False-negative MRI biomarkers of tumour response to targeted cancer therapeutics.
Boult JKR., Jamin Y., Jacobs V., Gilmour LD., Walker-Samuel S., Halliday J., Elvin P., Ryan AJ., Waterton JC., Robinson SP.
BACKGROUND: Non-invasive quantitative imaging biomarkers are essential for the evaluation of novel targeted therapeutics. Before deployment in clinical trials, such imaging biomarkers require qualification, typically through pre-clinical identification of imaging-pathology correlates. METHODS: First, in investigating imaging biomarkers of invasion, the response of orthotopic murine PC3 prostate xenografts to the Src inhibitor saracatinib was assessed using susceptibility contrast MRI. Second, the longitudinal response of chemically induced rat mammary adenocarcinomas to the VEGFR2 inhibitor vandetanib was monitored by intrinsic susceptibility MRI, to identify the time window of transient vascular normalisation. RESULTS: No significant differences in fractional blood volume (%), vessel calibre (μm), native T(1) (ms) or apparent water diffusion coefficient were determined, despite reduced expression of activated Fak and paxillin in the saracatinib cohort. Treatment with vandetanib elicited a 60% antitumour response (P<0.01), 80% inhibition in vessel density (P<0.05) and reduction in hypoxia (P<0.05). There was, however, no significant change in tumour baseline R(2)* (s(-1)) or carbogen-induced ΔR(2)* with treatment. CONCLUSION: Reporting negative imaging biomarker responses is important, to avoid the risk of clinical trials using the same biomarkers being undertaken with a false expectation of success, and the abandonment of promising new therapeutics based on a false-negative imaging biomarker response being mistaken for a true-negative.