The clinical and molecular heterogeneity of various cancer types is well documented. In the era of precision oncology whereby molecular profiling of tumors is incorporated into clinical care, both intra- and intertumoral molecular and genetic heterogeneity have been described. Together, they impact patient treatment and outcomes. Host genetics and the tumor microenvironment impact on tumor evolution and heterogeneity through variations in immune cell infiltration, stromal variations, and selection pressures from hypoxia or nutrient stress, among others. Tumor progression and exposure to therapeutic agents lead to further molecular evolution and heterogeneity that is clinically relevant. Moreover, tumors that evolve after diagnosis and as a function of therapy generally become more aggressive and refractory to available therapeutics, including targeted agents and immunotherapy. The evolving clinical and molecular heterogeneity of patient tumors can be explored with various clinical and research-based specimens and testing such as pre- and post-treatment biopsies; serial liquid biopsies; single cell analysis; PDX and organoid models; anatomic, functional, and molecular imaging; and rapid postmortem studies. Other factors that influence tumor heterogeneity include immune checkpoints, cancer stem cells, therapy-acquired resistance mechanisms that may occur through secondary mutations, and adaptive responses. Modern technologic advances for tumor characterization provide opportunities to understand tumor evolution and its impact on clinical outcomes to improve therapeutic regimens. Characterization of novel targets and development of effective therapeutics are needed to target heterogeneity and the evolution of resistance mechanisms.
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