Role of HER2-Related Biomarkers (HER2, p95HER2, HER3, PTEN, and PIK3CA) in the Efficacy of Lapatinib plus Capecitabine in HER2-Positive Advanced Breast Cancer Refractory to Trastuzumab

Nishimura, Reiki; Toh, Uhi; Tanaka, Maki; Saimura, Michiyo; Okumura, Yasuhiro; Saito, Tsuyoshi; Tanaka, Toshihiro; Teraoka, Megumi; Shimada, Kaoru; Katayama, Kazuhisa; Koga, Toshihiro; Kurashita, Kaname; Hasegawa, S.; Todoroki, Hidekazu; Kai, Yuichiro; Ohi, Yasuyo; Toyoshima, Satoshi; Arima, Nobuyuki; Mitsuyama, Shoshu; Tamura, Kazuo

doi:10.1159/000468521

Cited by 19 publications

(21 citation statements)

References 29 publications

(42 reference statements)

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“…Many studies did not find any demonstrable relationships between HER3 and patient survival [ 15 , 41 – 53 ]. Studies focusing on HER3 specifically in HER2 -amplified breast cancer [ 16 , 25 , 26 , 29 , 31 , 32 , 37 , 38 , 41 , 44 , 45 , 48 , 49 , 52 , 54 ] have not drawn conclusive results either. Interestingly, HER3 activation has been implicated as a molecular mechanism inducing inherent or acquired de novo resistance to anti-HER2 therapy [ 19 , 31 , 55 , 56 ].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological and prognostic correlations of HER3 expression and its degradation regulators, NEDD4–1 and NRDP1, in primary breast cancer

et al. 2018

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BackgroundHuman epidermal growth factor receptor HER3 (ErbB3), especially in association with its relative HER2 (ErbB2), is known as a key oncogene in breast tumour biology. Nonetheless, the prognostic relevance of HER3 remains controversial. NEDD4–1 and NRDP1 are signalling molecules closely related to the degradation of HER3 via ubiquitination. NEDD4–1 and NRDP1 have been reported to contribute to HER3-mediated signalling by regulating its localization and cell membrane retention. We studied correlations between HER3, NEDD4–1, and NRDP1 protein expression and their association with tumour histopathological characteristics and clinical outcomes.MethodsThe prevalence of immunohistochemically detectable expression profiles of HER3 (n = 177), NEDD4–1 (n = 145), and NRDP1 (n = 145) proteins was studied in primary breast carcinomas on archival formalin-fixed paraffin-embedded (FFPE) samples. Clinicopathological correlations were determined statistically using Pearson’s Chi-Square test. The Kaplan-Meier method, log-rank test (Mantel-Cox), and Cox regression analysis were utilized for survival analysis.ResultsHER3 protein was expressed in breast carcinomas without association with HER2 gene amplification status. Absence or low HER3 expression correlated with clinically aggressive features, such as triple-negative breast cancer (TNBC) phenotype, basal cell origin (cytokeratin 5/14 expression combined with ER negativity), large tumour size, and positive lymph node status. Low total HER3 expression was prognostic for shorter recurrence-free survival time in HER2-amplified breast cancer (p = 0.004, p = 0.020 in univariate and multivariate analyses, respectively). The majority (82.8%) of breast cancers demonstrated NEDD4–1 protein expression - while only a minor proportion (8.3%) of carcinomas expressed NRDP1. NEDD4–1 and NRDP1 expression were not associated with clinical outcomes in HER2-amplified breast cancer, irrespective of adjuvant trastuzumab therapy.ConclusionsLow HER3 expression is suggested to be a valuable prognostic biomarker to predict recurrence in HER2-amplified breast cancer. Neither NEDD4–1 nor NRDP1 demonstrated relevance in prognostics or in the subclassification of HER2-amplified breast carcinomas.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4917-1) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Clinicopathological and prognostic correlations of HER3 expression and its degradation regulators, NEDD4–1 and NRDP1, in primary breast cancer

et al. 2018

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“…Lapatinib is an orally available, small-molecule, reversible inhibitor of both EGFR and HER2 tyrosine kinases, and it has been approved for use in combination with capecitabine for the treatment of advanced HER2 -amplified breast cancer. 18 , 19 Additionally, it is reported that lapatinib has been used in the targeted chemotherapy for salivary ductal carcinoma with HER2 gene amplification. 20 It is necessary to elucidate the role of HER2 in tumor development and the mechanism by which lapatinib exerts effects on CXPA.…”

Section: Discussionmentioning

confidence: 99%

Human epithelial growth factor receptor 2 in human salivary carcinoma ex pleomorphic adenoma: a potential therapeutic target

Xia

Wang

et al. 2018

CMAR

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BackgroundTo inhibit human epithelial growth factor receptor 2 (HER2) in salivary carcinoma ex pleomorphic adenoma (CXPA) and investigate the effects on tumor cell proliferation, cell cycle, and apoptosis. To assess the possibility of blocking HER2 to improve the malignant biological behavior of CXPA.Materials and methodsHER2 expression and amplification were examined using an immunofluorescence assay and fluorescence in situ hybridization in 2 CXPA cell lines (SM-AP1 and SM-AP4 cells). The effects on tumor cell proliferation, cell cycle, apoptosis, and HER2 downstream pathways were verified after the application of a HER2 inhibitor.ResultsHER2 was overexpressed and amplified in SM-AP1 and SM-AP4 cell lines. After blocking HER2, the tumor proliferation and cell cycle were significantly induced, and the apoptosis process was activated. Moreover, the downstream pathways PI3K/AKT and MAPK/ERK were significantly inhibited.ConclusionHER2 was overexpressed and amplified in CXPA cell lines and might thus play an important role in tumor development. Inhibiting HER2 may be a novel targeted therapy for poor biological behavior of CXPA.

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“…Correlation of PFS with quantitative HER2, HER3 and p95HER2 expression has been examined in a similar cohort of trastuzumab-refractory patients treated with lapatinib and capecitabine [ 26 ]. No correlation with PFS was found for HER2 cutoffs, but a test for a potential U-shaped relationship with continuous HER2 was not performed.…”

Section: Discussionmentioning

confidence: 99%

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

Duchnowska

Sperinde

Czartoryska-Arłukowicz³

et al. 2017

Oncotarget

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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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Role of HER2-Related Biomarkers (HER2, p95HER2, HER3, PTEN, and PIK3CA) in the Efficacy of Lapatinib plus Capecitabine in HER2-Positive Advanced Breast Cancer Refractory to Trastuzumab

Cited by 19 publications

References 29 publications

Clinicopathological and prognostic correlations of HER3 expression and its degradation regulators, NEDD4–1 and NRDP1, in primary breast cancer

Clinicopathological and prognostic correlations of HER3 expression and its degradation regulators, NEDD4–1 and NRDP1, in primary breast cancer

Human epithelial growth factor receptor 2 in human salivary carcinoma ex pleomorphic adenoma: a potential therapeutic target

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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