Abstract 2959: Analysis of circulating tumor DNA reveals genomic alterations in metastatic prostate cancer patients treated with abiraterone acetate plus prednisone or enzalutamide

2018 ◽  
Author(s):  
Jelena Belic ◽  
Ricarda Graf ◽  
Thomas Bauernhofer ◽  
Yauheniya Cherkas ◽  
Ulz Peter ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Metastatic Prostate Cancer ◽  
Circulating Tumor Dna ◽  
Abiraterone Acetate ◽  
Genomic Alterations ◽  
Tumor Dna

scholarly journals The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

2018 ◽  
Vol 24 (15) ◽  
pp. 3528-3538 ◽  
Author(s):  
Oliver A. Zill ◽  
Kimberly C. Banks ◽  
Stephen R. Fairclough ◽  
Stefanie A. Mortimer ◽  
James V. Vowles ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Advanced Cancer ◽  
Circulating Tumor Dna ◽  
Advanced Cancer Patients ◽  
Genomic Alterations ◽  
Tumor Dna

scholarly journals Evaluation of Commercial Circulating Tumor DNA Test in Metastatic Prostate Cancer

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Sinja Taavitsainen ◽  
Matti Annala ◽  
Elisa Ledet ◽  
Kevin Beja ◽  
Patrick J. Miller ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Somatic Mutations ◽  
Circulating Tumor Dna ◽  
Research Approach ◽  
Cancer Genes ◽  
Dna Repair Gene ◽  
Clinical Scenarios ◽  
Tumor Dna ◽  
Allele Fraction

PURPOSE Circulating tumor DNA (ctDNA) sequencing provides a minimally invasive method for tumor molecular stratification. Commercial ctDNA sequencing is increasingly used in the clinic, but its accuracy in metastatic prostate cancer is untested. We compared the commercial Guardant360 ctDNA test against an academic sequencing approach for profiling metastatic prostate cancer. PATIENTS AND METHODS Plasma cell-free DNA was collected between September 2016 and April 2018 from 24 patients with clinically progressive metastatic prostate cancer representing a range of clinical scenarios. Each sample was analyzed using Guardant360 and a research panel encompassing 73 prostate cancer genes. Concordance of somatic mutation and copy number calls was evaluated between the two approaches. RESULTS Targeted sequencing independently confirmed 94% of somatic mutations identified by Guardant360 at an allele fraction greater than 1%. AR amplifications and mutations were detected with high concordance in 14 patients, with only three discordant subclonal mutations at an allele fraction lower than 0.5%. Many somatic mutations identified by Guardant360 at an allele fraction lower than 1% seemed to represent subclonal passenger events or non–prostate-derived clones. Most of the non- AR gene amplifications reported by Guardant360 represented single copy gains. The research approach detected several clinically relevant DNA repair gene alterations not reported by Guardant360, including four germline truncating BRCA2/ ATM mutations, two somatic ATM stop gain mutations, one BRCA2 biallelic deletion, 11 BRCA2 stop gain reversal mutations in a patient treated with olaparib, and a hypermutator phenotype in a patient sample with 42 mutations per megabase. CONCLUSION Guardant360 accurately identifies somatic ctDNA mutations in patients with metastatic prostate cancer, but low allele frequency mutations should be interpreted with caution. Test utility in metastatic prostate cancer is currently limited by the lack of reporting on actionable deletions, rearrangements, and germline mutations.

scholarly journals Considerations on the identification and management of metastatic prostate cancer patients with DNA repair gene alterations in the Canadian context

2021 ◽  
Vol 16 (4) ◽  
Author(s):  
Michael P. Kolinsky ◽  
Karen Y. Niederhoffer ◽  
Edmond M. Kwan ◽  
Sebastien J. Hotte ◽  
Zineb Hamilou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
Patient Population ◽  
Metastatic Prostate Cancer ◽  
Parp Inhibitors ◽  
Circulating Tumor Dna ◽  
Brca1 Brca2 ◽  
Tumor Dna ◽  
Germline Testing ◽  
Gene Alterations

Olaparib is the first Health Canada-approved agent in metastatic prostate cancer to use a companion diagnostic to identify alterations in BRCA1, BRCA2, or ATM. As olaparib is introduced, clinicians must learn to access and interpret germline and somatic next-generation sequencing (NGS) results, and how to manage affected patients who appear to have distinct clinical features. The traditional model of referring patients to a hereditary cancer clinic (HCC) for germline testing is likely impractical in this disease, as the metastatic prostate cancer patient population would be overwhelming. Alternate approaches to this are clinician-ordered genetic testing (so-called “mainstreaming”), out-of-pocket payment for third-party private company genetic testing, or germline testing done in conjunction with somatic testing, particularly cell free circulating tumor DNA (ctDNA). Germline testing alone is not sufficient for identifying Olaparib-eligible patients, as less than half of BRCA1, BRCA2, or ATM alterations are germline in origin, but it is critically important to identify family members who are carriers so that risk-reduction measures can be undertaken. Somatic testing is not widely available in Canada, but some patients can access it through research protocols or by paying out-of-pocket. Somatic testing can be performed on archival or fresh solid tissue biopsy samples, or through whole blood samples to access plasma-derived circulating tumor DNA (ctDNA). Both testing approaches have relative advantages and disadvantages, but neither may be informative in all patients and, therefore, ideal somatic NGS pathways should provide options for both tissue and ctDNA testing. We advocate that clinicians begin discussions with their provincial lab formularies, HCC, and molecular pathology labs to highlight the importance of germline and somatic testing in this population and identify pathways for patient access. While olaparib has approval for use in BRCA1, BRCA2, and ATM-altered mCRPC, emerging evidence suggests that PARP inhibitors have variable activity in these three genes, with BRCA2 alterations appearing to be the most responsive. Retrospective and prospective series have reported varying outcomes to standard of care therapies, such as ARATs and taxane-based chemotherapy, in metastatic castration-resistant prostate cancer (mCRPC) patients with DNA damage repair (DDR) gene alterations, such as BRCA2. In the absence of high-level evidence showing a lack of benefit, we believe this patient population should still be considered for these treatments. In addition, platinum-based chemotherapy appears to have activity in DDR gene-altered mCRPC and should be considered another option when access to olaparib is not possible. At present, there is no evidence to support an optimal treatment sequence in this patient population, therefore, physician and patient preferences will need to be taken into consideration when selecting therapies. As olaparib and other PARP inhibitors are tested in different disease states and in combination with other therapies, we will likely see a more refined approach to use of these agents and management of this new biomarker-defined patient population.

scholarly journals Genomic Alterations in Circulating Tumor DNA from Diverse Cancer Patients Identified by Next-Generation Sequencing

2017 ◽  
Vol 77 (19) ◽  
pp. 5419-5427 ◽  
Author(s):  
Maria Schwaederle ◽  
Ranajoy Chattopadhyay ◽  
Shumei Kato ◽  
Paul T. Fanta ◽  
Kimberly C. Banks ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Cancer Patients ◽  
Circulating Tumor Dna ◽  
Next Generation ◽  
Genomic Alterations ◽  
Tumor Dna ◽  
Generation Sequencing

scholarly journals Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

2019 ◽  
Vol 75 (4) ◽  
pp. 667-675 ◽  
Author(s):  
Gillian Vandekerkhove ◽  
Werner J. Struss ◽  
Matti Annala ◽  
Heini M.L. Kallio ◽  
Daniel Khalaf ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
De Novo ◽  
Circulating Tumor Dna ◽  
Potential Utility ◽  
Tumor Dna
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