Evolutionary dynamics of cancer in response to targeted combination therapy
Ivana Bozic,
Johannes G Reiter,
Benjamin Allen,
Tibor Antal,
Krishnendu Chatterjee,
Preya Shah,
Yo Sup Moon,
Amin Yaqubie,
Nicole Kelly,
Dung T Le,
Evan J Lipson,
Paul B Chapman,
Luis A Diaz Jr,
Bert Vogelstein,
Martin A Nowak
Affiliations
Ivana Bozic
Program for Evolutionary Dynamics, Harvard University, Cambridge, United States; Department of Mathematics, Harvard University, Cambridge, United States
Johannes G Reiter
Institute of Science and Technology Austria, Klosterneuburg, Austria
Benjamin Allen
Program for Evolutionary Dynamics, Harvard University, Cambridge, United States; Department of Mathematics, Emmanuel College, Boston, United States
Tibor Antal
School of Mathematics, Edinburgh University, Edinburgh, United Kingdom
Krishnendu Chatterjee
Institute of Science and Technology Austria, Klosterneuburg, Austria
Preya Shah
Harvard College, Cambridge, United States
Yo Sup Moon
Harvard College, Cambridge, United States
Amin Yaqubie
Memorial Sloan-Kettering Cancer Center, New York, United States
Nicole Kelly
Memorial Sloan-Kettering Cancer Center, New York, United States
Dung T Le
Department of Medical Oncology, Johns Hopkins University School of Medicine; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
Evan J Lipson
Department of Medical Oncology, Johns Hopkins University School of Medicine; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
Paul B Chapman
Memorial Sloan-Kettering Cancer Center, New York, United States
Luis A Diaz Jr
Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, United States
Bert Vogelstein
Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, United States
Martin A Nowak
Program for Evolutionary Dynamics, Harvard University, Cambridge, United States; Department of Mathematics, Harvard University, Cambridge, United States; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, United States
In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics.
