Cancer Genomics and Evolution

Overview Over 100 years ago, the Nobel Prize for Physiology and Medicine was given to Paul Ehrlich for postulating that “magic bullets” could specifically target and kill cells such as cancer cells based on their unique molecular features. The completed Human Genome Project and the cancer genomics revolution have now mapped many of the genetic changes underlying the unique features of common malignancies. Although cancer has long been recognized to be heterogeneous in its clinical presentation, course, pathology, and response to therapy, we now recognize that it is far more molecularly heterogeneous than anticipated and that such variability will require an individualized approach to patient care. Rather than a single magic bullet, we need an arsenal requiring precise delivery. While inter‐ and intratumoral genomic heterogeneity present significant challenges to cancer management and drug development, a number of developments foster hope for accelerated progress in the war on cancer. First, our catalogue of genomic targets underlying diverse cancers is rapidly growing. Second, we are beginning to understand how diverse mutations converge on a small number of druggable pathways. Third, we continue to develop drugs and biologic agents (e.g., immune checkpoint inhibitors) that target an increasingly diverse array of genomic subtypes of cancer. Finally, advances in “next‐generation” sequencing technologies now enable far earlier detection of disease and disease recurrence. This article focuses on these developments and how their integration is aiding in the precise delivery of “magic bullets.”