A number of other systems medicine tools could contribute to TKI-induced cardiovascular toxicity. The report discussed 3 in particular: microRNA, metabolic signatures in the bloodstream, and assessing the microbiome. microRNA is involved in vascular remodeling, heart failure, and coronary artery disease, and may “become a lucrative area” for investigating cardiovascular toxicity, the authors wrote. Metabolic signatures in the blood could allow for early identification of cardiovascular toxicity, and potentially lead to predictive and preventive treatment. The microbiome could be used to evaluate TKI-induced toxicity.

Additional systems biology tools, including epigenomics, proteomics, interactomics, network medicine, and computational biology have also been implemented in optimizing drug delivery, investigating the mechanisms underlying adverse effects, or determining the pathophysiology of cancers. Using these tools, the authors said, clinicians may soon be able to select optimal TKI dosing that minimizes toxicity and maximizes outcomes.

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“As results from additional systems medicine tools become available, these should also be investigated in clinical trials,” said Dr Brown. “Ultimately, technologies synthesizing various biotechnological tools in the same suite of algorithms should be harnessed for optimization of individualized care.” 

The authors made a number of recommendations for implementation of systems medicine in clinical practice. They proposed leveraging computational and mathematical modeling to measure the interactions among various cardiovascular components in response to TKI therapy. “Such interactions can often lead to complex phenotypes that are not additive but rather can be synergistic or antagonistic,” they wrote. They recommended employing predictive computer models to determine which patients are high or low risk for TKI-induced cardiovascular toxicity, and using that information to guide precision medicine.

The authors also recommended incorporating the P4 pathway to streamlining systems medicine; the pathway describes a clinical practice that is “predictive, personalized, preventive and participatory.”4 By applying the pathway’s model of systems medicine counseling—which is similar to genetic counseling—prior to systems medicine testing, patients could be assigned a composite systems medicine score (CSMS) that categorizes their risk for developing TKI-induced cardiovascular toxicity, they wrote. 

To integrate systems-based approaches to patient care, clinical trials will be necessary to assess whether implementation of systems medicine tools can have an impact on cardiovascular toxicity, and the trials should be designed to ask how systems medicine-based screening can be combined with management decisions, said Dr Brown.

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“For example, at which stage of therapy could antihypertensives prophylactically be initiated, if at all?” she said. “Should a vasodilator be started just prior to small molecule TKI therapy, early on during therapy, later on during therapy, or after therapy? Will clinical trials for prevention or management of cardiovascular toxicities from small molecule TKI therapy parallel similar studies for anthracycline-induced toxicity? Such questions should be addressed in order to potentially incorporate systems medicine into clinical practice guidelines.”


  1. Dahlen T, Edgren G, Lambe M, et al. Cardiovascular events associated with use of tyrosine kinase inhibitors in chronic myeloid leukemia: a population-based cohort study. Ann Intern Med. 2016;165(3):161-6. doi: 10.7326/M15-2306
  2. Lenneman CG, Sawyer DB. Cardio-oncology: an update on cardiotoxicity of cancer-related treatment. Circ Res. 2016;118(6):1008-20. doi: 10.1161/CIRCRESAHA.115.303633
  3. Brown SA, Nhola L, Herrmann J. Cardiovascular toxicities for small molecule TKIs: an opportunity for systems-based approaches. Clin Pharmacol Ther. 2016 Nov 2. doi: 10.1002/cpt.552 [Epub ahead of print]
  4. Hood L, Friend SH. Predictive, personalized, preventive, participatory (P4) cancer medicine. Nat Rev Clin Oncol. 2011;8(3):184-7. doi: 10.1038/nrclinonc.2010.227