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There has been significant progress made in individualizing cancer therapy, especially for colorectal and breast cancer. This has included objective determination of aggressiveness of therapy using molecular predictors of disease recurrence (i.e., Mammaprint, OncotypeDX), identifying altered drug activation for dose modifications (i.e., DPYD, CYP2D6, UGT1A1), or variation in drug targets or components of a pharmacodynamic pathway (TYMS, EGFR, KRAS). With patient-specific molecular characteristics increasingly guiding therapy, this review provides important and timely insights on targeted therapy. Ultimately, integration of both pharmacogenomic and clinical characteristics can provide powerful predictive tools for stratifying responders from nonresponders and identifying patients at increased risk for toxicity.