Associate Editor: B. TeicherLiquid biopsies for solid tumors: Understanding tumor heterogeneity and real time monitoring of early resistance to targeted therapies
Introduction
The spread of personalized medicine for cancer patients relies on the recognition of the molecular drivers of the disease. This approach aims at improving the clinical outcome by giving patients drugs tailored to the genomic makeup of their tumor. Biomarkers predicting therapy response are frequently evaluated on tumor biopsy samples. However, the biopsy depicts only a snapshot from a single metastatic site in a given moment. Therefore, it might be inadequate to characterize a tumor because of intratumoral and intermetastatic heterogeneity. Tumor heterogeneity is described in both ‘space and time’ (Swanton, 2012) — with anatomically different areas of the same primary tumor and metastases showing different genomic profiles (Gerlinger et al, 2012). Therefore, more comprehensive tumor genome information is needed to provide an accurate portrait of the whole tumor than those that can be offered by a single biopsy. Moreover, acquired drug resistance to targeted agents is common during the course of the disease, thus there is an urgent need to monitor tumor evolution and ideally predict the onset of resistance to targeted therapies. Circulating tumor DNA (ctDNA) offers a unique opportunity for serially monitoring tumor genomes in a non-invasive manner. As ctDNA is a potential surrogate for the tumor itself, it is often referred to as ‘liquid biopsy’. In our review, we focus on the clinical applications of liquid biopsies and on the recent findings in this field.
Section snippets
Biology of circulating tumor DNA
Data available about the origin, mechanism, and release of ctDNA in the circulation, are often conflicting. Some seem to derive from nucleated blood cells while some others seem to origin from the apoptosis and necrosis of cancer cells in the tumor microenvironment (Stroun et al., 2000). According to other data, ctDNA could derive from the lyses of circulating cancer cells or micrometastases shed by the tumor (Stroun et al., 2000). Also, it has been supposed that the tumor actively releases DNA
Minimal residual disease monitoring and early detection
Predicting whether a cancer patient will relapse remains a challenge in modern medicine. ctDNA can be counted in the plasma and serum of patients with advanced cancer (Leon et al., 1977, Kinde et al., 2011, Forshew et al., 2012, Dawson et al., 2013, Murtaza et al., 2013), but very few data are available for the early setting (Bettegowda et al., 2014). The detection of micrometastatic disease following surgical resection of a localized cancer requires the use of an alternative molecular assay to
Assessment of molecular heterogeneity of overall disease and monitoring of tumor dynamics
In the context of personalized medicine, molecular analysis is used to select appropriate and optimal therapies based on a patient's cancer genome. Changes of biological features between the primary tumors and metastasis can happen, but in routine clinical practice, where recurrent cancer may not be re-biopsied, the treatment choice for recurrent disease is based on the molecular picture of the primary tumor. In fact, the acquisition of tissue from a metastatic lesion can be technically
Monitoring treatment response and emerging molecular resistance
In all phases of cancer management it is crucial to monitor treatment response to prevent continuing inefficacious therapies and to avoid unnecessary side effects. It was demonstrated that dynamic variations in ctDNA levels, as revealed by monitoring serial PIK3CA and TP53 mutant ctDNA, reflect changes in tumor burden and can predict the finding of progressive disease by several months (Dawson et al., 2013). However, in the study of Dawson et al., mutations in PIK3CA and TP53 were detected in
CtDNA and CTCs as interrelating biomarkers
Circulating tumor cells (CTCs) can be found in the bloodstream of patients with cancer and their levels correlate with response to therapy and survival (Krebs et al., 2014). Progresses in single-cell genomic profiling have increased the ability to examine CTCs for ‘actionable’ aberrations and emerging resistant subclones, which will help patient treatment stratification. A comparison between ctDNA and CTCs was undertaken in 30 patients with breast cancer harboring somatic mutations in PIK3CA
Conclusions
Analysis of ctDNA offers a non-invasive clinical tool for real-time monitoring of primary tumor and metastatic disease burden and genetic features. It allows choosing the therapy according to the genetic changes correlated with therapeutic response. In the era of personalized medicine, in which the treatment of cancer patients is based on specific targets, real time identification of these targets could be made easier by genotype ctDNA. In the near future, studies will require tissue biopsies
Conflict of interest
The authors declare that there are no conflicts of interest.
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