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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Renata Duchnowska1, Jeff Sperinde2, Bogumiła Czartoryska-Arłukowicz3, Paulina Myśliwiec4, John Winslow2, Barbara Radecka5, Christos Petropoulos2, Regina Demlova6, Marlena Orlikowska7, Anna Kowalczyk8, Istvan Lang9, Barbara Ziółkowska10, Sylwia Dębska-Szmich11, Monika Merdalska12, Aleksandra Grela-Wojewoda13, Anton Żawrocki8, Wojciech Biernat8, Weidong Huang2 and Jacek Jassem8
1Military Institute of Medicine, Warsaw, Poland
2Monogram Biosciences, Integrated Oncology, Laboratory Corporation of America® Holdings, South San Francisco, CA, USA
3Białystok Oncology Center, Białystok, Poland
4Oncology Center, Zielona Góra, Poland
5Opole Oncology Center, Opole, Poland
6Masaryk Memorial Cancer Institute, Brno, Czech Republic
7Warmia and Masuria Oncology Center, Olsztyn, Poland
8Medical University of Gdańsk, Gdańsk, Poland
9National Institute of Oncology, Budapest, Hungary
10Regional Hospital, Wrocław, Poland
11Medical University of Łódź, Łódź, Poland
12Oncology Center, Kielce, Poland
13Oncology Institute, Kraków, Poland
Jacek Jassem, email: [email protected]
Keywords: breast cancer; trastuzumab; lapatinib; HER2; p95HER2
Received: August 13, 2017 Accepted: September 21, 2017 Published: October 24, 2017
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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