell-free DNA profiling of PI3K/Akt pathway aberrations in two multi-institutional independent metastatic castration-resistant prostate cancer (mCRPC) cohorts.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 159-159
Author(s):  
Edmond Michael Kwan ◽  
Chao Dai ◽  
Heidi Fettke ◽  
Christine Hauser ◽  
Patricia Bukczynska ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Outcomes ◽  
Plasma Cell ◽  
Akt Pathway ◽  
Castration Resistant Prostate Cancer ◽  
Cell Free Dna ◽  
Cox Regression Analysis ◽  
Pten Loss ◽  
Castration Resistant ◽  
Free Dna

159 Background: Tumour tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the phosphatidylinositol-3-kinase (PI3K)/Akt-signaling pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, cfDNA assays for robustly identifying PI3K/Akt pathway aberrations including CNVs are urgently required. Methods: In this multi-institutional prospective biomarker study, we used the Predicine cfDNA assay, optimised for CNV detection, to perform targeted sequencing in 231 mCRPC patients in two independent cohorts (Australian, n = 78; US, n = 153). Kaplan-Meier survival estimates and multivariable Cox regression analysis were used to assess associations between genomic aberrations and progression-free survival (PFS) and overall survival (OS). Results: PTEN loss and PIK3CA gain were detected in 37% (85/231) and 17% (39/231) of patients, respectively. Poorer outcomes were observed in patients with PI3K/Akt pathway aberrations, including those with dual PTEN loss and PIK3CA gain (HR 2.3, 95% CI 1.2-4.4). Similarly, cumulative CNV burden in the PI3K/Akt and AR pathways (0 vs 1 vs ≥2 CNVs in Australian cohort: median OS 33.5 vs 17.2 vs 9.7 months, p< 0.001; 0 vs 1 vs ≥2 CNVs in US cohort: median OS 35.5 vs 14.3 vs 9.2 months, p< 0.001) was associated with significantly worse clinical outcomes. Notably, 21% (31/146) of PTEN-neutral patients harbored other alterations in the PI3K/Akt pathway. Conclusions: Our cfDNA assay readily detected PI3K/Akt pathway CNVs, with the prevalence of PTEN loss comparable to prior tissue sequencing studies. CNVs in the PI3K/Akt pathway were associated with deleterious clinical outcomes, especially when concurrent with AR gain. Additional PI3K/Akt pathway aberrations were found in approximately one-fifth of PTEN-neutral mCRPC. Collectively, our data demonstrate the potential utility of profiling cfDNA to facilitate and optimize patient selection for treatment with Akt inhibitors in mCRPC. [Table: see text]

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