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.
J Theor Biol. 2010 Sep 7;266(1):124-39. doi: 10.1016/j.jtbi.2010.05.019. Epub 2010 May 31.
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.
本文提出了一种先进的、面向临床的乳腺癌肿瘤对化疗反应的多尺度模型。该模型针对早期乳腺癌患者接受表柔比星治疗的情况进行了研究，所依据的是一项实际临床试验（原则试验，TOP 试验）的一个分支。该模型源自雅典国立技术大学的计算机肿瘤学小组之前的工作，具有几个关键的新特征，例如将增殖细胞明确区分为具有无限有丝分裂潜能的干细胞和具有有限增殖能力的细胞、一个先进的通用细胞动力学模型和一个改进的肿瘤组成初始化技术。对模型关键参数的敏感性分析揭示了它们对生物系统行为的影响。本文展示并讨论了基于 TOP 临床试验匿名数据对模拟模型进行临床适应和验证的初步成功。模拟了来自 TOP 试验的两个具有不同分子特征的真实临床病例。通过选择合理的模型参数值，实现了两个病例的肿瘤直径的真实时间过程和与临床数据一致的肿瘤体积缩小，从而证明了模型对真实临床试验数据的可能适应过程。模型利用现有的成像、组织学、分子和治疗数据来增强患者个体化建模。在经过彻底的临床适应、优化和验证后，该模型的预期用途是模拟特定患者的几种候选治疗方案，并支持选择最佳方案，或者模拟给定时间点的肿瘤缩小程度，并决定模拟方案是否合适。
