Thomas Kaley

PURPOSE: With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base. METHODS: OncoKB annotates the biological and oncogenic effect and the prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response based on US Food and Drug Administration (FDA) labeling, National Comprehensive Cancer Network (NCCN) guidelines, disease-focused expert group recommendations and the scientific literature. RESULTS: To date, over 3000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5983 primary tumor samples in 19 cancer types. Forty-one percent of samples harbored at least one potentially actionable alteration, of which 7.5% were predictive of clinical benefit from a standard treatment. OncoKB annotations are available through a public web resource (http://oncokb.org/) and are also incorporated into the cBioPortal for Cancer Genomics to facilitate the interpretation of genomic alterations by physicians and researchers. CONCLUSION: OncoKB, a comprehensive and curated precision oncology knowledge base, offers oncologists detailed, evidence-based information about individual somatic mutations and structural alterations present in patient tumors with the goal of supporting optimal treatment decisions.

Evolving interest in meningioma, the most common primary brain tumor, has refined contemporary management of these tumors. Problematic, however, is the paucity of prospective clinical trials that provide an evidence-based algorithm for managing meningioma. This review summarizes the published literature regarding the treatment of newly diagnosed and recurrent meningioma, with an emphasis on outcomes stratified by WHO tumor grade. Specifically, this review focuses on patient outcomes following treatment (either adjuvant or at recurrence) with surgery or radiation therapy inclusive of radiosurgery and fractionated radiation therapy. Phase II trials for patients with meningioma have recently completed accrual within the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer consortia, and Phase III studies are being developed. However, at present, there are no completed prospective, randomized trials assessing the role of either surgery or radiation therapy. Successful completion of future studies will require a multidisciplinary effort, dissemination of the current knowledge base, improved implementation of WHO grading criteria, standardization of response criteria and other outcome end points, and concerted efforts to address weaknesses in present treatment paradigms, particularly for patients with progressive or recurrent low-grade meningioma or with high-grade meningioma. In parallel efforts, Response Assessment in Neuro-Oncology (RANO) subcommittees are developing a paper on systemic therapies for meningioma and a separate article proposing standardized end point and response criteria for meningioma.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.