Data from Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER⁺/HER2⁺ Breast Cancers: Implications to the ExteNET Trial

• DOI: 10.1158/1078-0432.c.6529268.v1
• Publication Date: 2023-04-01T06:20:27Z
• Authors: Dhivya R. Sudhan; Luis J. Schwarz; Angel Guerrero-Zo...; Luigi Formisano; Mellissa J. Nixon; Sarah Croessmann; Paula I. González...; Melinda Sanders; Justin M. Balko; Francesca Avogadr...; Richard E. Cutler; Alshad S. Lalani; Richard Bryce; Alan Auerbach; Carlos L. Arteaga
• Keywords: Neratinib; Fulvestrant; Palbociclib; Pertuzumab

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