scholarly journals Detection of Microsatellite Instability via Circulating Tumor DNA and Response to Immunotherapy in Metastatic Castration-Resistant Prostate Cancer: A Case Series

2021 ◽  
pp. 190-196
Author(s):  
Deepak Ravindranathan ◽  
Greta Anne Russler ◽  
Lauren Yantorni ◽  
Leylah M. Drusbosky ◽  
Mehmet Asim Bilen
Keyword(s):  
Prostate Cancer ◽  
Microsatellite Instability ◽  
Case Series ◽  
Circulating Tumor Dna ◽  
Castration Resistant Prostate Cancer ◽  
Liquid Biopsies ◽  
Castration Resistant ◽  
Before And After ◽  
Initiation Of Therapy ◽  
Tumor Dna

Pembrolizumab has been approved by the US Food and Drug Administration for the treatment of metastatic or unresectable solid tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient. Blood-based circulating tumor DNA (ctDNA) assays have been validated to identify tumors with MSI-H status without the need for tissue biopsy. We report 2 patients with metastatic castration-resistant prostate cancer (mCRPC) who had prior treatment with multiple lines of therapy and underwent ctDNA testing, which detected MSI-H status. Both patients were treated with pembrolizumab, resulting in an excellent clinical response measured with liquid biopsies before and after initiation of therapy, which demonstrated a significant reduction in somatic-variant allele frequency in addition to a decrease in prostate serum antigen levels.

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

AR gene rearrangement analysis in liquid biopsies reveals heterogeneity in lethal prostate cancer

2021 ◽  
Author(s):  
Mark Daniel ◽  
Todd P. Knutson ◽  
Jamie M. Sperger ◽  
Yingming Li ◽  
Anupama Singh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Analysis ◽  
Copy Number Variants ◽  
Case Series ◽  
Genetic Alterations ◽  
Gene Rearrangements ◽  
Castration Resistant Prostate Cancer ◽  
Liquid Biopsies ◽  
Castration Resistant ◽  
Different Sources

Castration-resistant prostate cancer (CRPC) is driven by AR gene aberrations that arise during androgen receptor (AR)-targeted therapy. AR amplification and mutations have been profiled in circulating tumor cells (CTCs), but whether AR gene rearrangements can be assessed in CTCs is unknown. In this study, we leveraged CRPC cell lines with defined AR gene rearrangements to develop and validate a CTC DNA analysis approach that utilized whole genome amplification and targeted DNA-sequencing of AR and other genes important in CRPC. We tested the utility of this approach by analyzing matched CTC DNA and plasma cell-free DNA (cfDNA) from a case series of ten CRPC patients. One of ten CTC samples and two of ten cfDNA samples were positive for AR gene rearrangements. All AR gene rearrangements were discordant between matched liquid biopsy samples. One patient harbored separate AR gene rearrangements in CTC DNA and cfDNA, but concordant AR amplification and AR T878A mutation. This patient also displayed concordant loss of TP53 and PTEN, but loss of RB1 in cfDNA only. The overall frequency of discordant alterations in these genes between matched CTC DNA and cfDNA was high. This study establishes the technical feasibility of analyzing structural rearrangements, mutations, and copy number variants in AR and other CRPC genes using two different sources of DNA from a single blood sample. Paired CTC DNA and cfDNA analysis may have utility for capturing the heterogeneity of genetic alterations in CRPC patients.

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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