Toward Personalized Computer Simulation of Breast Cancer Treatment: A Multiscale Pharmacokinetic and Pharmacodynamic Model Informed by Multitype Patient Data.

Autor:	Lai X; Oslo Centre for Biostatistics and Epidemiology, Faculty of Medicine, University of Oslo, Oslo, Norway., Geier OM; Department of Diagnostic Physics, Clinic of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway., Fleischer T; Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Garred Ø; Department of Pathology, Oslo University Hospital, Oslo, Norway., Borgen E; Department of Pathology, Oslo University Hospital, Oslo, Norway., Funke SW; Center for Biomedical Computing, Simula Research Laboratory, Lysaker, Norway., Kumar S; Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Rognes ME; Center for Biomedical Computing, Simula Research Laboratory, Lysaker, Norway., Seierstad T; Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway., Børresen-Dale AL; Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Kristensen VN; Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Division of Medicine, Akershus University Hospital, Lørenskog, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway., Engebraaten O; Department of Oncology, Oslo University Hospital, Oslo, Norway.; Department of Tumor Biology, Institute for Cancer Research, University of Oslo, Oslo, Norway., Köhn-Luque A; Oslo Centre for Biostatistics and Epidemiology, Faculty of Medicine, University of Oslo, Oslo, Norway., Frigessi A; Oslo Centre for Biostatistics and Epidemiology, Faculty of Medicine, University of Oslo, Oslo, Norway. arnoldo.frigessi@medisin.uio.no.; Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2019 Aug 15; Vol. 79 (16), pp. 4293-4304. Date of Electronic Publication: 2019 May 22.
DOI:	10.1158/0008-5472.CAN-18-1804
Abstrakt:	The usefulness of mechanistic models to disentangle complex multiscale cancer processes, such as treatment response, has been widely acknowledged. However, a major barrier for multiscale models to predict treatment outcomes in individual patients lies in their initialization and parametrization, which needs to reflect individual cancer characteristics accurately. In this study, we use multitype measurements acquired routinely on a single breast tumor, including histopathology, MRI, and molecular profiling, to personalize parts of a complex multiscale model of breast cancer treated with chemotherapeutic and antiangiogenic agents. The model accounts for drug pharmacokinetics and pharmacodynamics. We developed an open-source computer program that simulates cross-sections of tumors under 12-week therapy regimens and used it to individually reproduce and elucidate treatment outcomes of 4 patients. Two of the tumors did not respond to therapy, and model simulations were used to suggest alternative regimens with improved outcomes dependent on the tumor's individual characteristics. It was determined that more frequent and lower doses of chemotherapy reduce tumor burden in a low proliferative tumor while lower doses of antiangiogenic agents improve drug penetration in a poorly perfused tumor. Furthermore, using this model, we were able to correctly predict the outcome in another patient after 12 weeks of treatment. In summary, our model bridges multitype clinical data to shed light on individual treatment outcomes. SIGNIFICANCE: Mathematical modeling is used to validate possible mechanisms of tumor growth, resistance, and treatment outcome. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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