Abstract
Tumor molecular profiling of single gene-variant (‘first-order’) genomic alterations informs potential therapeutic approaches. Interactions between such first-order events and global molecular features (for example, mutational signatures) are increasingly associated with clinical outcomes, but these ‘second-order’ alterations are not yet accounted for in clinical interpretation algorithms and knowledge bases. We introduce the Molecular Oncology Almanac (MOAlmanac), a paired clinical interpretation algorithm and knowledge base to enable integrative interpretation of multimodal genomic data for point-of-care decision making and translational-hypothesis generation. We benchmarked MOAlmanac to a first-order interpretation method across multiple retrospective cohorts and observed an increased number of clinical hypotheses from evaluation of molecular features and profile-to-cell line matchmaking. When applied to a prospective precision oncology trial cohort, MOAlmanac nominated a median of two therapies per patient and identified therapeutic strategies administered in 47% of patients. Overall, we present an open-source computational method for integrative clinical interpretation of individualized molecular profiles.
Highlights
Tumor molecular profiling of single gene-variant (‘first-order’) genomic alterations informs potential therapeutic approaches
We evaluated whether an expanded set of molecular features could further broaden the actionability landscape for individual patients (Fig. 2b,d)
We present a clinical interpretation method paired with a new knowledge base to facilitate decision making in precision oncology
Summary
BRCA2 variant, p.S1882*, was observed in one patient along with a 39% mutational signature attribution to COSMIC signature 3, both of which may suggest homologous-recombination repair deficiency and sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition[31,32,33] By considering these feature types, MOAlmanac identified an additional 557 clinically relevant molecular features in 329 patients, resulting in 395 patients with at least one event associated with therapeutic sensitivity, resistance, or prognosis (Fig. 3). FDA-approved or clinical-guideline associations resulted in a highlighted therapy for 235 of 419 patients (79 with melanoma, 109 with mCRPC, 36 with KIRP, and 11 with OS); 16 patients obtained a therapeutic hypothesis from feature types other than somatic variants and copy number alterations, such as pathogenic BRCA2 germline variants (two patients) or NTRK fusions (one patient).
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