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Prognostic value of ErbB2/HER2 in human meningiomas.

ABSTRACT: INTRODUCTION:Among clinical challenges regarding human meningiomas is their propensity to recur even in cases with benign histology. Reliable biomarkers that can identify these cases are therefore highly desired. ErbB2/HER2 status is important in the medical management of patients with various human malignancies, whereas its clinical relevance in human meningiomas is ambiguous. For this reason, we wanted to investigate the expression of intra- and extracellular domains of ErbB2/HER2 as well as the level of activated receptor in these tumors. Further, we wanted to elucidate any clinicopathological associations to antibody expression and if gene amplification was present. METHODS:In total, 186 human meningiomas of all malignancy grades were included in the study, 163 of these were in tissue microarrays (TMA). Antibody expression was assessed by means of immunohistochemistry (IHC) and gene amplification by fluorescence in situ hybridization (FISH). RESULTS:All cases were immunoreactive with antibodies targeting the intracellular domain, whereas about 48% and 11% were positive with antibodies against the extracellular domain and against the activated receptor, respectively. Normal meninges were not immunoreactive. There were no relations to malignancy grade, and only the activated receptor was significantly correlated with increased risk for recurrence or death (time to recurrence: HR 1.568, CI (1.153 to 2.132), p = 0.004). No gene amplification was found. CONCLUSION:ErbB2/HER2 is generally upregulated in human meningiomas, but in an activated state only in a few cases. Only the activated receptor is associated with poorer prognosis, a link that needs further investigations.

SUBMITTER: Arnli MB

PROVIDER: S-EPMC6193666 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Prognostic value of ErbB2/HER2 in human meningiomas.

Arnli Magnus B MB Winther Theo L TL Lydersen Stian S Torp Sverre H SH

PloS one 20181018 10

<h4>Introduction</h4>Among clinical challenges regarding human meningiomas is their propensity to recur even in cases with benign histology. Reliable biomarkers that can identify these cases are therefore highly desired. ErbB2/HER2 status is important in the medical management of patients with various human malignancies, whereas its clinical relevance in human meningiomas is ambiguous. For this reason, we wanted to investigate the expression of intra- and extracellular domains of ErbB2/HER2 as w ...[more]

PMID: 30335819

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Project description:BackgroundMeningiomas are common intracranial tumors in humans that frequently recur despite having a predominantly benign nature. Even though these tumors have been shown to commonly express EGFR/c-erbB1 (epidermal growth factor receptor), results from previous studies are uncertain regarding the expression of either intracellular or extracellular domains, cellular localization, activation state, relations to malignancy grade, and prognosis.AimsThis study was designed to investigate the expression of the intracellular and extracellular domains of EGFR and of the activated receptor as well as its ligands EGF and TGFα in a large series of meningiomas with long follow-up data, and investigate if there exists an association between antibody expression and clinical and histological data.MethodsA series of 186 meningiomas consecutively operated within a 10-year period was included. Tissue microarrays were constructed and immunohistochemically analyzed with antibodies targeting intracellular and extracellular domains of EGFR, phosphorylated receptor, and EGF and TGFα. Expression levels were recorded as a staining index (SI).ResultsPositive immunoreactivity was observed for all antibodies in most cases. There was in general high SIs for the intracellular domain of EGFR, phosphorylated EGFR, EGF, and TGFα but lower for the extracellular domain. Normal meninges were negative for all antibodies. Higher SIs for the phosphorylated EGFR were observed in grade II tumors compared with grade I (p = 0.018). Survival or recurrence was significantly decreased in the time to recurrence analysis (TTR) with high SI-scores of the extracellular domain in a univariable survival analysis (HR 1.152, CI (1.036-1.280, p = 0.009)). This was not significant in a multivariable analysis. Expression of the other antigens did not affect survival.ConclusionEGFR is overexpressed and in an activated state in human meningiomas. High levels of ligands also support this growth factor receptor system to be involved in meningioma tumorigenesis. EGFR may be a potential candidate for targeted therapy.

Project description:BackgroundIdentification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.MethodsA research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated.ResultsA total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01).ConclusionsCombining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.

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Prognostic value of ErbB2/HER2 in human meningiomas.

Publications

Prognostic value of ErbB2/HER2 in human meningiomas.

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