Support systems to guide clinical decision making in precision oncology: The Cancer Core Europe Molecular Tumor Board Portal
To the Editor The optimal management of patients with cancer is increasingly dependent on individualized treatments guided by tumor sequencing data. As comprehensive genomic tests become routine in many disease settings and academic centers promote omics guided' recruitment into clinical trials, accurate and scalable data interpretation represents a major challenge. The meticulous task of matching tumor alterations with approved or experimental therapies relies heavily on the expertise of each center. Unsurprisingly, we see similar sequencing results leading to different clinical recommendations1. While the number of drug biomarkers with target specificities is constantly growing, these disparities are likely to escalate, which may ultimately impair patients' outcomes and research progress. Access to commercial test results does not simplify decision making, as such tests often deliver generic reports that lack the necessary information for prioritizing emerging therapies. In addition, data interpretation must also contend with incidental germline findings, which further complicates the process. Medical teams face the extra burden of manually searching for the latest scientific evidence associated with detected gene alterations, which is a complex, time consuming and error prone task. Here we argue for the need to streamline expert driven genomic data interpretation and reporting workflows and to employ user friendly decision support tools that foster interactive treatment planning. In response, we have developed the Molecular Tumor Board Portal (MTBP) a clinical decision support system that unifies the analysis of sequencing results across seven European comprehensive cancer centers under the umbrella of the Cancer Core Europe (CCE) network2. The portal is used to select candidates for the Basket of Baskets trial (NCT03767075) a modular multi arm study for genomically defined populations, as well as other clinical studies with active recruitment across CCE sites. Following a process agreed among CCE experts, the system automates omics' data capture, interpretation and reporting, and creates a framework with which to share and harness results (Fig. 1) MTBP reports are discussed at weekly virtual meetings during which multidisciplinary representatives from each CCE center decide on clinical interventions. These reports are patient centric web based documents with the annotations that support a given variant classification and the complete provenance of all assertions readily accessible through interactive elements. This approach, in contrast to 'black box' static documents, empowers intuitive decision making and case discussion, which may require an in depth revision of the available information. Variants of clinical interest, such as those that qualify for genetic counseling referral or clinical trial allocation, appear automatically flagged according to CCE predefined criteria. Oncologists acknowledge the advantages of reports that have a modern user interface design and that are systematically structured and tailored to the needs of ongoing clinical initiatives, in a system that enables sharing of the responsibility of treatment allocation with experts in a truly collaborative manner. Of note, we have observed a learning curve to use the portal that lasts for approximately 25 reviewed patients. After that, the amount of time devoted to discussing each patient's case (more than 500 at the time of this writing) rarely exceeds 4 minutes, which is key to scaling the process. A precision oncology decision support tool must give access to the latest clinical actionability evidence and computational analytical tools. Data interpretation can benefit from a variety of publicly available genomics resources, but as variant information exchange standards have not yet been adopted by the community3, the MTBP implements an extensive data format harmonization to ensure their accurate aggregation. We interpret the patient's germline and tumor variants in terms of both functional relevance and predictive relevance, two distinct and complementary analyses required for the full range of decision making of a molecular tumor board. First, the variants' functionality informs the need for genetic counseling referral when deleterious (pathogenic) germline events in actionable disease causing genes are detected4 6. Importantly, this analysis also provides the necessary information for matching of the patient to clinical trials with 'categorical' inclusion criteria those that rely on estimating the functional effect of variants observed in drug targets, such as 'activating' mutations in a given oncogene or 'loss of function' alterations of a tumor suppressor. The MTBP classifies a variant as functionally relevant by integrating up to date evidence from multiple expert curated knowledge bases, bona fide biological assumptions and bioinformatics predictions. Second, the predictive interpretation matches functionally relevant variants to biomarkers of disease diagnosis, prognosis and drug response reported at present7 9. In addition to on label prescribing, this informs off label and experimental drug opportunities to be considered according to current knowledge. Decision support tools are especially useful for target drug prioritization in complex molecular scenarios, such as tumors with co occurring alterations known to interact and modify the efficacy of a given drug. The portal ranks the variants' predictive relevance according to the Clinical Actionability of Molecular Targets scale of the European Society for Medical Oncology10, which factors in the scientific evidence that supports the biomarker effect and gene drug disease interactions. As a resource to investigators outside of our network, we recently launched an open access version of the MTBP genomics interpretation pipeline (https:/mtbp.org) which provides a general framework for classifying the functional and predictive relevance of a given list of variants. We believe that the adoption of cancer type focused treatment guidelines or access to medical records equipped with clinical pathways is insufficient to meet the full potential of omics guided' precision oncology. Instead, the use of standalone health technology tools that can provide patient centered predictive analyses that move beyond generic rules based criteria will be increasingly important. We advocate that decision support systems driven by academic networks such as the MTBP facilitate the cross institutional development of clinical trials and real world data
Nature Medicine