Predictive value of quantitative HER2, HER3 and p95HER2 levels in HER2-positive advanced breast cancer patients treated with lapatinib following progression on trastuzumab

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Authors

DUCHNOWSKA Renata SPERINDE Jeff CZARTORYSKA-ARŁUKOWICZ Bogumiła MYŚLIWIEC Paulina WINSLOW John RADECKA Barbara PETROPOULOS Christos DEMLOVÁ Regina ORLIKOWSKA Marlena KOWALCZYK Anna LANG Istvan ZIÓŁKOWSKA Barbara DĘBSKA-SZMICH Sylwia MENDALSKA Monika GRELA- WOJEWODA Aleksandra ŻAWROCKI Anton BIERNAT Wojciech HUANG Weidong JASSEM Jacek

Year of publication 2017
Type Article in Periodical
Magazine / Source Oncotarget
MU Faculty or unit

Faculty of Medicine

Citation
Web http://dx.doi.org/10.18632/oncotarget.22027
Doi http://dx.doi.org/10.18632/oncotarget.22027
Field Pharmacology and pharmaceutical chemistry
Keywords Breast cancer; HER2; Lapatinib; P95HER2; Trastuzumab
Description Lapatinib is a HER1 and HER2 tyrosine kinase inhibitor (TKI) approved in second line treatment of advanced or metastatic breast cancer following progression on trastuzumab-containing therapy. Biomarkers for activity of lapatinib and other TKIs are lacking. Formalin-fixed, paraffin-embedded primary tumor samples were obtained from 189 HER2-positive patients treated with lapatinib plus capecitabine following progression on trastuzumab. The HERmark® Breast Cancer Assay was used to quantify HER2 protein expression. HER3 and p95HER2 protein expression was quantified using the VeraTag® technology. Overall survival (OS) was inversely correlated with HER2 (HR = 1.9/log; P = 0.009) for patients with tumors above the cut-off positivity level by the HERmark assay. OS was significantly shorter for those with above median HER2 levels (HR = 1.7; P = 0.015) and trended shorter for those below the cut-off level of positivity by the HERmark assay (HR = 1.7; P = 0.057) compared to cases with moderate HER2 overexpression. The relationship between HER2 protein expression and OS was best captured with a U-shaped parabolic function (P = 0.004), with the best prognosis at moderate levels of HER2 protein overexpression. In a multivariate model including HER2, increasing p95HER2 expression was associated with longer OS (HR = 0.35/ log; P = 0.027). Continuous HER3 did not significantly correlate with OS. Patients with moderately overexpressed HER2 levels and high p95HER2 expression may have best outcomes while receiving lapatinib following progression on trastuzumab. Further study is warranted to explore the predictive utility of quantitative HER2 and p95HER2 in guiding HER2-directed therapies.
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