Implementing Genome-Driven Oncology

Abstract

Early successes in identifying and targeting individual oncogenic drivers, together with the increasing feasibility of sequencing tumor genomes, have brought forth the promise of genome-driven oncology care. As we expand the breadth and depth of genomic analyses, the biological and clinical complexity of its implementation will be unparalleled. Challenges include target credentialing and validation, implementing drug combinations, clinical trial designs, targeting tumor heterogeneity, and deploying technologies beyond DNA sequencing, among others. We review how contemporary approaches are tackling these challenges and will ultimately serve as an engine for biological discovery and increase our insight into cancer and its treatment.

Keywords: Precision medicine; basket studies; genome-driven oncology; next-generation sequencing; targeted therapy.

Figure 1. Druggable Alterations in Oncology Today and in the Near Future

The percent of patients by cancer type harboring a biomarker that, at present, guides the use of either FDA-approved or standard-of-care therapies (open circles) compared to the fraction of patients in the same tumor type harboring a genomic alteration with compelling clinical evidence that it predicts response to a drug but neither the genomic biomarker nor the drug are standard-of-care yet in that indication represented by an arrow.

Figure 2. Approaches to Novel Target Validation

Discovery of a novel target is traditionally followed by biologic validation before proceeding with clinical credentialing. This “monogenic” low-throughput process involves evaluation of one genomic alteration at a time. Next-generation sequencing at the point of care now routinely identifies novel genomic alterations in patients who are in need of new treatment strategies and cannot wait for initial biologic validation. In a “polygenic” high-throughput model, novel genomic alterations observed in patients undergo an initial prequalification using a computational framework that considers allelic recurrence, paralogy, structure, expression, and gene dosage to evaluate the likelihood of clinical relevance. Patients whose tumors harbor qualifying alterations that are identified as potentially activating can then be enrolled in genome-driven clinical trials and the responses observed, potentially providing initial clinical credentialing before biologic characterization. In this model, clinical studies become platforms for exploring the functional consequences of novel genomic alterations detected in the same patient populations.

Figure 3. The Hallmarks of a Precision-Oncology Study

Shown are multiple facets of a modern oncology trial that not only refines a biomarker hypothesis in a scientifically principled manner but also can serve as an engine to drive new scientific discoveries. The hallmarks of a modern precision-oncology study include four primary scientific objectives: identification of the target, confirmation of target inhibition, biologic credentialing of the target, and description of the mechanisms underlying acquired resistance. Collection and analysis of biospecimens should be organized around, and driven by, these key objectives.