More sound cancer therapy biomarker development with active noise control.

Noise can be hazardous to health or simply irritating [1]. Acoustics engineers have developed methods to abate risk in hazardous environments, as well as minimize irritation and create unusual comfort in others. For example, many modern dishwashers come equipped with active noise control devices. These microphone/speaker units detect specific sound waves and generate “antiwaves” of equivalent amplitude, actively cancelling the noise [2]. This technology allows someone in your kitchen to clean dishes without having to turn up the television volume so loud as to not hear a pot of water over boiling on the stove. On international airplane flights, attendants may distribute headsets with similar devices to provide a trip free from engine noise. Cancer therapy can be hazardous to patients, and it never seems comfortable no matter how good the supportive care. For the past decade, investigators with various skills applying numerous strategies have promised “precision” medicine. Nearly all of these efforts employ biomarkers—that is, objectively measured characteristics that are evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions [3]. However, the absence of engineering principles and methods for developing, testing, and implementing biomarkers in parallel with the development of new drugs obstructs delivery of precision medicine. The failure to develop biomarkers soundly for drugs that disrupt the vascular endothelial growth factor (VEGF) signaling pathway (VSP) exemplifies the problem. In the past decade, nine companies have developed nine drugs that specifically inhibit the downstream signaling through VEGF/VEGF receptor-2: aflibercept, axitinib, bevacizumab, cabozantinib, pazopanib, regorafenib, sorafenib, sunitinib, and vandetanib. More agents in this class have been tested, but most will never become available. Each effort has been associated with numerous studies of mechanisms of action, preclinical models, and human candidate biomarkers, but there remains no qualified biomarker to improve the therapeutic index of VSP inhibitors [4–8]. In this issue, Hurwitz et al. [9] report on the candidate biomarker of change in blood pressure (BP) after beginning bevacizumab therapy. Hypertension was identified as a common occurrence and dose-limiting toxicity related to the mechanism of action of VSP inhibitors [10–13]. Measurement of BP change after starting VSP inhibitor treatment was proposed as a candidate biomarker to improve the therapeutic index of VSP inhibitors [14–16], but how to apply this marker in practice was unclear. After many preliminary reports, several well-conducted retrospective investigations of axitinib, bevacizumab, and sunitinib suggested the early development of BP elevation after therapy to predict better treatment outcomes across multiple diseases [17–19]. In contrast, Hurwitz et al., with the largest retrospective analysis to date, only found association between BP response and tumor response in one of seven phase III trials with bevacizumab. They have clearly demonstrated that there is no basis for an oncologist using routine office BP measurements during the first eight weeks of treatment to predict whether or not a patient is benefitting from bevacizumab therapy. However, the case for BP as a biomarker for improving VSP inhibitor therapy is far from closed. Two common and significant sources of noise that limit detection of clinically important associations in concurrent new drug and biomarker development are the (im)precision of the assay detecting the marker and the strength of the relationship between the marker and the clinical endpoint of interest. The term “noise” means that the measurements and associations have high variance. BP is a noisy biomarker. A single BP measurement in a patient reflects imprecisely the patient's average BP. Similarly, although a patient can show early evidence of pharmacodynamic effects of docetaxel by developing neutropenia with the first dose, numerous additional variables determine whether docetaxel will in fact prolong that patient's survival. A major challenge for the effective development of biomarkers for novel therapeutics is to identify and minimize the sources of noise. For both positive and negative biomarker studies, the reader should consider several basic questions to determine how to interpret the findings.