Abstract:Background. Over the past few years, next-generation tumor sequencing (NGS) panels have evolved in complexity and have changed from selected gene panels with a handful of genes to larger panels with hundreds of genes, sometimes in combination with paired germline filtering and/or testing. With this move toward increasingly large NGS panels, we have rapidly outgrown the available literature supporting the utility of treatments targeting many reported gene alterations making it challenging for oncology providers… Show more
“…Therefore therapies are directed toward treating the cancer to extend and improve quality of life. Currently this is where the bulk of precision oncology efforts are focused: to find molecular alterations that have targeted therapies ( 11 , 32 , 33 ). Also, because metastatic disease is largely incurable, there tends to be more latitude in pursuing therapies that may not be standard of care but may realistically still afford a chance of benefit ( 11 , 31 , 32 , 34 ).…”
Section: Precision Oncology In Early-stage and Metastatic Cancermentioning
confidence: 99%
“…Currently this is where the bulk of precision oncology efforts are focused: to find molecular alterations that have targeted therapies ( 11 , 32 , 33 ). Also, because metastatic disease is largely incurable, there tends to be more latitude in pursuing therapies that may not be standard of care but may realistically still afford a chance of benefit ( 11 , 31 , 32 , 34 ). Such strategies, however, must be considered carefully and are nowadays often discussed at molecular tumor boards ( 33 ), and have led to guidelines to contextualize a framework for prioritizing actionable NGS results ( 35 ).…”
Section: Precision Oncology In Early-stage and Metastatic Cancermentioning
Cancer cells shed naked DNA molecules into the circulation. This circulating tumor DNA (ctDNA) has become the predominant analyte for liquid biopsies to understand the mutational landscape of cancer. Coupled with next-generation sequencing, ctDNA can serve as an alternative substrate to tumor tissues for mutation detection and companion diagnostic purposes. In fact, recent advances in precision medicine have rapidly enabled the use of ctDNA to guide treatment decisions for predicting response and resistance to targeted therapies and immunotherapies. An advantage of using ctDNA over conventional tissue biopsies is the relatively noninvasive approach of obtaining peripheral blood, allowing for simple repeated and serial assessments. Most current clinical practice using ctDNA has endeavored to identify druggable and resistance mutations for guiding systemic therapy decisions, albeit mostly in metastatic disease. However, newer research is evaluating potential for ctDNA as a marker of minimal residual disease in the curative setting and as a useful screening tool to detect cancer in the general population. Here we review the history of ctDNA and liquid biopsies, technologies to detect ctDNA, and some of the current challenges and limitations in using ctDNA as a marker of minimal residual disease and as a general blood-based cancer screening tool. We also discuss the need to develop rigorous clinical studies to prove the clinical utility of ctDNA for future applications in oncology.
“…Therefore therapies are directed toward treating the cancer to extend and improve quality of life. Currently this is where the bulk of precision oncology efforts are focused: to find molecular alterations that have targeted therapies ( 11 , 32 , 33 ). Also, because metastatic disease is largely incurable, there tends to be more latitude in pursuing therapies that may not be standard of care but may realistically still afford a chance of benefit ( 11 , 31 , 32 , 34 ).…”
Section: Precision Oncology In Early-stage and Metastatic Cancermentioning
confidence: 99%
“…Currently this is where the bulk of precision oncology efforts are focused: to find molecular alterations that have targeted therapies ( 11 , 32 , 33 ). Also, because metastatic disease is largely incurable, there tends to be more latitude in pursuing therapies that may not be standard of care but may realistically still afford a chance of benefit ( 11 , 31 , 32 , 34 ). Such strategies, however, must be considered carefully and are nowadays often discussed at molecular tumor boards ( 33 ), and have led to guidelines to contextualize a framework for prioritizing actionable NGS results ( 35 ).…”
Section: Precision Oncology In Early-stage and Metastatic Cancermentioning
Cancer cells shed naked DNA molecules into the circulation. This circulating tumor DNA (ctDNA) has become the predominant analyte for liquid biopsies to understand the mutational landscape of cancer. Coupled with next-generation sequencing, ctDNA can serve as an alternative substrate to tumor tissues for mutation detection and companion diagnostic purposes. In fact, recent advances in precision medicine have rapidly enabled the use of ctDNA to guide treatment decisions for predicting response and resistance to targeted therapies and immunotherapies. An advantage of using ctDNA over conventional tissue biopsies is the relatively noninvasive approach of obtaining peripheral blood, allowing for simple repeated and serial assessments. Most current clinical practice using ctDNA has endeavored to identify druggable and resistance mutations for guiding systemic therapy decisions, albeit mostly in metastatic disease. However, newer research is evaluating potential for ctDNA as a marker of minimal residual disease in the curative setting and as a useful screening tool to detect cancer in the general population. Here we review the history of ctDNA and liquid biopsies, technologies to detect ctDNA, and some of the current challenges and limitations in using ctDNA as a marker of minimal residual disease and as a general blood-based cancer screening tool. We also discuss the need to develop rigorous clinical studies to prove the clinical utility of ctDNA for future applications in oncology.
“…For discussion at molecular tumor boards (MTBs), only the most pertinent information is summarized and prioritized in a clinical report such that actionability of alterations is displayed clearly for the expert panel (Fig. 1 E) [ 65 – 68 ]. Fig.…”
Background
The promise of precision cancer medicine presently centers around the genomic sequence of a patient’s tumor being translated into timely, actionable information to inform clinical care. The analysis of cell-free DNA from liquid biopsy, which contains circulating tumor DNA (ctDNA) in patients with cancer, has proven to be amenable to various settings in oncology. However, open questions surrounding the clinical validity and utility of plasma-based analyses have hindered widespread clinical adoption.
Main body
Owing to the rapid evolution of the field, studies supporting the use of ctDNA as a biomarker throughout a patient’s journey with cancer have accumulated in the last few years, warranting a review of the latest status for clinicians who may employ ctDNA in their precision oncology programs. In this work, we take a step back from the intricate coverage of detection approaches described extensively elsewhere and cover basic concepts around the practical implementation of next generation sequencing (NGS)-guided liquid biopsy. We compare relevant targeted and untargeted approaches to plasma DNA analysis, describe the latest evidence for clinical validity and utility, and highlight the value of genome-wide ctDNA analysis, particularly as it relates to early detection strategies and discovery applications harnessing the non-coding genome.
Conclusions
The maturation of liquid biopsy for clinical application will require interdisciplinary efforts to address current challenges. However, patients and clinicians alike may greatly benefit in the future from its incorporation into routine oncology care.
“…1 Results of NGS cancer panels are often discussed at molecular tumor boards, where oncologists, molecular pathologists, and staff scientists decide on the best treatment options for a patient. [2][3][4][5][6] With the transition from small panels covering hotspot regions of actionable genes to larger comprehensive panels, NGS results have become more challenging to understand and interpret. 7 Typically, only a subset of the detected alterations are well-known actionable mutations.…”
PURPOSE Comprehensive targeted next-generation sequencing (NGS) panels are routinely used in modern molecular cancer diagnostics. In molecular tumor boards, the detected genomic alterations are often discussed to decide the next treatment options for patients with cancer. With the increasing size and complexity of NGS panels, the discussion of these results becomes increasingly complex, especially if they are reported in a text-based form, as it is the standard in current molecular pathology. METHODS We have developed the Molecular Tumor Profiling pilot ( MTPpilot) webservice using HTML, PHP, JavaScript, and MySQL to support the clinical discussion of NGS results at molecular tumor boards. RESULTS MTPpilot integrates various public genome, network, and cancer mutation databases with interactive visualization tools to assess the functional impact of mutations and support clinical decision making at tumor boards. CONCLUSION MTPpilot is tailored for discussion of NGS gene panel results at molecular tumor boards. It is freely available as a webservice at MTPpilot.
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