Genomic analysis of circulating tumor DNA (ctDNA) in plasma of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with abiraterone acetate (abi) and enzalutamide (enza).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 5021-5021 ◽  
Author(s):  
Arun Azad ◽  
Stanislav Volik ◽  
Alexander Wyatt ◽  
Anne Haegert ◽  
Colin Collins ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genomic Analysis ◽  
Circulating Tumor Dna ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Tumor Dna

Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer to identify targetable BRCA alterations and AR resistance mechanisms.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 25-25
Author(s):  
Hanna Tukachinsky ◽  
Russell Madison ◽  
Jon Chung ◽  
Lucas Dennis ◽  
Bernard Fendler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Acquired Resistance ◽  
Genomic Analysis ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Cancer Tissue ◽  
Castration Resistant Prostate Cancer ◽  
High Level ◽  
Tumor Dna

25 Background: Comprehensive genomic profiling (CGP) by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from plasma provides a minimally invasive method to identify targetable genomic alterations (GAs) and resistance mechanisms in patients with metastatic castration-resistant prostate cancer (mCRPC). The circulating tumor fraction in patients with mCRPC and the clinical validity of GAs detected in plasma remain unknown. We evaluated the landscape of GAs using ctDNA-based CGP and assessed concordance with tissue-based CGP. Methods: Plasma from 3,334 patients with advanced prostate cancer (including 1,674 mCRPC screening samples from the TRITON2/3 trials and 1,660 samples from routine clinical CGP) was analyzed using hybrid-capture-based gene panel NGS assays. Results were compared with CGP of 2,006 metastatic prostate cancer tissue biopsies. Concordance was evaluated in 837 patients with both tissue (archival or contemporaneous) and plasma NGS results. Results: 3,127 patients [94%] had detectable ctDNA. BRCA1/2 were mutated in 295 patients [8.8%]. In concordance analysis, 72/837 [8.6%] patients had BRCA1/2 mutations detected in tissue, 67 [93%] of whom were also identified by ctDNA, and 20 patients were identified using ctDNA but not tissue [23% of all patients identified using ctDNA]. ctDNA detected subclonal BRCA1/2 reversions in 10 of 1,660 [0.6%] routine clinical CGP samples. AR alterations, including amplifications and hotspot mutations, which were detected in 940/2,213 patients [42%]. Rare AR compound mutations, rearrangements, and novel in-frame deletions were identified. Altered pathways included PI3K/AKT/mTOR [14%], WNT/β-catenin [17%], and RAS/RAF/MEK [5%]. Microsatellite instability was detected in 31/2,213 patients [1.4%]. Conclusions: In the largest study of mCRPC plasma samples conducted to date, CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 alterations. It also identified patients who may have gained somatic BRCA1/2 alterations since archival tissue was collected. ctDNA detected more acquired resistance GAs than tissue, including novel AR-activating variants. The large percentage of patients with rich genomic signal from ctDNA, and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.

Circulating tumor DNA-targeted sequencing to reveal germline and somatic alterations that can guide decision-making in metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17556-e17556
Author(s):  
Baijun Dong ◽  
Liancheng Fan ◽  
Bin Yang ◽  
Wei Chen ◽  
Yonghong Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Circulating Tumor Dna ◽  
Targeted Sequencing ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Genomic Landscape ◽  
Platinum Based Chemotherapy ◽  
Somatic Alterations ◽  
Multiple Treatments ◽  
Tumor Dna

e17556 Background: The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) is dynamic with the application of multiple treatments. The circulating tumor DNA (ctDNA), which reveals germline and somatic alterations, provides a mini-invasive tool for monitoring tumor evolution. Methods: We performed an exploratory analysis of 299 ctDNA samples from 8 centers through application of multiple-gene deep targeted sequencing. Results: The most common recurrent genomic alterations were in AR(34.7%), TP53(18.9%), CDK12(15.4%), BRCA2(13.3%), and the majority of these clinically actionable gene alterations were identified in somatic level (CDK12 100% in somatic). The results showed the frequency of AR amplification and TP53 defect significantly increased in post-second and later line treatment group compared with treatment-naive group. AR amplification and TP53 or RB1 defect were associated with resistance to abiraterone or docetaxel. CDK12 was more frequently altered in our cohort than those in previous reports which mainly focused on Caucasian population. The patients with CDK12 defect showed rapid resistance to abiraterone and limited efficacy of Poly (ADP-ribose) polymerase inhibitors (PARPi). However, these patients seemed to benefit from chemotherapy, especially platinum-based chemotherapy. Conclusions: This multi-institutional real-world study explored the genomic landscape and captured the significant diversity of mCRPC at different treatment stages by liquid biopsy. These findings established genomic drivers associated with resistance to multiple treatments (including PARPi and platinum-based chemotherapy) in mCRPC. Hence, ctDNA targeted sequencing can help guide clinical decision making in mCRPC throughout the whole treatment process. CDK12 might be able to be a novel predictive biomarker to guide treatment selection in mCRPC.

scholarly journals Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer

Cancer ◽  
2019 ◽  
Vol 125 (9) ◽  
pp. 1459-1469 ◽  
Author(s):  
Guru Sonpavde ◽  
Neeraj Agarwal ◽  
Gregory Russell Pond ◽  
Rebecca J. Nagy ◽  
Roberto H. Nussenzveig ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Circulating Tumor Dna ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Dna Alterations ◽  
Tumor Dna

Circulating tumor DNA-targeted sequencing to reveal germline and somatic alterations that can guide decision-making in metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 173-173
Author(s):  
Baijun Dong ◽  
Liancheng Fan ◽  
Bin Yang ◽  
Wei Chen ◽  
Yonghong Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Decision Making ◽  
Circulating Tumor Dna ◽  
Targeted Sequencing ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Genomic Landscape ◽  
Somatic Alterations ◽  
Multiple Treatments ◽  
Tumor Dna

173 Background: The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) is dynamic with the application of multiple treatments. The circulating tumor DNA(ctDNA), which reveals germline and somatic alterations, provides a mini-invasive tool for monitoring tumor evolution. Methods: We performed an exploratory analysis of 299 ctDNA samples from 8 centers through application of multiple-gene deep targeted sequencing. Results: The most common recurrent genomic alterations were in AR(34.7%), TP53(18.9%), CDK12(15.4%), BRCA2(13.3%), and the majority of these clinically actionable gene alterations were identified in somatic level(CDK12 100% in somatic). The results showed the frequency of AR amplification and TP53 defect significantly increased in post-second and later line treatment group compared with treatment-naive group. AR amplification and TP53 or RB1 defect were associated with resistance to abiraterone or docetaxel. CDK12 was more frequently altered in our cohort than those in previous reports which mainly focused on Caucasian population. The patients with CDK12 defect showed rapid resistance to abiraterone and limited efficacy of PARPi. However, these patients seemed to benefit from chemotherapy, espeacially platnium-based chemotherapy. Conclusions: This multi-institutional real-world study explored the genomic landscape and captured the significant diversity of mCRPC at different treatment stages by liquid biopsy. These findings established genomic drivers associated with resistance to multiple treatments (including PARPi and platinum-based chemotherapy) in mCRPC. Hence, ctDNA targeted sequencing can help guide clinical decision making in mCRPC throughout the whole treatment process. CDK12 might be able to be a novel predictive biomarker to guide treatment selection in mCRPC.

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