Genomic immunotherapy (IO) biomarkers detected on comprehensive genomic profiling (CGP) of tissue and circulating tumor DNA (ctDNA).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2541-2541
Author(s):  
Takayuki Yoshino ◽  
Hanna Tukachinsky ◽  
Jessica Kim Lee ◽  
Ethan Sokol ◽  
Dean C. Pavlick ◽  
...  
Keyword(s):  
Limit Of Detection ◽  
Predictive Biomarkers ◽  
Principal Component ◽  
Pathogenic Mutation ◽  
Circulating Tumor Dna ◽  
Driver Mutations ◽  
Cancer Type ◽  
Liquid Biopsies ◽  
Mutational Burden ◽  
Relative Prevalence

2541 Background: The dramatic impact of IO on treatment outcomes has heightened interest in predictive biomarkers, including genomic markers such as tumor mutational burden (TMB) and microsatellite instability (MSI). The recent FDA approval of pembrolizumab for previously treated advanced solid tumors with elevated TMB (≥10 mut/Mb on FoundationOne CDx, F1CDx) now requires a better understanding of the prevalence of this and other IO biomarkers detected on CGP, including differences between TMB detected in tissue and mutational burden detected in blood (bTMB). Methods: Tissue and plasma biopsies were profiled with two CGP panels of 324 genes with 0.8 Mb genome coverage (F1CDx and FoundationOne LiquidCDx). Mutational burden was calculated by counting somatic variants (single nucleotide and indels, including synonymous variants, excluding germline and driver mutations) with variant allele frequency (VAF) ≥5% in tissue (TMB) or ≥0.5% in ctDNA (bTMB). MSI score was assessed using 95 repetitive loci and principal component analysis (tissue) or >1,800 repetitive loci (plasma). ctDNA levels were estimated using composite tumor fraction (cTF), a metric based on aneuploidy and VAF. Results: Pan-cancer, TMB ≥10 was detected in 19% of tissue cases (29,238/156,294) and was common in melanoma (53%), small cell (41%), NSCLC (40%), bladder (39%), and endometrial (24%). bTMB ≥10 was detected in 13% of liquid biopsies (806/6,295); prevalence by cancer type was correlated with prevalence of elevated TMB (r = 0.81). Samples with bTMB ≥10 had an elevated cTF (median 13%, IQR 5 - 31%) as compared to samples with bTMB <10 (median 1.8%, IQR 0.6 - 7%, p < 0.001). Among 353 cases with both tissue and liquid CGP results (median 11 months apart), the relative prevalence of TMB ≥10 (12%) and bTMB ≥10 (13%) were similar, with concordant detection in 303 cases (86%). MSI-high (MSI-H) was seen in 2.2% of tissue CGP (3,461/156,294), most often in endometrial (19%), stomach (6.0%), and colorectal (5.3%) cancers, while MSI-H was detected in 0.68% of ctDNA specimens (43/6,295), which were also those with elevated cTF (median 11%, IQR 7 - 23%). Of 3,504 cases with MSI-H signature on tissue or liquid CGP, 1,619 (46%) had a pathogenic mutation detected in MLH1/MSH2/MSH6/PMS2 (15% predicted germline). CD274 amplification was detected in 1,207 cases (0.77%) of tissue CGP and 11 cases (0.17%) in ctDNA. Conclusions: Elevated bTMB is overall less prevalent than elevated tissue TMB, though these biomarkers are detected in similar cancer types. Detection of bTMB ≥10 and MSI-H in liquid biopsy was associated with elevated ctDNA levels, suggesting a limit of detection, and potentially indicating a more aggressive biology in samples positive for these biomarkers. Further investigation is needed to understand the utility of bTMB for identifying high TMB tumors that may benefit from IO.

scholarly journals Additive effects of variants of unknown significance in replication repair-associated DNA polymerase genes on mutational burden and prognosis across diverse cancers

2021 ◽  
Vol 9 (9) ◽  
pp. e002336
Author(s):  
Jieer Ying ◽  
Lin Yang ◽  
Jiani C Yin ◽  
Guojie Xia ◽  
Minyan Xing ◽  
...  
Keyword(s):  
Hot Spot ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Cancer Type ◽  
Additive Effects ◽  
Variants Of Unknown Significance ◽  
Mutational Burden ◽  
Pathway Gene ◽  
Exonuclease Domain ◽  
Unknown Significance

BackgroundDefects in replication repair-associated DNA polymerases often manifest an ultra-high tumor mutational burden (TMB), which is associated with higher probabilities of response to immunotherapies. The functional and clinical implications of different polymerase variants remain unclear.MethodsTargeted next-generation sequencing using a 425-cancer gene panel, which covers all exonic regions of three polymerase genes (POLE, POLD1, and POLH), was conducted in a cohort of 12,266 patients across 16 different tumor types from January 2017 to January 2019. Prognostication of POL variant-positive patients was performed using a cohort of 4679 patients from the The Cancer Genome Atlas (TCGA) datasets.ResultsThe overall prevalence of somatic and germline polymerase variants was 4.2% (95% CI 3.8% to 4.5%) and 0.7% (95% CI 0.5% to 0.8%), respectively, with highest frequencies in endometrial, urinary, prostate, and colorectal cancers (CRCs). While most germline polymerase variants showed no clear functional consequences, we identified a candidate p.T466A affecting the exonuclease domain of POLE, which might be underlying the early onset in a case with childhood CRC. Low frequencies of known hot-spot somatic mutations in POLE were detected and were associated with younger age, the male sex, and microsatellite stability. In both the panel and TCGA cohorts, POLE drivers exhibited high frequencies of alterations in genes in the DNA damage and repair (DDR) pathways, including BRCA2, ATM, MSH6, and ATR. Variants of unknown significance (VUS) of different polymerase domains showed variable penetrance with those in the exonuclease domain of POLE and POLD1 displaying high TMB. VUS in POL genes exhibited an additive effect as carriers of multiple VUS had exponentially increased TMB and prolonged overall survival. Similar to cases with driver mutations, the TMB-high POL VUS samples showed DDR pathway involvement and polymerase hypermutation signatures. Combinatorial analysis of POL and DDR pathway status further supported the potential additive effects of POL VUS and DDR pathway genes and revealed distinct prognostic subclasses that were independent of cancer type and TMB.ConclusionsOur results demonstrate the pathogenicity and additive prognostic value of POL VUS and DDR pathway gene alterations and suggest that genetic testing may be warranted in patients with diverse solid tumors.

scholarly journals Rapid identification of genomic structural variations with nanopore sequencing enables blood-based cancer monitoring

2019 ◽  
Author(s):  
Jose Espejo Valle-Inclan ◽  
Christina Stangl ◽  
Anouk C. de Jong ◽  
Lisanne F. van Dessel ◽  
Markus J. van Roosmalen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Rapid Development ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Rapid Identification ◽  
Cancer Type ◽  
Nanopore Sequencing ◽  
Structural Variations ◽  
Liquid Biopsies ◽  
Random Forest Classification

AbstractSomatic genomic structural variations (SVs) are promising personalized biomarkers for sensitive and specific detection of circulating tumor DNA (ctDNA) in liquid biopsies. However, affordable and fast identification of such SV biomarkers is challenging, which hinders routine use in the clinic. Here, we developed a novel approach - termed SHARC - for rapid discovery of somatic SVs as personalized tumor biomarkers. SHARC combines low coverage cancer genome sketching by using Oxford Nanopore sequencing with random forest classification and a dedicated filtering pipeline to enrich for somatic SVs. Our method leverages the real-time and long-read capabilities of nanopore sequencing to identify somatic SV breakpoints at nucleotide resolution from a tumor tissue biopsy within three days. We applied SHARC to tumor samples of high-grade ovarian and prostate cancer and validated on average ten somatic SVs per sample with PCR mini-amplicons. An accompanying method for SV breakpoint detection from liquid biopsies was devised based on digital PCR, enabling detection of cancer in a quantitative manner. Using this method, we retrospectively monitored treatment response in patients with metastatic prostate cancer. Our work demonstrates that SHARC forms a universal framework for rapid development of personalized biomarker assays for blood-based monitoring of any cancer type.

scholarly journals Circulating Cell-Free DNA in Liquid Biopsies as Potential Biomarker for Bladder Cancer: A Review

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1448
Author(s):  
Raquel Herranz ◽  
Julia Oto ◽  
Emma Plana ◽  
Álvaro Fernández-Pardo ◽  
Fernando Cana ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Specific Treatment ◽  
Predictive Biomarkers ◽  
Liquid Biopsies ◽  
Cell Free Dna ◽  
Specific Patient ◽  
Free Dna ◽  
Potential Biomarker ◽  
Cancer Types

Bladder cancer (BC) is among the most frequent cancer types in the world and is the most lethal urological malignancy. Presently, diagnostic and follow-up methods for BC are expensive and invasive. Thus, the identification of novel predictive biomarkers for diagnosis, progression, and prognosis of BC is of paramount importance. To date, several studies have evidenced that cell-free DNA (cfDNA) found in liquid biopsies such as blood and urine may play a role in the particular scenario of urologic tumors, and its analysis may improve BC diagnosis report about cancer progression or even evaluate the effectiveness of a specific treatment or anticipate whether a treatment would be useful for a specific patient depending on the tumor characteristics. In the present review, we have summarized the up-to-date studies evaluating the value of cfDNA as potential diagnostic, prognostic, or monitoring biomarker for BC in several biofluids.

scholarly journals Detection of Prostate Cancer via IR Spectroscopic Analysis of Urinary Extracellular Vesicles: A Pilot Study

Membranes ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 591
Author(s):  
Xin-Le Yap ◽  
Bayden Wood ◽  
Teng-Aik Ong ◽  
Jasmine Lim ◽  
Bey-Hing Goh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Prostate Cancer Screening ◽  
Principal Component ◽  
Urine Samples ◽  
Cancer Type ◽  
Marker Proteins ◽  
Novel Strategy ◽  
Ir Spectroscopic

Extracellular vesicles (EVs) are membranous nanoparticles naturally released from living cells which can be found in all types of body fluids. Recent studies found that cancer cells secreted EVs containing the unique set of biomolecules, which give rise to a distinctive absorbance spectrum representing its cancer type. In this study, we aimed to detect the medium EVs (200–300 nm) from the urine of prostate cancer patients using Fourier transform infrared (FTIR) spectroscopy and determine their association with cancer progression. EVs extracted from 53 urine samples from patients suspected of prostate cancer were analyzed and their FTIR spectra were preprocessed for analysis. Characterization of morphology, particle size and marker proteins confirmed that EVs were successfully isolated from urine samples. Principal component analysis (PCA) of the EV’s spectra showed the model could discriminate prostate cancer with a sensitivity of 59% and a specificity of 81%. The area under curve (AUC) of FTIR PCA model for prostate cancer detection in the cases with 4–20 ng/mL PSA was 0.7, while the AUC for PSA alone was 0.437, suggesting the analysis of urinary EVs described in this study may offer a novel strategy for the development of a noninvasive additional test for prostate cancer screening.

scholarly journals Systematic Review of Recurrent Osteosarcoma Systemic Therapy

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1757
Author(s):  
Ioanna Gazouli ◽  
Anastasios Kyriazoglou ◽  
Ioannis Kotsantis ◽  
Maria Anastasiou ◽  
Anastasios Pantazopoulos ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
Treatment Effectiveness ◽  
Treatment Strategies ◽  
Bone Cancer ◽  
Predictive Biomarkers ◽  
Mtor Inhibitors ◽  
Cytotoxic Chemotherapy ◽  
Driver Mutations ◽  
Preclinical Research ◽  
Primary Bone

Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review of the available clinical evidence, regarding treatment of recurrent and/or refractory osteosarcoma over the last two decades. Among the 72 eligible studies, there were 56 prospective clinical trials, primarily multicentric, single arm, phase I or II and non-randomized. Evaluated treatment strategies included cytotoxic chemotherapy, tyrosine kinase and mTOR inhibitors and other targeted agents, as well as immunotherapy and combinatorial approaches. Unfortunately, most treatments have failed to induce objective responses, albeit some of them may sustain disease control. No driver mutations have been recognized, to serve as effective treatment targets, and predictive biomarkers of potential treatment effectiveness are lacking. Hopefully, ongoing and future clinical and preclinical research will unlock the underlying biologic mechanisms of recurrent and refractory osteosarcoma, expanding the therapeutic choices available to pre-treated osteosarcoma patients.

scholarly journals Emerging Lab-on-a-Chip Approaches for Liquid Biopsy in Lung Cancer: Status in CTCs and ctDNA Research and Clinical Validation

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2101
Author(s):  
Ângela Carvalho ◽  
Gabriela Ferreira ◽  
Duarte Seixas ◽  
Catarina Guimarães-Teixeira ◽  
Rui Henrique ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Liquid Biopsy ◽  
Residual Disease ◽  
Lab On A Chip ◽  
Microfluidic Devices ◽  
Early Recurrence ◽  
Circulating Tumor Dna ◽  
Clinical Validation ◽  
Liquid Biopsies ◽  
Lung Cancer Patients

Despite the intensive efforts dedicated to cancer diagnosis and treatment, lung cancer (LCa) remains the leading cause of cancer-related mortality, worldwide. The poor survival rate among lung cancer patients commonly results from diagnosis at late-stage, limitations in characterizing tumor heterogeneity and the lack of non-invasive tools for detection of residual disease and early recurrence. Henceforth, research on liquid biopsies has been increasingly devoted to overcoming these major limitations and improving management of LCa patients. Liquid biopsy is an emerging field that has evolved significantly in recent years due its minimally invasive nature and potential to assess various disease biomarkers. Several strategies for characterization of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been developed. With the aim of standardizing diagnostic and follow-up practices, microfluidic devices have been introduced to improve biomarkers isolation efficiency and specificity. Nonetheless, implementation of lab-on-a-chip platforms in clinical practice may face some challenges, considering its recent application to liquid biopsies. In this review, recent advances and strategies for the use of liquid biopsies in LCa management are discussed, focusing on high-throughput microfluidic devices applied for CTCs and ctDNA isolation and detection, current clinical validation studies and potential clinical utility.

scholarly journals RNA-Based Assay for Next-Generation Sequencing of Clinically Relevant Gene Fusions in Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 139
Author(s):  
Caterina De Luca ◽  
Francesco Pepe ◽  
Antonino Iaccarino ◽  
Pasquale Pisapia ◽  
Luisella Righi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Limit Of Detection ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Clinical Samples ◽  
Gene Fusions ◽  
Small Cell Lung ◽  
Relevant Gene

Gene fusions represent novel predictive biomarkers for advanced non-small cell lung cancer (NSCLC). In this study, we validated a narrow NGS gene panel able to cover therapeutically-relevant gene fusions and splicing events in advanced-stage NSCLC patients. To this aim, we first assessed minimal complementary DNA (cDNA) input and the limit of detection (LoD) in different cell lines. Then, to evaluate the feasibility of applying our panel to routine clinical samples, we retrospectively selected archived lung adenocarcinoma histological and cytological (cell blocks) samples. Overall, our SiRe RNA fusion panel was able to detect all fusions and a splicing event harbored in a RNA pool diluted up to 2 ng/µL. It also successfully analyzed 46 (95.8%) out of 48 samples. Among these, 43 (93.5%) out of 46 samples reproduced the same results as those obtained with conventional techniques. Intriguingly, the three discordant results were confirmed by a CE-IVD automated real-time polymerase chain reaction (RT-PCR) analysis (Easy PGX platform, Diatech Pharmacogenetics, Jesi, Italy). Based on these findings, we conclude that our new SiRe RNA fusion panel is a valid and robust tool for the detection of clinically relevant gene fusions and splicing events in advanced NSCLC.

scholarly journals Diving into the Pleural Fluid: Liquid Biopsy for Metastatic Malignant Pleural Effusions

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2798
Author(s):  
Maria Alba Sorolla ◽  
Anabel Sorolla ◽  
Eva Parisi ◽  
Antonieta Salud ◽  
José M. Porcel
Keyword(s):  
Pleural Fluid ◽  
Liquid Biopsy ◽  
Cell Types ◽  
Circulating Tumor Dna ◽  
Therapeutic Interventions ◽  
Driver Mutations ◽  
Pleural Effusions ◽  
Malignant Pleural Effusions ◽  
Micro Rnas ◽  
Low Sensitivity

Liquid biopsy is emerging as a promising non-invasive diagnostic tool for malignant pleural effusions (MPE) due to the low sensitivity of conventional pleural fluid (PF) cytological examination and the difficulty to obtain tissue biopsies, which are invasive and require procedural skills. Currently, liquid biopsy is increasingly being used for the detection of driver mutations in circulating tumor DNA (ctDNA) from plasma specimens to guide therapeutic interventions. Notably, malignant PF are richer than plasma in tumor-derived products with potential clinical usefulness, such as ctDNA, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), and circulating tumor cells (CTC). Tumor-educated cell types, such as platelets and macrophages, have also been added to this diagnostic armamentarium. Herein, we will present an overview of the role of the preceding biomarkers, collectively known as liquid biopsy, in PF samples, as well as the main technical approaches used for their detection and quantitation, including a proper sample processing. Technical limitations of current platforms and future perspectives in the field will also be addressed. Using PF as liquid biopsy shows promise for use in current practice to facilitate the diagnosis and management of metastatic MPE.

scholarly journals Molecular disease monitoring using circulating tumor DNA in myelodysplastic syndromes

Blood ◽  
2017 ◽  
Vol 129 (12) ◽  
pp. 1685-1690 ◽  
Author(s):  
Paul Yeh ◽  
Michael Dickinson ◽  
Sarah Ftouni ◽  
Tane Hunter ◽  
Devbarna Sinha ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Myelodysplastic Syndromes ◽  
Circulating Tumor Dna ◽  
Driver Mutations ◽  
Disease Monitoring ◽  
Key Points ◽  
Tumor Dna ◽  
Predict Treatment Failure

Key PointsCirculating tumor DNA can monitor disease and predict treatment failure by tracking driver mutations and karyotypic abnormalities in MDS.

scholarly journals Circulating Tumor DNA Reflects Uveal Melanoma Responses to Protein Kinase C Inhibition

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1740
Author(s):  
John J. Park ◽  
Russell J. Diefenbach ◽  
Natalie Byrne ◽  
Georgina V. Long ◽  
Richard A. Scolyer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Benefit ◽  
Trial Design ◽  
Phase 1 ◽  
Clinical Trial Design ◽  
Roc Curves ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Driver Mutations ◽  
Targeted Next Generation Sequencing

The prognosis for patients with UM is poor, and recent clinical trials have failed to prolong overall survival (OS) of these patients. Over 95% of UM harbor activating driver mutations, and this allows for the investigation of ctDNA. In this study, we investigated the value of ctDNA for adaptive clinical trial design in metastatic UM. Longitudinal plasma samples were analyzed for ctDNA in 17 metastatic UM patients treated with PKCi-based therapy in a phase 1 clinical trial setting. Plasma ctDNA was assessed using digital droplet PCR (ddPCR) and a custom melanoma gene panel for targeted next generation sequencing (NGS). Baseline ctDNA strongly correlated with baseline lactate dehydrogenase (LDH) (p < 0.001) and baseline disease burden (p = 0.002). Early during treatment (EDT) ctDNA accurately predicted patients with clinical benefit to PKCi using receiver operator characteristic (ROC) curves (AUC 0.84, [95% confidence interval 0.65–1.0, p = 0.026]). Longitudinal ctDNA assessment was informative for establishing clinical benefit and detecting disease progression with 7/8 (88%) of patients showing a rise in ctDNA and targeted NGS of ctDNA revealed putative resistance mechanisms prior to radiological progression. The inclusion of longitudinal ctDNA monitoring in metastatic UM can advance adaptive clinical trial design.

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