Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039)

Abstract

Purpose: Not all breast cancers respond to lapatinib. A change in Ki67 after short-term exposure may elucidate a biomarker profile for responsive versus nonresponsive tumors.Experimental Design: Women with primary breast cancer were randomized (3:1) to 10 to 14 days of preoperative lapatinib or placebo in a multicenter phase II trial (ISRCTN68509377). Biopsies pre-/posttreatment were analyzed for Ki67, apoptosis, HER2, EGFR, ER, PgR, pAKT, pERK, and stathmin by IHC. Further markers were measured by RT-PCR. Primary endpoint was change in Ki67. HER2þ was defined as 2þ/3þ by IHC and FISH þ . Results: One hundred twenty-one patients (lapatinib, 94; placebo, 27) were randomized; of these, 21% were HER2 þ , 78% were HER2 À nonamplified, 26% were EGFR þ . Paired samples containing tumor were obtained for 98% (118 of 121). Ki67 fell significantly with lapatinib (À31%; P < 0.001), but not with placebo (À3%). Whereas Ki67 reduction with lapatinib was greatest in HER2 þ breast cancer (À46%; P ¼ 0.003), there was a significant Ki67 decrease in HER2 À breast cancer (À27%; P ¼ 0.017) with 14% of HER2 À breast cancer demonstrating !50% Ki67 reduction with lapatinib. Among HER2 þ patients, the only biomarker predictive of Ki67 response was the EGFR/HER4 ligand epiregulin (EREG) (rho ¼ À0.7; P ¼ 0.002). Among HER2 À tumors, only HER3 mRNA levels were significantly associated with Ki67 response on multivariate analysis (P ¼ 0.01). In HER2 À breast cancer, HER2 and HER3 mRNA levels were highly correlated (rho ¼ 0.67, P < 0.001), with all Ki67 responders having elevated HER3 and HER2 expression. See related commentary by Campbell and Moasser, p. 2886 IntroductionLapatinib is a tyrosine kinase inhibitor (TKI) of both the epidermal growth factor receptor (EGFR, HER1) and human epidermal growth factor receptor-2 (HER2), which is an FDAapproved and commonly used drug in patients with HER2-positive (HER2 þ ) breast cancer (1-3). Targeting this drug to the most appropriate subset of breast cancer patients depends on a full understanding of the molecular determinants of response. Although HER2 overexpression [3þ by immunohistochemistry (IHC)] or amplification is an important predictor of response to lapatinib, it may not be the only requirement. EGFR (HER1) protein expression by IHC has not been shown to correlate with response to lapatinib (4), whereas the sensitizing EGFR gene mutations described in other tumor types (5) have not been reported in breast cancer. Either moderate levels of HER2 expression in the absence of gene amplification, the expression of other HER partners (i.e., EGFR, HER3), elevated levels of HER ligands, or activation of downstream effectors such as AKT and ERK could all be relevant to lapatinib responsiveness in breast cancer. As such, these additional biomarkers potentially could identify a subset of HER2 À nonamplified tumors that might respond to an EGFR/HER2 TKI. Changes in the marker of cell proliferation as determined by Ki67 following 2 weeks of treatment have been shown to predict recurrence-fre...

HER2-HER3 dimer quantification by FLIM-FRET predicts breast cancer metastatic relapse independently of HER2 IHC status

“…Figure 3 demonstrates that mRNA levels of HER2 and HER3 were positively correlated amongst HER2 negative tumors, consistent with findings published from the MAPLE study [38]. However, samples with high FRET efficiency (red circles) were not restricted to samples with high HER2 and HER3 mRNA levels, consistent with our finding that HER2 protein levels were not correlated with HER2-HER3 dimerization as measured by FRET efficiency.…”

“…Some clinical studies have shown that HER2 overexpressing breast cancers are more likely to respond to lapatinib yet a small group of patients with normal or absent levels of HER2 can potentially also benefit from this treatment [52]. Other recent studies also suggest that some HER2 negative tumors can gain moderate benefit from trastuzumab treatment although robust biomarkers are needed for this indication (NSABP B-47) [53].…”

Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells

“…The CELx test results with exogenous ligand equally applied to all samples suggest that there are other more systemic causes besides abundance of ligand. Other published work proposes elevated HER3 expression in HER2-negative cancers as leading to abnormal signaling in HER2 negative patients [8]. Several authors propose increased expression of HER2 in cancer stem cells to explain HER2– patient abnormal signaling or responsiveness to HER2-targeted therapy [63, 64].…”

BGRMI: A method for inferring gene regulatory networks from time-course gene expression data and its application in breast cancer research

“…3C). In Liu et al .’s study57, SIX5 expression had a statistically significant association with the response of cancer cells to the HER2 inhibitor Lapatinib (p-value 0.014 ) and the MEK inhibitor PD-0325901 (p-value 0.0184 ), both of which inhibit proliferation in cancer cells5859. The expression of CHD2, a chromatin remodeller, did not correlate with BC patient survival.…”