Between and within patient imaging heterogeneity highlights differences between Vemurafenib, Dabrafenib and Trametinib in metastatic melanoma


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Hitesh Mistry1,David Orrell2
1University of Manchester,2Systems Forecasting

Abstract

Background

Tumour heterogenity has predominantly been explored at the molecular level using various genetic techniques.  How this heterogeneity at the microscopic level relates to the shrinkage and growth dynamics at the macroscopic level measured via routine imaging has largely been unexplored. Here we use routine imaging data collected during clinical trials to explore the within patient and between patient heterogeneity using a mathematical model of tumour growth. 

Method

We collected individual lesion imaging data on patients from the investigational treatment arms of the phase III studies of Vemurafenib, Dabrafenib and Trametinib. 

A mathematical model of tumour growth was developed based on emperical observations and biological understanding. The model was used to answer the following questions by placing it within a mixed-effects statistical framework:

  1. Is there correlation in the dynamic of tumour shrinkage and rate of resistance within a patient?
  2. Is there evidence of cell-cell competition, analsyed via correlation between tumour shrinkage and resistance rates?
  3. Can Vemurafenib and Dabrafenib be differentiated at the individual lesion level given that they cannot be seperated at the study level?

Results

Correlation within a patient in terms of tumour dyanmics of shrinkage and resistance rates was found to exist implying there is some degree of homogeneity. No correlation between the shrinkage and resistance rates suggesting that there is no cell-cell competition visible at the whole tumour imaging level. Vemurafenib and Dabrafenib can be differentiated using the modelling and anlsysis techniques described here.  The main difference is that the variation in tumour shrinkage within a patient is greater for Vemurfaenib than Dabrafenib.

Conclusion

We highlight how a mathemical model developed based on emperical observations and mechanistic insight was able to highlight both within and between heteorogenity and homogenityusing routinely collected imaging data. The framework was able to differentitae between Dabrafenib and Trametinib, routine drugs used in treating metastatic melanoma.