Abstract
Simple SummaryA new methodology of cancer testing, called “liquid biopsy”, has been under investigation in the past few years. It is based on blood tests that can be analyzed by novel genetics and bioinformatics tools, in order to detect cancer, predict or follow the response to therapies and understand the mechanisms of relapse. This technology is still experimental, yet it has sparked much interest within the scientific community because it promises a new era of cancer management. We here review its application in a subset of tumors characterized by the presence of the ALK oncogene: patients affected by these tumors can benefit from targeted therapy, but show frequent relapses, which call for improved methods of disease detection.Cancer cells are characterized by high genetic instability, that favors tumor relapse. The identification of the genetic causes of relapse can direct next-line therapeutic choices. As tumor tissue rebiopsy at disease progression is not always feasible, noninvasive alternative methods are being explored. Liquid biopsy is emerging as a non-invasive, easy and repeatable tool to identify specific molecular alterations and monitor disease response during treatment. The dynamic follow-up provided by this analysis can provide useful predictive information and allow prompt therapeutic actions, tailored to the genetic profile of the recurring disease, several months before radiographic relapse. Oncogenic fusion genes are particularly suited for this type of analysis. Anaplastic Lymphoma Kinase (ALK) is the dominant driver oncogene in several tumors, including Anaplastic Large-Cell Lymphoma (ALCL), Non-Small Cell Lung Cancer (NSCLC) and others. Here we review recent findings in liquid biopsy technologies, including ctDNA, CTCs, exosomes, and other markers that can be investigated from plasma samples, in ALK-positive cancers.
Highlights
Cancer is a clonal disease characterized by the evolution of heterogeneous subpopulations that follow Darwinian processes of selection
In another study aimed to establish the role of plasma genotyping in conjunction with tumor genotyping, 323 metastatic Non-Small Cell Lung Cancer (NSCLC) patients were assessed for actionable targets and to guide clinical decisions
A recent case report illustrates the potential real-world use of circulating tumor DNA (ctDNA) in this setting: following disease progression on chemotherapy, echinoderm microtubule-associated protein-like 4 (EML4)-Anaplastic Lymphoma Kinase (ALK) fusion was detected in plasma ctDNA, the patient switched to alectinib and achieved a durable complete response [131]
Summary
Cancer is a clonal disease characterized by the evolution of heterogeneous subpopulations that follow Darwinian processes of selection. From pioneering multi-region sequencing studies to current single-cell analyses, the accumulated data point to high intra-tumor heterogeneity, which poses significant challenges to treatments: tumors continue to evolve under treatment and tend to adapt to a new environment represented by therapies Under these circumstances, rare clones that are resistant to drugs will emerge due to the evolutionary pressure exerted by the treatment. It has become clear that personalized molecular portraying of tumors and their clonal architecture, as well as dynamic monitoring of response to treatments, should become a routine procedure in order to optimize the outcome, predict relapses and allow prompt intervention These concepts are rather obvious for most cancers with heterogeneous mutational profiles, they apply to special cases of tumors driven by a dominant oncogene, such as those harboring oncogenic fusion kinases. We review current technologies and results obtained by liquid biopsy approaches in ALK-dependent tumors
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