Research ArticleCancer

Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)

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Sci. Signal.  09 Oct 2018:
Vol. 11, Issue 551, eaat9773
DOI: 10.1126/scisignal.aat9773

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Neratinib for resistant metastatic breast cancer

Breast cancers with amplification or mutation in the epidermal growth factor receptor (EGFR) family member HER2 are usually treated with targeted inhibitors, but resistance is common. Amplification and mutation of HER2 are generally considered mutually exclusive occurrences in treatment-naïve patients. However, Cocco et al. discovered a small proportion of treatment-naïve and, more often, previously treated patients with metastatic breast cancer in which HER2 amplification and mutation were coincident. It is not yet clear why, but these co-amplified/mutant cells were resistant to currently approved HER2-specific and HER2/EGFR-specific inhibitors but were sensitive to the new pan-EGFR inhibitor neratinib. Neratinib, which inhibits EGFR and HER2, as well as HER3 and HER4, was more effective at blocking the activity of the EGFR pathway and other receptor tyrosine kinases, common modes of resistance in HER2-driven tumors. Patients and mice bearing their tumor cells showed improved survival and even tumor regression on neratinib, suggesting that this may be a treatment option for certain breast cancer patients.

Abstract

Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of “HER2-negative” (not ERBB2 amplified) tumors but are rare in “HER2-positive” (ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor. HER2 mutations were present in ~7% of HER2-positive tumors, all of which were metastatic but not all were previously treated. Compared to HER2 amplification alone, in both patients and cultured cell lines, the co-occurrence of HER2 mutation and amplification was associated with poor response to trastuzumab and lapatinib, the standard-of-care anti-HER2 agents. In mice, xenografts established from a patient whose HER2-positive tumor acquired a D769Y mutation in HER2 after progression on trastuzumab-based therapy were resistant to trastuzumab or lapatinib but were sensitive to neratinib. Clinical data revealed that six heavily pretreated patients with tumors bearing coincident HER2 amplification and mutation subsequently exhibited a statistically significant response to neratinib monotherapy. Thus, these findings indicate that coincident HER2 mutation reduces the efficacy of therapies commonly used to treat HER2-positive breast cancer, particularly in metastatic and previously HER2 inhibitor–treated patients, as well as potentially in patients scheduled for first-line treatment. Therefore, we propose that clinical studies testing the efficacy of neratinib are warranted selectively in breast cancer patients whose tumors carry both amplification and mutation of ERBB2/HER2.

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