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The combination of next-generation sequencing and analysis as applied to experiments studying the cancer genome has revolutionized our understanding of cancer biology. Large-scale cancer genomics has further established a baseline that is now poised to effect the translation of cancer genomics into the clinical setting, effectively transforming patient care. The barriers and challenges to translation are significant, not the least of which involves the transition of research-grade computational and interpretational analysis to clinical-grade analysis. Assays must be highly refined, validated and accurate. How the use of genomic approaches to monitor patient response to therapy, the onset of acquired resistance to therapy and other aspects of patient care will be accepted as a more sensitive partner with conventional imaging approaches must be addressed. Appropriate assignment of therapies to specific gene/protein alterations also will be of paramount importance, especially as the numbers and types of targeted therapies increase. Genomics will also impact our understanding of the immune system's interaction with tumors, leading to the development of personalized vaccine strategies that may provide more durable responses.