Purpose: The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2þ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ERþ/HER2þ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib. Experimental Design: Mice with established ERþ/HER2þ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab pertuzumab for 4 weeks, and then randomized to fulvestrant neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses. Results: Mice receiving "extended adjuvant" therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ERþ/ HER2þ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ERþ/HER2 MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ERþ/HER2þ breast cancer cells. Conclusions: These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ERþ/HER2þ breast cancer.
ASJC Scopus subject areas
- Cancer Research