Health Economic Analysis in Glaucoma.

The pressure on glaucoma services is ever-growing, and policymakers seek robust cost-effectiveness arguments in their decisions around resource allocation. The benefits of glaucoma are in preventing or delaying a future loss of vision and associated quality of life, and this expectation is quantified using a metric called utility which can be compared against other disease states. In recent clinical trials lasting up to 3 years, it has been difficult to show a difference in utility between glaucoma treatments in this limited period of time. When it comes to cost, the direct medical costs are only part of the broad range of costs that glaucoma brings to patients and communities, and the estimation of these costs can be difficult and imprecise. While the cost-effectiveness of glaucoma care, in general, is not in dispute, especially over longer time frames, the inability to measure changes in utility in shorter time frames impedes the uptake of innovations around the world. A number of approaches to improve the sensitivity and specificity of utility measurements are under investigation.

A pathway-based approach for identifying biomarkers of tumor progression to trastuzumab-resistant breast cancer.

Although trastuzumab is a successful targeted therapy for breast cancer patients with tumors expressing HER2 (ERBB2), many patients eventually progress to drug resistance. Here, we identified subpathways differentially expressed between trastuzumab-resistant vs. -sensitive breast cancer cells, in conjunction with additional transcriptomic preclinical and clinical gene datasets, to rigorously identify overexpressed, resistance-associated genes. From this approach, we identified 32 genes reproducibly upregulated in trastuzumab resistance. 25 genes were upregulated in drug-resistant JIMT-1 cells, which also downregulated HER2 protein by >80% in the presence of trastuzumab. 24 genes were downregulated in trastuzumab-sensitive SKBR3 cells. Trastuzumab sensitivity was restored by siRNA knockdown of these genes in the resistant cells, and overexpression of 5 of the 25 genes was found in at least one of five refractory HER2 + breast cancer. In summary, our rigorous computational approach, followed by experimental validation, significantly implicate ATF4, CHEK2, ENAH, ICOSLG, and RAD51 as potential biomarkers of trastuzumab resistance. These results provide further proof-of-concept of our methodology for successfully identifying potential biomarkers and druggable signal pathways involved in tumor progression to drug resistance.