Genetic mutations linked to treatment outcomes in dogs

Abstract

Splenic hemangiosarcoma (HSA) is a common canine tumor with histology and genetics analogous to human angiosarcoma (AS), a rare and aggressive malignancy arising from vascular cells. To assess biomarkers and inform therapeutics options, spontaneously arising HSAs were systematically profiled for genetic mutations prior to long-term assessment of patient response to chemotherapy and/or targeted therapy. We leveraged the real-world clinical-genomic data of dogs from the FidoCureplatform, a next-generation sequencing (NGS) screen of cancer loci. For all dogs, regardless of therapeutic approach, PTEN and P53 mutations were overall predictors of poor outcome, while NRAS mutation predicted better outcome. However, P53, PIK3CA, ATRX and NRAS predicted a better response to therapies that specifically included a targeted drug. Analyzing gene-drug interactions, we found tumors with P53 mutation were highly responsive to HDAC or MTOR inhibition, while tumors with PIK3CA mutation only predicted response to MTOR inhibition. For veterinarians, this real-world evidence bridges an important translational gap for targeted therapies, demonstrating a comparable or better outcome compared to standard adjuvant chemotherapy alone and an even further enhancement of survival with combined targeted therapy and chemotherapy. The investigation also uncovered a relationship between specific therapeutic interventions and outcomes when particular gene mutations were present, suggesting they could serve as biomarkers. Since canine HSA is a likely correlate for human AS, the study highlights the benefit of canine HSA as a model to inform precision medicine for AS, a rare human malignancy.