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  • Finally we found that macroscopic analysis of

    2018-11-05

    Finally, we found that macroscopic analysis of whole tumours could predict response, and baseline Ktrans was the strongest predictor, which suggests VEGF is main determinant of vascular leakiness, though not necessarily angiogenesis. Although baseline gene expression did not strongly correlate with MRI variation, once an environmental stress was induced there was strong concordance between imaging and mRNA changes, enabling patient classification by gene response linked to imaging changes with therapy implications. Control theory indicates difficulty of relating response to baselines if rules for connection are unknown, but our results show how quickly tumours adapt and then allow the characteristics to be defined. We conclude that bevacizumab has been prematurely discontinued, rather than focusing on finding subgroups of patients who most benefit using monitoring during 2week window before continuing therapy. This would be cost-effective and help stratify patients for combination or other targeted therapies. Finally, we suggest new paradigms for clinical research. Firstly, trials should incorporate appropriate initial enrichment of patients with high Ktrans, and a range of therapeutic options to meet potential early resistance pathways induced. Then, early imaging will be needed to stratify patients into categories likely to have different mechanism of adaptation, and biopsies to select patients for appropriate combinations. Repeatability of these assays makes this widely feasible. Multi-arm adaptive trials are ongoing using molecular markers for targeted agents, but we suggest this needs to be further modified by much earlier hiv protease when using drugs affecting the tumor microenvironment.
    Introduction Cell-free DNA (cfDNA) refers to nucleic acids detected in body fluids and are thought to arise from two sources: passive release through cell death (Jahr et al., 2001), and active release by cell secretion (Stroun et al., 2000). DNA from cancer cells also contributes to the total load of cfDNA (Schwarzenbach et al., 2011), and the fraction of cfDNA that comes from cancer cells is called circulating-tumor DNA (ctDNA). ctDNA has been estimated to make up about 0.01%–1% of cfDNA for early-stage disease, reaching over 40% for late-stage disease (Beaver et al., 2014; Bettegowda et al., 2014; Couraud et al., 2014; Diehl et al., 2007; Forshew et al., 2012; Newman et al., 2014; Sausen et al., 2015). Despite its intrinsic limitations, including technical issues in the sample collection, detection, and identification of tumor origin, ctDNA is emerging as a key potential biomarker for monitoring response to treatment and relapse (Dawson et al., 2013; Esposito et al., 2014; Forshew et al., 2012; Garcia-Murillas et al., 2015; Murtaza et al., 2013; Roschewski et al., 2015; Siravegna et al., 2015). The potential of ctDNA is not limited to post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. If successful, this could be translated into much improved cancer survival, in particular for those cancer sites that are typically diagnosed at a late stage, and for which survival is poor, such as lung, pancreatic, or esophageal cancer (Brennan and Wild, 2015). However, implementation of ctDNA tests that detect pre-clinical disease in a non-symptomatic population will have to show an extremely high specificity if they are to provide meaningful results, or be part of a multi-modal screening program. Very few studies have focused on the evaluation of ctDNA detection in early-stage cancers (i.e. stage I-II tumors) with even less data available on the detection of ctDNA in blood samples from pre-symptomatic cancer patients (Amant et al., 2015; Beaver et al., 2014; Bettegowda et al., 2014; Garcia-Murillas et al., 2015; Gormally et al., 2006; Jamal-Hanjani et al., 2016; Sausen et al., 2015); Table S1). In addition, these studies have aimed to detect specific mutations in cfDNA (most of them using digital droplet PCR) following previous assessment of the tumor mutational profile. This approach is only viable for cancers with common hot-spot mutations and is not amenable for most screening purposes. This is because early detection of pre-clinical cancer requires variant detection to be done without prior knowledge from tumor tissue of the expected mutations. Another limitation of these studies is the major assumption that circulating-mutated fragments would be absent (or very rare) in individuals without cancer. Demonstrating that any ctDNA detection marker has a specificity close to 100% would be of fundamental importance for large-scale utility in an asymptomatic population (Wentzensen and Wacholder, 2013).