Abstract
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.
Highlights
Lapatinib is a HER1 and HER2 tyrosine kinase inhibitor (TKI) first approved for treatment of advanced or metastatic breast cancer patients that had progressed on trastuzumab-containing therapy [1]
We examined the association between lapatinib efficacy and downstream signaling markers, including phosphorylated adenosine monophosphate-activated protein (p-AMPK), phosphorylated mitogen-activated protein kinase (p-MAPK), phosphorylated p70 S6 kinase (p-p70S6K), hypoxia-inducible factor 2 alpha (HIF-2α), cyclin E, phosphatase and tensin homolog (PTEN), and estrogen receptor alpha (ERɑ) [14]
Quantitative HER2, HER3 and p95HER2 protein expression was measured in FFPE samples obtained from the primary tumors of 189 patients treated with lapatinib plus capecitabine following progression on trastuzumab (Table 1)
Summary
Lapatinib is a HER1 (human epidermal growth factor receptor type 1) and HER2 (type 2) tyrosine kinase inhibitor (TKI) first approved for treatment of advanced or metastatic breast cancer patients that had progressed on trastuzumab-containing therapy [1]. Little is known about the factors that may cause sensitivity or resistance to lapatinib beyond HER2 status [2, 3]. Several biomarkers and clinical variables have been investigated, including serum HER2 extracellular domain [4, 5], p95HER2 truncated form of HER2 [6, 7] activation of the PI3K/AKT pathway [8], EGFR gene copy number [9], intrinsic breast cancer subtypes [10] and time to progression to first line trastuzumab [11], but none have found application in clinical practice.
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