Contrasting genomic profiles from metastatic sites, primary tumors, and liquid biopsies of advanced prostate cancer

Cancer ◽  
2021 ◽  
Author(s):  
Andrea Necchi ◽  
Vito Cucchiara ◽  
Petros Grivas ◽  
Gennady Bratslavsky ◽  
Joseph Jacob ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Liquid Biopsies ◽  
Primary Tumors ◽  
Metastatic Sites

Abstract 2195: Differential transcriptomic profiling of primary tumors and metastatic sites in advanced prostate cancer

2021 ◽  
Author(s):  
Luke B. Soliman ◽  
Andre L. De Souza ◽  
Praveen Srinivasan ◽  
Matthew Danish ◽  
Dragan J. Golijanin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Transcriptomic Profiling ◽  
Primary Tumors ◽  
Metastatic Sites

Abstract CC06-01: Identifying therapeutic options for patients with advanced prostate cancer through genes in liquid biopsies

2021 ◽  
Author(s):  
Seta Derderian ◽  
Edouard Jarry ◽  
Arynne Santos ◽  
Mohanachary Amaravadi ◽  
Quentin Vesval ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Therapeutic Options ◽  
Liquid Biopsies

Comprehensive genomic profiling (CGP) in post-systemic treatment (Post) metastatic sites (MET) and pretreatment (Pre) primary tumors (PT) of metastatic prostate cancer (mPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 175-175
Author(s):  
Andrea Necchi ◽  
Petros Grivas ◽  
Gennady Bratslavsky ◽  
Oleg Shapiro ◽  
Joseph Jacob ◽  
...  
Keyword(s):  
Systemic Treatment ◽  
High Status ◽  
Liquid Biopsies ◽  
Primary Tumors ◽  
Virtual Absence ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Metastatic Sites ◽  
Systemic Therapies

175 Background: CGP was performed on Pre PT and Post MET including bone (BO), liver (LIV), lung (LU), brain (BN), lymph node (LN) and soft tissue (ST) mPC. Methods: 1,294 mPC underwent hybrid-capture based CGP. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: GA in AR were lowest in the Pre PT (2%) and highest in Post LU (24%) and LIV (50%). GA/tumor was significantly higher in BN (8.0) compared to PT (3.8). BR MET also featured higher PTEN GA than PT. BRCA2 GA varied from 0% in BR to 7-9% in PT, BO, LU, LN and ST to a high of 15% in LI MET. ATM GA were significantly higher in LU MET and RAD21 GA highest in LN MET. Potential predictors of IO drug response included high CDK12 GA in LU MET, MSI high status at 29% in BR MET associated with higher TMB levels, but virtual absence of high PD-L1 expression. ERBB2 GA appeared to be increased in the MET group compared with PT but BRAF GA were not. RB1 GA were significantly increased in LIV MET cases. Conclusions: CGP of mPC PT and MET demonstrates significant differences likely linked to exposure to systemic therapies. These findings suggest that, in the future, liquid biopsies may have advantages over individual MET site biopsies in their ability to capture the entire range of therapeutic opportunities for patients with advanced mPC.[Table: see text]

Treatment facility volume and survival in patients with advanced prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 274-274
Author(s):  
Shreyas Joshi ◽  
Elizabeth A. Handorf ◽  
Abhishek Srivastava ◽  
Selma Masic ◽  
David B. Cahn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Active Treatment ◽  
Advanced Prostate Cancer ◽  
High Volume ◽  
Sensitivity Analyses ◽  
Bottom Quartile ◽  
Treatment Volume ◽  
Treatment Facilities ◽  
Contemporary Management ◽  
Metastatic Sites

274 Background: Despite improvements in the medical management of advanced prostate cancer (aPC), it continues to be the 2nd leading cause of cancer death in American men. The contemporary management of men with aPC is increasingly complex and can vary based on access to up-to-date treatments, which is often found at busier treatment centers. We thus evaluated the relationship between facility volume and survival outcomes in aPC. Methods: The National Cancer Database (NCDB) was queried from 2004-2014 for aPC, defined as T4, N+, or M+ disease. Six pre-defined patient cohorts were evaluated. Cohort A = patients with aPC (N = 64,815); cohort B = M0 patients (N = 27,155); cohort C = M0 patients undergoing active treatment (N = 21,755); cohort = all M1 patients (N = 37,660); cohort E = M0 patients undergoing active treatment (N = 30,643); and cohort F = M1 patients who underwent active treatment and who had known metastatic sites (N = 12,452). Treatment facilities were divided into quartiles based on median treatment volume: <1.8 patients/year, 1.8-3.3 patients/year, 3.4-5.6 patients/year, and >5.6 patients/year. Regression models were adjusted along a set of covariates available in the NCDB. The primary outcome was overall survival (OS). Results: OS improved with each increase in volume quartile. The top quartile (>5.6 pts/yr) demonstrated significantly greater OS compared to the bottom quartile (<1.8 pts/yr) [HR 0.82, 95% CI 0.77-0.88, p<0.001]. The improved OS in the top volume quartile remained consistent when analyzed across the six pre-defined patient cohorts. Sensitivity analyses were conducted on Cohort A, adjusting for Gleason score and facility type, which did not change the effect of volume on survival. Conclusions: In this retrospective analysis of nearly 65K men who presented with aPC, we demonstrate that management at a high-volume facility (top quartile, >5.6 pts/yr) confers a significant OS advantage when compared to management at a facility in the lowest quartile (<1.8 pts/yr). This OS advantage persisted with similar magnitudes of effect after narrowing the cohorts by disease and treatment characteristics. These findings may have implications on the optimal management of men with advanced PC.

The Veterans Health Administration Precision Oncology Program for Advanced Prostate Cancer Patients: Expanding tumor NGS opportunities to a broader patient population.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 193-193 ◽  
Author(s):  
Alexandra Sokolova ◽  
Heather H. Cheng ◽  
Bradley J Hintze ◽  
Michael J. Kelley ◽  
Neil L Spector ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Rural Areas ◽  
Advanced Prostate Cancer ◽  
Sequence Data ◽  
Clinical Care ◽  
Precision Oncology ◽  
Veterans Health ◽  
Health Administration ◽  
Prostate Tumors ◽  
Primary Tumors

193 Background: Progress in understanding molecular changes in advanced prostate cancer has led to promising precision oncology opportunities; to date, most have been concentrated at tertiary research centers and urban centers and unequally available to patients. The VHA is the largest integrated healthcare system in the U.S. and provides medical care to >6 million veterans (~40% living in rural areas). The VHA has implemented a system-wide National Precision Oncology Program (NPOP) to offer tumor NGS testing to veterans with cancer. Methods: VHA patients with advanced stage cancers were offered targeted NGS gene panels (Personalis ACE Extended Cancer Panel; PGDx CancerSELECT/PlasmaSELECT) as part of clinical care. Annotated sequence data is collected by NPOP. We report preliminary findings of the participating veterans with prostate cancer. Results: 372 veterans from 81 sites underwent NGS sequencing of their prostate tumors (n=311) or cfDNA (n=61). Tumors from 165 (44%) were found to have mutations (allelic ratio ≥5%) in 47 genes. Of 372, 62 harbored mutations in TP53 (17%), 9 in NOTCH1 (2%), 16 in PTEN (4%), 16 in AR (4%), 13 in ATM (4%), 11 in BRCA2 (3%), 2 in MSH2 (0.5%), 1 in NBN (0.3%), and 1 in PALB2 (0.3%). 7 men (1.8%) had adequate tumor, but no identifiable somatic mutations. NPOP findings were compared to the existing databases SU2C/PCF (of metastatic biopsies in metastatic castration resistant disease) and TCGA (of primary tumors in localized disease), see table. Findings will be updated at presentation. Conclusions: The VA NPOP has been successfully implemented, and prostate tumors from veterans were found to carry potentially actionable mutations, including BRCA2 and ATM, for which there are precision treatment trials. The program will be expanded and will facilitate more diverse and equitable distribution of access to precision oncology diagnostics and therapeutic opportunities, in alignment with the Cancer Moonshot Initiative. (e.g. VA-ABCD clinicaltrials.gov; NCT02985021). [Table: see text]

Contrasting genomic profiles in post-systemic treatment metastatic sites (MET), pretreatment primary tumors (PT), and liquid biopsies (LB) of clinically advanced prostate cancer (PC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5534-5534
Author(s):  
Andrea Necchi ◽  
Petros Grivas ◽  
Gennady Bratslavsky ◽  
Oleg Shapiro ◽  
Joseph M Jacob ◽  
...  
Keyword(s):  
Systemic Treatment ◽  
Post Treatment ◽  
High Status ◽  
Selection Methods ◽  
Liquid Biopsies ◽  
Primary Tumors ◽  
Comprehensive Genomic Profiling ◽  
Potential Impact ◽  
Metastatic Sites ◽  
Systemic Therapies

5534 Background: Comprehensive genomic profiling (CGP) was done on pre-systemic treatment (pre) PT, post-treatment (post) MET sites and LB in PC to uncover differences in genomic alterations (GA) and potential impact on therapy selection. Methods: 1,294 PC tissues and 782 LB underwent hybrid-capture based CGP. PT biopsies and resections were compared with post-treatment MET biopsies from bone (BO), liver (LIV), lung (LU), brain (BN), lymph node (LN) and soft tissue (ST) sites and LB. TMB was determined on up to 1.1 Mbp of sequenced DNA for tumor samples. Tumor cell PD-L1 IHC was measured (Dako 22C3). Results: Differences in alteration frequencies between PT, MET and LB for selected genes are shown in the Table. TMPRSS2:ERG fusion frequencies were similar between PT and MET (35% vs 33%) but varied between MET sites (27% in BO and ST to 40% in LN). GA in AR were lowest in pre PT (2%) and highest in MET (24% in LU to 50% in LIV). BN had the highest GA/tumor (8) and the most PTEN GA. BRCA2 GA frequency varied from 0% in BN to 15% in LI. Potential predictors of IO response included CDK12 GA (16% in LU) and MSI high status (29% in BN). High PD-L1 expression was found in only two cases (LN) and low PD-L1 expression was relatively uncommon. ERBB2 amplifications were increased in MET compared with PT. RB1 GA were increased in LIV cases. LB GA had a similar increase in AR and TP53 GA to MET and appeared to be a blend of MET site biopsies across alteration frequencies. Conclusions: CGP of PT, MET and LB in PC demonstrates differences most likely associated with exposure to systemic therapies. Differences identified in the MET GA landscape suggest that liquid biopsies may capture a broader range of therapeutic opportunities for PC patients. [Table: see text]

Next-generation sequencing (NGS) of tissue and cell free DNA (cfDNA) to identify somatic and germline alterations in advanced prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5010-5010 ◽  
Author(s):  
Michael L. Cheng ◽  
Wassim Abida ◽  
Dana E. Rathkopf ◽  
Maria E. Arcila ◽  
David Barron ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Tumor Tissue ◽  
Bone Biopsy ◽  
Primary Tumors ◽  
Damage Response ◽  
Genomic Characterization ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

5010 Background: With the goal of accelerating enrollment onto appropriate clinical trials, we performed prospective genomic characterization of pts with advanced prostate cancer. Given the long natural history and osseous disease predominance, we also analyzed plasma cfDNA to assess the feasibility of identifying targetable alterations in pts for whom adequate tumor tissue was unavailable. Methods: 1038 tumors from 896 pts along with matched normal DNA were analyzed with a capture-based NGS assay (MSK-IMPACT) targeting 341–468 genes. In 5/2015, the protocol was amended to allow pts to opt-in for a formal germline analysis of 76 genes associated with heritable cancer risk. In select pts, plasma cfDNA was collected and analyzed using the same assay. Results: Between 2/2014 and 2/2017, 576 primary tumors and 462 metastases were sequenced. The most notable finding was the high frequency of known or likely pathogenic germline and somatic mutations in genes that regulate DNA damage response (DDR). In the subset with both tumor and germline analysis, 28.84% (169/586) had a DDR mutation identified compared to only 10.65% (33/310) of pts with somatic only analysis. In the subset with tumor and germline analysis, 9.39% (55/586) had somatic only DDR mutations and 16.38% (96/586) had germline only DDR mutations, including 8 pts with two germline mutations. 3.07% (18/586) had co-occurring somatic and germline DDR mutations, with only 0.68% (4/586) involving the same DDR gene (all BRCA2). Prostate cancer had the highest tissue failure rate among the overall MSK-IMPACT solid tumor cohort, and bone biopsy-derived tissue was successfully sequenced in only 42% of pts. Profiling of cfDNA did identify somatic DDR or AR mutations in 12.5% (4/32) of pts without adequate tumor for analysis. Conclusions: This prospective genomic profiling effort identified frequent somatic and germline DDR mutations that may guide PARPi or platinum therapy. Both somatic and germline analyses were required to identify all pts with likely pathogenic DDR alterations. NGS-based cfDNA analysis is feasible in advanced prostate cancer and may identify mutations missed by tumor only sequencing.

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