The Clinical Significance of Hypoxia in Human Cancers

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.

Introduction

Advances in medical genomics and bioinformatics have revolutionized cancer research in recent years and generated unprecedented enthusiasm for the development of treatments that target specific molecular or genomic susceptibilities. There is optimism that such approaches will result in more durable tumor control and fewer side effects compared with traditional treatments such as radiotherapy or cytotoxic chemotherapy. However, given the molecular complexity inherent in cancer, it is increasingly apparent that highly specific targeted treatments yield improved clinical outcome in only limited subsets of patients. In fact, recent genomic profiling studies have suggested that more generalized clinical utility of molecular treatment strategies will only be achieved by targeting pathophysiological vulnerabilities as opposed to specific signaling pathways.¹

Hypoxia, the pathophysiological sequela of a mismatch between oxygen supply and demand, is a defining hallmark of malignancy that arises directly from the high metabolic demands of rapidly proliferating cancer cells reliant on a dynamic, unpredictable, and ineffective microvasculature. Still, hypoxia is not merely a microenvironmental by-product of uncontrolled and poorly supported cellular growth but rather an active participant in oncogenesis and the clinical evolution of cancer over time. This is mediated via a wide range of hypoxia-related processes, including genomic instability that exerts selection pressure for the outgrowth of aggressive and resistant malignant phenotypes.2, 3, 4 Hypoxia represents a unique tumor vulnerability to be exploited in the context of newly emerging precision cancer medicine strategies.

Evidence implicating hypoxia as a key determinant of cancer behavior and treatment outcome in patients has been accumulating for several decades but largely has failed to influence clinical practice. There are many reasons for this, including the intensification of standard treatment over the same time frame and the complex, dynamic interplay between hypoxia and other molecular determinants of outcome that confounds the identification of optimal patient subgroups for hypoxia-targeted treatment. This review highlights the key clinical evidence in support of hypoxia as a driver of cancer progression, metastasis formation, and treatment response in patients. It also addresses priorities to assure the success of future precision cancer medicine strategies, including the importance of considering hypoxia in the context of other etiologic, genomic, and host-tumor factors to optimally select patients for emerging targeted therapeutic approaches.