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Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma.

Abstract：

BACKGROUND:Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo. METHODS:Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/- Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity. RESULTS:The trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules. CONCLUSIONS:Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

De Silva N,Schulz L,Paterson A,Qain W,Secrier M,Godfrey E,Cheow H,O'Donovan M,Lao-Sirieix P,Jobanputra M,Hochhauser D,Fitzgerald R,Ford H

doi

10.1038/bjc.2015.342

subject

Has Abstract

pub_date

2015-11-03 00:00:00

pages

1305-12

issue

eissn

0007-0920

issn

1532-1827

pii

bjc2015342

journal_volume

113

pub_type

临床试验,杂志文章,多中心研究

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Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma.