An advanced discrete state-discrete event multiscale simulation model of the response of a solid tumor to chemotherapy: Mimicking a clinical study.
In this paper an advanced, clinically oriented multiscale cancer model of breast tumor response to chemotherapy is presented. The paradigm of early breast cancer treated by epirubicin according to a branch of an actual clinical trial (the Trial of Principle, TOP trial) has been addressed. The model, stemming from previous work of the In Silico Oncology Group, National Technical University of Athens, is characterized by several crucial new features, such as the explicit distinction of proliferating cells into stem cells of infinite mitotic potential and cells of limited proliferative capacity, an advanced generic cytokinetic model and an improved tumor constitution initialization technique. A sensitivity analysis regarding critical parameters of the model has revealed their effect on the behavior of the biological system. The favorable outcome of an initial step towards the clinical adaptation and validation of the simulation model, based on the use of anonymized data from the TOP clinical trial, is presented and discussed. Two real clinical cases from the TOP trial with variable molecular profile have been simulated. A realistic time course of the tumor diameter and a reduction in tumor size in agreement with the clinical data has been achieved for both cases by selection of reasonable model parameter values, thus demonstrating a possible adaptation process of the model to real clinical trial data. Available imaging, histological, molecular and treatment data are exploited by the model in order to strengthen patient individualization modeling. The expected use of the model following thorough clinical adaptation, optimization and validation is to simulate either several candidate treatment schemes for a particular patient and support the selection of the optimal one or to simulate the expected extent of tumor shrinkage for a given time instant and decide on the adequacy or not of the simulated scheme.
In Silico Oncology Group, Laboratory of Microwaves and Fiber Optics, Institute of Communication and Computer Systems, School of Electrical and Computer Engineering, National Technical University of Athens, Iroon Polytechniou 9, Zografos GR 157 80, Greece. gestam@central.ntua.gr
G S
GS
Stamatakos
E A
EA
Kolokotroni
D D
DD
Dionysiou
E Ch
ECh
Georgiadi
C
C
Desmedt
D000465:Algorithms; D000951:Antigens, Neoplasm / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D015251:Epirubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects; D057285:Precision Medicine / Q000379:methods; D012985:Software Design; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D015251:Epirubicin; D004250:DNA Topoisomerases, Type II