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What if every patient’s oncologist or lab testing personnel had access to an online digital encyclopedia of cancer mutations, associated therapies, and available clinical trials? Now they can, with The Clinical Knowledgebase (CKB), powered by The Jackson Laboratory (JAX). The advent of DNA sequencing enables identification of thousands of possible cancer-driving mutations in a tumor, while at the same time creating an information bottleneck. Trying to tease apart all these cancer mutations is a medical literature scavenger hunt that is both time- and labor-intensive in a constantly shifting landscape with hundreds of new papers published each day. CKB overcomes these barriers by providing a continuously updated genomic digital encyclopedia of cancer.
Despite the annual death rate from cancer decreasing over the last two decades, this devastating, heterogeneous disease remains the second leading cause of death in the United States, surpassed only by cardiovascular disease. Mainstream tools, such as next-generation sequencing (NGS) and other technologies, can reveal details of a patient’s genome, including disease-causing variants, which can provide insight into the selection of individualized cancer treatment. However, genomic data are complex and many types of variants exist, including multiple mutations, aberrant expression, copy number variations (CNVs), fusions, tumor mutational burden (TMB), and microsatellite instability (MSI). Some aberrations may be clinically significant while others are not, which adds to the challenge.
Many available resources that attempt to decipher and match genomic information to potential therapies are challenging to use for many reasons, including: disparate data sources may not contain the full complement of information; may not use standardized nomenclature; have inconsistent interpretations; or may not be up to date due to the rapidly expanding literature base and clinical trial landscape.
A Comprehensive Integrated Approach
CKB is specifically designed to give oncology clinicians, lab testing personnel, and researchers access to an up-to-date, standardized, curated database that can be used to probe complex molecular profiles and treatment response.1 Initially developed to address the bottleneck of data interpretation and communication to support JAX’s own in-house clinical genomics laboratory, this scalable, interpretative tool provides deep insight by allowing searches by gene, gene variant, drug, drug class, tumor type, and clinical trials.
Adopted by over 40,000 oncology stakeholders worldwide, CKB’s dynamic digital curation of data connects genomic variants to phenotype and protein effect, in addition to therapeutic relevance and potential treatment approaches. The result is timely, evidence-based information that removes the complexity of variant interpretations and improves the clinical decision-making process to the benefit of patients.
Due to the intricate network of heterogeneous and often discrepant available data, the CKB platform is professionally and rigorously “curated” in-house at JAX by a dedicated and experienced MD/PhD clinical scientific team to ensure data integrity and trustworthiness. To facilitate timely updates from current published findings extracted from about 4,000 biomedical journal papers daily, a Microsoft-driven AI system, Project Hanover2, is being implemented to scan, identify, and rank publications for curator review.
Standardization Eliminates Ambiguity
Built-in standardization protocols enable mapping and identification of clinically meaningful variants in a scalable and reproducible manner. All curated data are hyperlinked to the original data source. Each variant in CKB aligns to a common standard reference genome and includes all relevant corresponding technical information including protein domain, protein functional effect, and all variant reference transcripts, among other information. Biological classification (i.e., protein impact on function) of the variant is curated independently of the variant clinical classification (i.e., response to treatment).
As part of the standardization process, CKB strives to organize the data in a meaningful and user-friendly way. Using AMP/ASCO/CAP guidelines designed to help clinicians understand the significance of genomic findings, variants are automatically assigned a tier based on current clinical evidence. For example, tier 1 variants are those with strong clinical significance associated with FDA approval or professional guidelines. Furthermore, following strict SOPs, gene variants are built into complex molecular profiles and are curated to relevant efficacy evidence, gleaned from current published data and clinical trials. In cases of incomplete information, variant parent categories (e.g., EGFR mutation) are used to compile and accurately communicate potentially related evidence for the specific variant (e.g., EGFR C797S).
Daily updated data are easily searchable and can be filtered by a variety of options, including FDA-approved data, approved companion diagnostics, professional guidelines, clinical studies, and preclinical evidence. Treatment approaches provide actionable information on drug classes, and mono- or combination therapies—either FDA-approved, or currently in preclinical development or clinical trials. Forward-thinking flexibility built into the infrastructure of CKB allows for easy accommodation of new guidelines, genomic modalities, and clinical findings as they emerge.
Flexible Options for Use
CKB is available in three formats. CKB CORE™ provides free access to over 85 of the most highly-actionable genes with limited access to therapies, drug classes, and clinical trials. CKB BOOST™ subscription version provides web-based access for 1400+ genes with full access to therapies, drug classes, and clinical trials, along with variant tier coding and advanced search capabilities and content. Importantly, CKB BOOST curates detailed molecular eligibility criteria for targeted therapy and immunotherapy clinical trials, in addition to offering visuals for navigating and viewing aggregate CKB data. Subscribers to CKB BOOST utilize these features as a complement to their existing reporting systems. The third option, CKB FLEX™, has the same content as CKB BOOST, but enables scalable and flexible content integration in a plug-and-play model with third-party applications.
Identifying New Opportunities for Intervention
Published applications of CKB have demonstrated the need for stronger evidence supporting preclinical efficacy in order to identify the most appropriate therapeutic targets for clinical trial design, increase the number of productive trials, and identify potentially beneficial combinatorial therapies for resistant disease.
For example, Statz and colleagues used CKB to identify a class of targeted therapies for prostate cancer.3 Based on their analysis, a link was revealed between a loss of PTEN, a tumor suppressor, and the mTOR pathway. Although many trials investigating mTOR inhibition in prostate cancer were found, limited efficacy was identified and predicted when analyzing the retrospective preclinical data. Use of CKB pinpointed a need for clinical trials targeting both the PI3K and androgen receptor pathways.
In another study, Patterson and colleagues demonstrated the utility of CKB to associate data with complex profiles to illustrate the context-dependent impacts of sensitivity to various ALK inhibitors.4 By evaluating complex molecular profiles comprised of ALK fusions and missense mutations, the therapeutic efficacy in relation to resistance was effortlessly assessed. This study highlights the capabilities of CKB to quickly assess mutations that are potentially conferring resistance to targeted therapies in the context of sensitive genomic alterations. Instead of relying on traditional methods that would likely have two separate categories of response data, CKB brings together these data for straightforward query and retrieval. CKB’s complex profiles aid in patient stratification, clinical trial design, and analysis, thereby saving valuable time and resources.
These peer-reviewed, illustrative studies further validate the power of CKB to identify unique opportunities for clinical intervention based on a deep dive into molecular targets and therapies, and to uncover potential avenues for new research and development to advance cancer treatment.
CKB incorporates data interpreted by subject matter experts to relate cancer-associated genomic variants to therapeutic efficacy and clinical metadata. This effort further exemplifies JAX’s long-term, global commitment to innovation and empowers the global biomedical community in the shared quest to improve human health.
References
1. Patterson et al., Human Genomics (2016) 10:4 doi: 10.1186/s40246-016-0061-7
2. ia et al., (2019) arXiv:1904.02347v3
3. Statz et al., Target Oncol. 2017 Feb;12(1):47-59. doi: 10.1007/s11523-016-0453-6
4. Patterson et al., npj Precision Oncology (2019) 3:2; doi.org/10.1038/s41698-018-0073-y
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