Data from eight breast cancer genome sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized thirteen HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGFR exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings demonstrate that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.

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Introduction: Glioblastoma is the most common primary brain tumor in adults. Standard of care includes maximal surgical resection of the tumor followed by concurrent chemotherapy and radiation. The treatment of glioblastoma must account for an increased disease severity and treatment intensity compared to other cancers which places a significant cost burden on the patient and health system. Cost assessments of glioblastoma treatment have been sparse in comparison to other solid cancer subtypes. This study evaluates all current available cost literature with an emphasis on the modern treatment paradigm to properly assess the economic implications of this disease.Methods: A critical review of 21 studies from 13 different countries measuring direct costs related to glioblastoma management was performed. Evaluated data included itemized costs, total costs of treatment regimens from diagnosis until death, the cost of second-line care after recurrence, and the incremental costs and cost-effectiveness of emerging therapies.Results: The average cost of a craniotomy was $10,042 across studies. Imaging for the duration of glioblastoma care had a mean cost of $2,788±3,719. Studies examined different combinations of treatment modalities. Utilization of the modern treatment paradigm led to a survival of 16.3 months across studies and had a mean cost of $62,602. Surgery for recurrent disease had an average cost of $27,442±18,992.Limitations and Conclusions: Direct cost estimates for glioblastoma varied substantially between institutions and countries and often failed to uniformly describe direct cost estimates associated with care for glioblastoma. The limitations of these studies make true economic assessment of standards of care, costs of recurrence, and incremental costs associated with adjunctive therapy uncertain.

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