Imaging biomarker roadmap for cancer studies

Abstract

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

TNM staging of a patient with stage IV non-small-cell lung cancer (T2 N0 M1) identified by a | T2 lung tumour on CT, b | no evidence of local nodal involvement on PET–CT, and c | brain metastases on MRI.

a | A patient with cervical cancer (T3b N0 M0) had a bulky primary tumour at baseline, but b | showed a complete response and reconstitution of the cervix following therapy with chemoradiation.

In a patient with breast cancer, scintigraphy shows a | diastole and b | systole maps of c | photon count. d | Maps of phase and e | stroke volume are also shown. In this patient, the LVEF was calculated as 66% (within the normal range). Treatment with doxorubicin was initiated, followed by trastuzumab.

A patient with a metastatic neuroendocrine tumour undergoing a diagnostic ⁶⁸Ga-dotatate PET–CT has a | multiple disease sites on fused coronal images, and b | maximum intensity projection. The patient then received therapeutic ¹⁷⁷Lu-dotatate, which enables demonstration of drug uptake at the disease sites, confirmed by SPECT– CT examination on c | fused coronal images and d | maximum intensity projection.

Clinical trial of the PI3K inhibitor pictilisib shows >30% reduction in the ¹⁸F-FDG-PET SUV_max in a patient with peri-hepatic disease from primary ovarian cancer before (left) and after (right) therapy. Adapted from Clin. Cancer Res., 2015, 21/1, Sarker, D. et al. First-in-human phase I study of pictilisib (GDC0941), a potent pan–class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors, with permission from AACR.

Example DCE–MRI data from patients with stage IV colorectal cancer receiving bevacizumab. a | Double baseline scanning enables calculation of IB precision; here, K^trans has been calculated in a liver metastasis on two scan visits performed 24 h apart. b | Serial mapping of K^trans in the same tumour reveals pharmacodynamic (PD) changes within 4 h of initiating therapy that were maintained to day 12. c | The IB ΔK^trans is shown for tumours from six patients.

Figure 1. Overview of the imaging biomarker roadmap.

Imaging biomarkers must cross translational gap 1 to become robust medical research tools, and translational gap 2 to be integrated into routine patient care. This goal is achieved through three parallel tracks of technical (assay) validation, biological and clinical validation, and cost effectiveness.

Figure 2. The imaging biomarker roadmap.

A detailed schematic roadmap is depicted. The imaging biomarker (IB) roadmap differs from those described for biospecimen-derived biomarkers. For imaging, the technical and biological/clinical validation occur in parallel rather than sequentially. Of note, essential technical validation occurs late in the roadmap in many cases (such as full multicentre and multivendor reproducibility). Definitive clinical validation studies (IB measured against outcome) are deferred until technical validation is adequate for large trials. In the absence of definitive outcome studies, early biological validation can rely on a platform of very diverse graded evidence linking the IB to the underlying pathophysiology. Cost-effectiveness impacts on the roadmap at every stage, owing to the equipment and personnel costs of performing imaging studies. Technical validation and cost-effectiveness are important for IBs after crossing the translational gaps because hardware and software updates occur frequently. Therefore, technical performance and economic viability must be re-evaluated continuously. SOP, standard operating procedure. Image reproduced from http://www.cancerresearchuk.org/sites/default/files/imaging_biomarker_roadmap_for_cancer_studies.pdf.