High HER2 Expression Correlates with Response to the Combination of Lapatinib and Trastuzumab

Abstract

Purpose: Expression of p95HER2 has been associated with resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Conversely, high levels of HER2 have been linked with increased clinical benefit from anti-HER2 therapy. In this work, we aimed to investigate whether the levels of p95HER2 and HER2 can predict response to anti-HER2 therapy in patients with breast cancer.Experimental Design: We measured p95HER2 and HER2 by VeraTag and HERmark, respectively, in primary tumors of patients enrolled in the neoadjuvant phase III study NeoALTTO and correlated these variables with pathologic complete response (pCR) and progression-free survival (PFS) following lapatinib (L), trastuzumab (T), or the combination of both agents (LþT).Results: A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) in which quantification of both markers was possible. High levels of these markers were predictive for pCR, especially in the hormone receptor (HR)-positive subset of patients. High HER2 expression was associated with increased pCR rate upon LþT irrespective of the HR status. To examine whether the levels of either p95HER2 or HER2 could predict for PFS in patients treated with lapatinib, trastuzumab or LþT, we fit to the PFS data in Cox models containing log 2 (p95HER2) or log 2 (HER2). Both variables correlated with longer PFS.Conclusions: Increasing HER2 protein expression correlated with increased benefit of adding lapatinib to trastuzumab. HER2 expression is a stronger predictor of pCR and PFS than p95HER2 for response to lapatinib, trastuzumab and, more significantly, LþT.

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“…Generally, EGFR levels or gene amplification status fail to predict response to EGFR-targeted agents across indications, which is in contrast to, e.g., HER2 and MET, where gene amplification status correlates well with response to targeted agents (21,22). The reason for this difference is currently unknown.…”

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Recent Progress in HER2 Associated Breast Cancer

“…Joyfully, about the mutant mechanism, researchers newly reported a case that a breast cancer patient harboring an activating EGFR mutation clinically benefiting from EGFR-targeted treatment (Ali et al, 2014). The immune way ADCC (Nahta, 2012) multiple mAbs HER2 internalization (Ben-Kasu et al, 2009) anti-HER2 vaccine Peptide-based/DNA-based/ anti-idiotypic (Cao et al, 2013;Tagliabue and Campiglio, 2014) Trastuzumab mitogenic signaling (Schroeder et al, 2014;Kawajiri et al, 2015) ADCC 188Re-labeled HYNIC-trastuzuma radioactivity dose-dependent fashion (Luo et al, 2015) 64Cu-DOTA-trastuzumab metastatic breast cancer (Mortimer et al, 2014) Trastuzumab resistance Upregulation of HER3 (Nahta, 2012;Brady et al, 2014;Rimawi et al, 2014;Zang et al, 2014;Nam et al, 2015) miRNAs (miRNA-21, miR-7, miR-200c) (Bai et al, 2014;Chen and Bourguignon, 2014;Huynh and Jones, 2014; H E R 2 c o p y n u m b e r / dimerization status Interaction between HER2 and other ERBB (Lee et al, 2015) autophagy (Yeh et al, 2014) Anthracyclines HER2/TOP2A (Fountzilas et al, 2012) S-222611 ERBB family dimmers (Spicer et al, 2015) NCT Increase pCR rates (Shinde et al, 2015) Flotillin reduction of ErbB2-ErbB3 (Asp and Pust, 2014) CC apoptosis/ proliferation (Khan et al, 2015) Taspase1 Cyclins E, A, and B (Dong et al, 2014) Combined therapy Trastuzumab, carboplatin, paclitaxel (Shinde et al, 2015) Trastuzumab, MK-2206 (Hudis et al, 2013) Trastuzumab, lapatinib (Rimawi et al, 2014;Scaltriti et al, 2014;Schroeder et al, 2014) lapatinib , BYL719 (Brady et al, 2014) AZD8931, paclitaxel (Kurata et al, 2014) Hsp90, laptinib ( …”

“…also takes a large part (Schroeder et al, 2014), but this can be reversed by a p110a-Selective PI3K inhibitor (Brady et al, 2014). if not for the resistance, high expression of HER2 have a significantly higher probability to achieve benefit from the combination of trastuzumab and lapatinib (Scaltriti et al, 2014). Several recent studies indicate that activation of autophagy, which itself is closely connected to signaling crosstalk to apoptotic pathways, and therefore influences tumor cell survival contributes to trastuzumab and lapatinib resistance.…”

“…Dual HER2-targeting with lapatinib. (a dual reversible tyrosine kinase inhibitor targeting the cytoplasmic domain of EGFR and HER2) and trastuzumab (Rimawi et al, 2014;Scaltriti et al, 2014;Schroeder et al, 2014), with the fomer increasing HER3 expression followed HER2 inhibition, would also be superior to trastuzumab alone. while the lapatinib plus BYL719 combination can overcome acquired lapatinib resistance of breast cancer cells with simultaneous PIK3CA mutation and amplification (Brady et al, 2014).…”