Celebrating the 10th Anniversary
A decade of discoveries in Cancer Discovery. For the community. By the Community.
Their impactful studies. In their words.
Three clinical trials were conducted based on this publication: MutHER phase II (led by Cynthia Ma), SUMMIT Basket, and PlasmaMATCH. All 3 clinical trials have shown that neratinib has good clinical efficacy for patients with HER2-mutated, metastatic breast cancer. Further, ongoing clinical trials are testing neratinib drug combinations to increase the clinical efficacy and improve outcomes for these patients.
Activating HER2 Mutations in HER2 Gene Amplification Negative Breast Cancer
Q: What unanswered questions in the field was this study addressing?
A: (Ron Bose) When the study was started, there was no information if HER2 missense mutations were drivers for breast cancer. Our study was the first to show that these HER2 mutations were activating mutations and were druggable with an oral tyrosine kinase inhibitor, neratinib.
A: (Matthew J. Ellis) Before this paper, HER2 mutations were not a recognized therapeutic target in breast cancer, only HER2 gene amplification. The demonstration that HER2 mutations without amplification are recurrent and constitutively activate HER2 was therefore novel and impactful. In the paper we demonstrated that cell growth driven by mutationally activated HER2 can be inhibited with neratinib, raising a new therapeutic hypothesis. While these mutations occurred in less than 5% of metastatic cases overall, breast cancer is so common that we proposed that thousands of patients must have HER2-mutant driven disease and could therefore benefit from this discovery.
Q: What surprised or excited you most about the findings?
A: (Ron Bose) The dogma in the breast cancer field had been that HER2 is only amplified and overexpressed in breast cancer, not mutated. That conclusion was based on Sanger sequencing data, performed in the late 1980s and 1990s. With the advent of next-generation sequencing (NGS), we found that patients who tested HER2 “negative” by routine pathology criteria could occasionally have a HER2 activating mutation identified by NGS testing and potentially were candidates for existing anti-HER2 drugs.
A: (Matthew J. Ellis) A new and straightforward therapeutic hypothesis in breast cancer is always welcome and exciting. We, and subsequently several other groups, were able to rapidly translate this finding into clinical trials as neratinib was readily available for clinical investigation. Most cases occur in ER+ breast cancer, with a clear signal that HER2 mutations are associated with lobular carcinoma and are likely more common in advanced disease.
Q: What has been the paper’s greatest impact in the years that followed?
A: (Ron Bose) Three clinical trials were conducted based on this publication: the MutHER phase II clinical trial (led by Cynthia Ma), the SUMMIT Basket Trial, and the PlasmaMATCH trial. All 3 clinical trials have shown that neratinib has good clinical efficacy for patients with HER2-mutated, metastatic breast cancer. Further, ongoing clinical trials are testing neratinib drug combinations to increase the clinical efficacy and improve outcomes for these patients.
A: (Matthew J. Ellis) All studies subsequently showed neratinib in combination with fulvestrant to target coexpressed ER is clinically active. Currently the highest clinical activity is observed with a combination of trastuzumab and neratinib. The diagnosis of HER2-mutant breast cancer is now straightforward with the development of circulating tumor DNA sequencing. It does seem likely that targeting HER2 mutations will become an approved treatment in the near future.