Abstract
PurposeExplore the heterogeneity in dynamics of tumour response to vemurafenib, dabrafenib and trametinib using routinely collected clinical trial imaging data.MethodsTime-series imaging data from the phase III studies of vemurafenib, dabrafenib and trametinib were collected through a data repository. A mathematical model based on basic mechanisms of tumour growth was placed within a statistical modelling framework to analyse the data.ResultsThe analysis revealed: (1) existence of homogeneity in drug response and resistance development within a patient; (2) tumour shrinkage rate does not relate to rate of resistance development; (3) vemurafenib and dabrafenib, two BRAF inhibitors, have different variability in tumour shrinkage rates.ConclusionsOverall these results show how analysis of the dynamics of individual lesions can shed light on the within and between patient differences in tumour shrinkage and resistance rates, which could be used to gain a macroscopic understanding of tumour heterogeneity.
Highlights
Tumour heterogeneity at the molecular level is known to exist between patients and between lesions within a patient and within an individual lesion [1,2,3]
It is noticeable that the number of patients is larger in the vemurafenib study than the dabrafenib and trametinib studies; again this mirrors the original studies
It shows that the frequency of data collection is consistent over time and that the distribution of initial values is similar across all studies
Summary
Tumour heterogeneity at the molecular level is known to exist between patients and between lesions within a patient and within an individual lesion [1,2,3]. At the individual lesion level, we can envisage that the molecular heterogeneity is likely to lead to differential cell killing, under a given treatment, within the lesion [4]. Differential killing is likely to vary across lesions within a patient and across patients This variability in cell killing could well be visible at the whole tumour level via measurements obtained through routine clinical imaging. Data from clinical trials are likely to be the best source for exploring the variability described as the imaging data collection process is standardised for a large number of patients. This is due to most clinical trials employing the Response Evaluation Criteria In Solid Tumours (RECIST) [5]. This criterion, limits the analysis of variability to the between patient and within patient level, as we explain
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