Emergence of Mutation as a Biomarker and an Actionable Target in Solid Cancers.

The oncogenic role amplification is well established in breast and gastric cancers. This has led to the development of a well-known portfolio of monoclonal antibodies and kinase inhibitors targeting the ERBB2 kinase. More recently, activating mutations in the gene have been increasingly reported in multiple solid cancers and were shown to play an oncogenic role similar to that of amplification. Thus, mutations define a distinct molecular subtype of solid tumors and serve as actionable targets. However, efforts to target mutation has met with limited clinical success, possibly because of their low frequency, inadequate understanding of the biological activity of these mutations, and difficulty in separating the drivers from the passenger mutations. Given the current impetus to deliver molecularly targeted treatments for cancer, there is an important need to understand the therapeutic potential of mutations. Here we review the distribution of mutations in different tumor types, their potential as a novel biomarker that defines new subsets in many cancers, and current data on preclinical and clinical efforts to target these mutations. IMPLICATIONS FOR PRACTICE: A current trend in oncology is to identify novel genomic drivers of solid tumors and developing precision treatments that target them. amplification is an established therapeutic target in breast and gastric cancers, but efforts to translate this finding to other solid tumors with amplification have not been effective. Recently the focus has turned to targeting activating mutations. The year 2018 marked an important milestone in establishing mutation as an important actionable target in multiple cancer types. There have been several recent preclinical and clinical studies evaluating mutation as a therapeutic target with varying success. With increasing access to next-generation sequencing technologies in the clinic, oncologists are frequently identifying activating mutations in patients with cancer. There is a significant need both from the clinician and bench scientist perspectives to understand the current state of affairs for mutations.