Celebrating the 10th Anniversary

A decade of discoveries in Cancer Discovery. For the community. By the Community.

Research

A New Opportunity for an Old Target

One of the earliest successes of precision medicine was the development of HER2-targeted therapy in the late 1990s for the approximately 20% of breast cancers with HER2 gene amplification resulting in HER2 protein overexpression. In 2013, Bose, Ellis, and colleagues identified rare somatic mutations in HER2 in breast cancers lacking HER2 gene amplification, most of which would have been considered HER2-negative based on immunohistochemistry and FISH. Functional characterization confirmed seven different mutants capable of activating HER2 signaling and promoting anchorage-independent growth and growth of tumor xenografts, suggesting that these were bona fide oncogenic drivers. Some of the HER2 mutants were sensitive to the reversible EGFR/HER2 kinase inhibitor lapatinib, but all seven mutants were sensitive to the irreversible EGFR/HER2 inhibitor neratinib. These findings suggested that the population of patients with breast cancer considered eligible for HER2-targeted therapy could be expanded, and in later years patients harboring HER2 mutations (ultimately found to represent up to 5% of patients with breast cancer) began to be included in clinical trials of HER2-targeted therapies. Moreover, subsequent identification of somatic HER2 mutations in gastric, lung, bladder, and other cancers led to the initiation of basket trials to evaluate HER2-targeted therapies such as kinase inhibitors (e.g., neratinib) and antibody–drug conjugates (e.g., trastuzumab deruxtecan) in a tissue-agnostic manner that led to responses in patients.

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