scholarly journals Circulating tumour DNA as a cancer biomarker

2018 ◽  
Vol 56 (1) ◽  
pp. 42-48 ◽  
Author(s):  
Michael J Duffy
Keyword(s):  
Kinase Inhibitors ◽  
Cancer Biomarkers ◽  
Therapy Resistance ◽  
Genetic Alterations ◽  
Clinical Use ◽  
Dna Assays ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Polymerase Chain ◽  
New Generation ◽  
Circulating Tumour Dna

Measurement of genetically altered DNA shed from tumours into the circulation can potentially provide a new generation of blood-based cancer biomarkers. Compared with tissue DNA biomarkers which require surgery or biopsy, samples for circulating tumour DNA assays can be obtained with minimal inconvenience and at lower cost. Furthermore, in contrast to tissue, the use of circulating tumour DNA allows serial monitoring, faster delivery of results and potentially provides an integrative representation of genetic alterations across all tumour sites within a patient. In contrast to existing protein-based cancer biomarkers, all of which can be produced by benign disease, circulating tumour DNA biomarkers would be expected to be more specific for malignancy. Furthermore, unlike the available blood cancer biomarkers, circulating tumour DNA can be used to predict response to specific therapies, identify mechanisms of therapy resistance and detect potentially actionable mutations. One of the first circulating tumour DNA assays recommended for clinical use involves EGFR mutation testing for predicting response to EGFR tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer, especially when tumour tissue is unavailable. In order to accelerate the introduction of circulating tumour DNA assays into routine clinical use, laboratory medicine staff will have to undergo training in the use of polymerase chain reaction and DNA sequencing. Furthermore, existing circulating tumour DNA assays will need to be simplified, standardized, shown to have clinical utility, be made available at reasonable costs and be reimbursable.

scholarly journals Use of Circulating Tumour DNA (ctDNA) for Measurement of Therapy Predictive Biomarkers in Patients with Cancer

2022 ◽  
Vol 12 (1) ◽  
pp. 99
Author(s):  
Michael J. Duffy ◽  
John Crown
Keyword(s):  
Gold Standard ◽  
Kinase Inhibitors ◽  
Predictive Biomarkers ◽  
Lower Sensitivity ◽  
Cancer Therapies ◽  
Gold Standard Method ◽  
Biomarker Analysis ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Biomarker Testing ◽  
Circulating Tumour Dna

Biomarkers that predict likely response or resistance to specific therapies are critical in personalising treatment for cancer patients. Such biomarkers are now available for an increasing number of anti-cancer therapies, especially targeted therapy and immunotherapy. The gold-standard method for determining predictive biomarkers requires tumour tissue. Obtaining tissue, however, is not always possible and even if possible, the amount or quality of tissue obtained may be inadequate for biomarker analysis. Tumour DNA, however, can be released into the bloodstream, giving rise to what is referred to as circulating tumour DNA (ctDNA). In contrast to tissue, blood can be obtained from effectively all patients in a minimally invasive and safe manner. Other advantages of blood over tissue for biomarker testing include a shorter turn-around time and an ability to perform serial measurements. Furthermore, blood should provide a more complete profile of mutations present in heterogeneous tumours than a single-needle tissue biopsy. A limitation of blood vis-à-vis tissue, however, is lower sensitivity and, thus, the possibility of missing an actionable mutation. Despite this limitation, blood-based predictive biomarkers, such as mutant EGFR for predicting response to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer and mutant PIK3CA for predicting response to alpelisib in combination with fulvestrant in advanced breast cancer, may be used when tissue is unavailable. Although tissue remains the gold standard for detecting predictive biomarkers, it is likely that several further blood-based assays will soon be validated and used when tissue is unavailable or unsuitable for analysis.

scholarly journals Targeting Oncogenic BRAF: Past, Present, and Future

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1197 ◽  
Author(s):  
Zaman ◽  
Wu ◽  
Bivona
Keyword(s):  
Kinase Inhibitors ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Wild Type ◽  
Braf Mutations ◽  
Molecular Alterations ◽  
Mutant Braf

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.

scholarly journals Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia with kinase fusions in Taiwan

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yin-Chen Hsu ◽  
Chih-Hsiang Yu ◽  
Yan-Ming Chen ◽  
Kathryn G. Roberts ◽  
Yu-Ling Ni ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Lymphoblastic Leukaemia ◽  
B Cell ◽  
Lymphoblastic Leukaemia ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Genetic Alterations ◽  
Childhood All ◽  
Free Survival ◽  
Polymerase Chain

AbstractPhiladelphia chromosome-like (Ph-like) acute lymphoblastic leukaemia (ALL), a high-risk subtype characterised by genomic alterations that activate cytokine receptor and kinase signalling, is associated with inferior outcomes in most childhood ALL clinical trials. Half of the patients with Ph-like ALL have kinase rearrangements or fusions. We examined the frequency and spectrum of these fusions using a retrospective cohort of 212 newly diagnosed patients with childhood B-cell ALL. Samples without known chromosomal alterations were subject to multiplex reverse transcription polymerase chain reaction to identify known Ph-like kinase fusions. Immunoglobulin heavy chain locus (IGH) capture and kinase capture were applied to samples without known kinase fusions. We detected known kinase fusions in five of 212 patients, comprising EBF1-PDGFRB, ETV6-ABL1, ZC3HAV1-ABL2, EPOR-IGH, and CNTRL-ABL1. Two patients with P2RY8-CRLF2 were identified. Patients with non-Ph kinase fusions had inferior 5-year event-free survival and overall survival compared with patients with other common genetic alterations. The prevalence of non-Ph kinase fusions in our Taiwanese cohort was lower than that reported in Caucasian populations. Future clinical trials with tyrosine kinase inhibitors may be indicated in Taiwan because of the inferior outcomes for B-cell ALL with kinase fusions.

High performance Nanogold™-in situ hybridzation and its use in the detection of hybridized and PCR-amplified microscopical preparations

1996 ◽  
Vol 54 ◽  
pp. 896-897
Author(s):  
G. W. Hacker ◽  
I. Zehbe ◽  
J. Hainfeld ◽  
A.-H. Graf ◽  
C. Hauser-Kronberger ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Messenger Rna ◽  
High Performance ◽  
Detection System ◽  
Direct Methods ◽  
Genetic Alterations ◽  
Chain Reaction ◽  
Protein Encoding ◽  
Polymerase Chain

In situ hybridization (ISH) with biotin-labeled probes is increasingly used in histology, histopathology and molecular biology, to detect genetic nucleic acid sequences of interest, such as viruses, genetic alterations and peptide-/protein-encoding messenger RNA (mRNA). In situ polymerase chain reaction (PCR) (PCR in situ hybridization = PISH) and the new in situ self-sustained sequence replication-based amplification (3SR) method even allow the detection of single copies of DNA or RNA in cytological and histological material. However, there is a number of considerable problems with the in situ PCR methods available today: False positives due to mis-priming of DNA breakdown products contained in several types of cells causing non-specific incorporation of label in direct methods, and re-diffusion artefacts of amplicons into previously negative cells have been observed. To avoid these problems, super-sensitive ISH procedures can be used, and it is well known that the sensitivity and outcome of these methods partially depend on the detection system used.

scholarly journals Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

2021 ◽  
Vol 22 (6) ◽  
pp. 3117
Author(s):  
Loredana Lorusso ◽  
Virginia Cappagli ◽  
Laura Valerio ◽  
Carlotta Giani ◽  
David Viola ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Progression Free Survival ◽  
Thyroid Cancers ◽  
Poorly Differentiated ◽  
Differentiated Thyroid Cancers ◽  
Approved Drugs ◽  
New Generation ◽  
Systemic Therapies

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.

scholarly journals Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yotaro Ochi ◽  
Kenichi Yoshida ◽  
Ying-Jung Huang ◽  
Ming-Chung Kuo ◽  
Yasuhito Nannya ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Genetic Abnormalities ◽  
Prior Use

AbstractBlast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.

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