A Decision Support Framework for Genomically Informed Investigational Cancer Therapy

Abstract

Rapidly improving understanding of molecular oncology, emerging novel therapeutics, and increasingly available and affordable next-generation sequencing have created an opportunity for delivering genomically informed personalized cancer therapy. However, to implement genomically informed therapy requires that a clinician interpret the patient's molecular profile, including molecular characterization of the tumor and the patient's germline DNA. In this Commentary, we review existing data and tools for precision oncology and present a framework for reviewing the available biomedical literature on therapeutic implications of genomic alterations. Genomic alterations, including mutations, insertions/deletions, fusions, and copy number changes, need to be curated in terms of the likelihood that they alter the function of a "cancer gene" at the level of a specific variant in order to discriminate so-called "drivers" from "passengers." Alterations that are targetable either directly or indirectly with approved or investigational therapies are potentially "actionable." At this time, evidence linking predictive biomarkers to therapies is strong for only a few genomic markers in the context of specific cancer types. For these genomic alterations in other diseases and for other genomic alterations, the clinical data are either absent or insufficient to support routine clinical implementation of biomarker-based therapy. However, there is great interest in optimally matching patients to early-phase clinical trials. Thus, we need accessible, comprehensive, and frequently updated knowledge bases that describe genomic changes and their clinical implications, as well as continued education of clinicians and patients.

Integration of Technical, Bioinformatic, and Variant Assessment Approaches in the Validation of a Targeted Next-Generation Sequencing Panel for Myeloid Malignancies

“…40,41 Several other somatic variant classification systems have been recently reported in the literature. [42][43][44][45][46] Although these classification systems are adaptable to the hematologic malignancy context, applying those focused more specifically on drug trials, as well as those focused on variant-level interpretation and classification, poses greater challenges.…”

Clinical Outcomes of TP53 Mutations in Cancers

“…However, obstacles abound because of the experimental nature of the clinical trials, the lack of a clear targetable drug for the vast majorityof mutations found through large-scale sequencing, and the absence of strong evidence that a particular treatment might actually be effective for an individual patient. TP53 mutations, in particular, are not currently "clinically actionable" (Meric-Bernstam et al 2015); thus, making use of the molecular genetic information, including the tumor status of TP53, to effectively improve patient care remains a challenge in clinical settings. In the not-too-distant future, however, the presence of TP53 mutations may indeed inform targeted therapeutic approaches.…”

The Genomic Era of Clinical Oncology: Integrated Genomic Analysis for Precision Cancer Care

“…These actionable or potentially actionable genomic alterations often include gene amplifications containing well-characterized oncogenes such as MYCN , ERBB2 , ALK , etc. or deletions including certain tumor suppressor genes [Meric-Bernstam et al, 2015]. Identification of these CNVs, together with additional genomic informa- 168 tion revealed by other high-throughput technologies, has created an opportunity for delivering genomically informed personalized therapy.…”

“…Genomic alteration data on a patient's primary and/or metastatic tumor generated by NGS may qualify patients to enroll in active clinical trials or be treated "off-label or off-protocol" [Meric-Bernstam et al, 2015]. Since genomic testing is revolutionizing the field of cancer therapy, the traditional trial design is also undergoing changes.…”