Hypoxia is present to some extent in most solid malignant human cancers because of an imbalance between the limited oxygen delivery capacity of the abnormal vasculature and the high oxygen consumption of tumor cells. This drives a complex and dynamic compensatory response to enable continued cell survival, including genomic changes leading to selection of hypoxia-adapted cells with a propensity to invade locally, metastasize, and recur following surgery or radiotherapy. There is indisputable clinical evidence from numerous observational and therapeutic studies across a range of tumor types to implicate hypoxia as a key determinant of cancer behavior and treatment outcome. Despite this, hypoxia-targeted treatment has failed to influence clinical practice. This is explained, in part, by emerging findings to indicate that hypoxia is not equally important in all patients even when present to the same extent. The impact of hypoxia on patient outcome and the benefit of hypoxia-targeted treatments are greatest in situations where hypoxia is a primary biological driver of disease behavior-patients with tumors having a "hypoxic driver" phenotype. The challenge for the clinical and scientific communities moving forward is to develop robust precision cancer medicine strategies for identifying these patients in the setting of other etiologic, genomic, and host-tumor factors, considering not only the state of the tumor at diagnosis but also changing patient and tumor characteristics over time.
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