scholarly journals Circulating Tumor DNA Testing for Homology Recombination Repair Genes in Prostate Cancer: From the Lab to the Clinic

2021 ◽  
Vol 22 (11) ◽  
pp. 5522
Author(s):  
Alessia Cimadamore ◽  
Liang Cheng ◽  
Francesco Massari ◽  
Matteo Santoni ◽  
Laura Pepi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Peripheral Blood ◽  
Tissue Sample ◽  
Treatment Options ◽  
Parp Inhibitors ◽  
Circulating Tumor Dna ◽  
Resistance Mutations ◽  
Recombination Repair ◽  
Repair Genes ◽  
Tumor Dna

Approximately 23% of metastatic castration-resistant prostate cancers (mCRPC) harbor deleterious aberrations in DNA repair genes. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) therapy has shown improvements in overall survival in patients with mCRPC who harbor somatic and/or germline alterations of homology recombination repair (HRR) genes. Peripheral blood samples are typically used for the germline mutation analysis test using the DNA extracted from peripheral blood leucocytes. Somatic alterations can be assessed by extracting DNA from a tumor tissue sample or using circulating tumor DNA (ctDNA) extracted from a plasma sample. Each of these genetic tests has its own benefits and limitations. The main advantages compared to the tissue test are that liquid biopsy is a non-invasive and easily repeatable test with the value of better representing tumor heterogeneity than primary biopsy and of capturing changes and/or resistance mutations in the genetic tumor profile during disease progression. Furthermore, ctDNA can inform about mutation status and guide treatment options in patients with mCRPC. Clinical validation and test implementation into routine clinical practice are currently very limited. In this review, we discuss the state of the art of the ctDNA test in prostate cancer compared to blood and tissue testing. We also illustrate the ctDNA testing workflow, the available techniques for ctDNA extraction, sequencing, and analysis, describing advantages and limits of each techniques.

Abstract 435: Cell-free circulating tumor DNA (ctDNA) detects somatic copy number loss in homologous recombination repair genes

2019 ◽  
Author(s):  
Catalin Barbacioru ◽  
Victoria M. Raymond ◽  
Marcin Sikora ◽  
Elena Helman ◽  
Sante Gnerre ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Copy Number ◽  
Circulating Tumor Dna ◽  
Homologous Recombination Repair ◽  
Copy Number Loss ◽  
Recombination Repair ◽  
Repair Genes ◽  
Tumor Dna

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.

Abstract 435: Cell-free circulating tumor DNA (ctDNA) detects somatic copy number loss in homologous recombination repair genes

2019 ◽  
Author(s):  
Catalin Barbacioru ◽  
Victoria M. Raymond ◽  
Marcin Sikora ◽  
Elena Helman ◽  
Sante Gnerre ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Copy Number ◽  
Circulating Tumor Dna ◽  
Homologous Recombination Repair ◽  
Copy Number Loss ◽  
Recombination Repair ◽  
Repair Genes ◽  
Tumor Dna

scholarly journals Novel therapies are changing treatment paradigms in metastatic prostate cancer

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Eric Powers ◽  
Georgia Sofia Karachaliou ◽  
Chester Kao ◽  
Michael R. Harrison ◽  
Christopher J. Hoimes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Treatment Options ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Damage Repair ◽  
Systemic Treatments ◽  
Terminal Diagnosis ◽  
Specific Membrane ◽  
Repair Genes

Abstract Metastatic castration-resistant prostate cancer (mCRPC) remains a terminal diagnosis with an aggressive disease course despite currently approved therapeutics. The recent successful development of poly ADP-ribose polymerase (PARP) inhibitors for patients with mCRPC and mutations in DNA damage repair genes has added to the treatment armamentarium and improved personalized treatments for prostate cancer. Other promising therapeutic agents currently in clinical development include the radiotherapeutic 177-lutetium-prostate-specific membrane antigen (PSMA)-617 targeting PSMA-expressing prostate cancer and combinations of immunotherapy with currently effective treatment options for prostate cancer. Herein, we have highlighted the progress in systemic treatments for mCRPC and the promising agents currently in ongoing clinical trials.

scholarly journals Clinical Utility of Circulating Tumor DNA in Advanced Rare Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Hitomi Sumiyoshi Okuma ◽  
Kan Yonemori ◽  
Yuki Kojima ◽  
Maki Tanioka ◽  
Kazuki Sudo ◽  
...  
Keyword(s):  
Treatment Options ◽  
Circulating Tumor Dna ◽  
Resistance Mutations ◽  
Plasma Dna ◽  
Invasive Approach ◽  
Therapeutic Implications ◽  
Non Invasive ◽  
Rare Cancers ◽  
Dna Alterations ◽  
Tumor Dna

PurposePatients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach.Patients and MethodsRare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS.ResultsNinety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS.ConclusionPlasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers.Clinical Registration[https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.

scholarly journals Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gillian Vandekerkhove ◽  
Jean-Michel Lavoie ◽  
Matti Annala ◽  
Andrew J. Murtha ◽  
Nora Sundahl ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Treatment Options ◽  
Circulating Tumor Dna ◽  
Molecular Stratification ◽  
Clinical Biomarkers ◽  
Surgery Patient ◽  
Metastatic Urothelial Carcinoma ◽  
Ctdna Analysis ◽  
Clinical Genomic ◽  
Tumor Dna

AbstractMolecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

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.

A graphene oxide coated gold nanostar based sensing platform for ultrasensitive electrochemical detection of circulating tumor DNA

2020 ◽  
Vol 12 (4) ◽  
pp. 440-447 ◽  
Author(s):  
Mahbubur Rahman ◽  
Daxiang Cui ◽  
Shukui Zhou ◽  
Amin Zhang ◽  
Di Chen
Keyword(s):  
Graphene Oxide ◽  
Gastric Carcinoma ◽  
Electrochemical Reduction ◽  
Electrochemical Detection ◽  
Peripheral Blood ◽  
High Performance ◽  
Circulating Tumor Dna ◽  
Electrochemical Sensing ◽  
Sensing Platform ◽  
Tumor Dna

A high-performance electrochemical sensing platform inspired by a functional ‘green’ electrochemical reduction pathway was developed to identify and detect circulating tumor DNA (ctDNA) of gastric carcinoma in peripheral blood.

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