Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma.
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.
MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
Nadeera
N
De Silva
MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
Laura
L
Schulz
MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
Anna
A
Paterson
Cambridge Clinical Trials Unit, Coton House, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.
Wendi
W
Qain
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Maria
M
Secrier
Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
Edmund
E
Godfrey
Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
Heok
H
Cheow
Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
Maria
M
O'Donovan
MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
Pierre
P
Lao-Sirieix
Glaxosmithkline, Stevenage SG1 2NY, UK.
Minesh
M
Jobanputra
University College Hospital, 235 Euston Road, London NW1 2BU, UK.
Daniel
D
Hochhauser
MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
Rebecca
R
Fitzgerald
Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
Hugo
H
Ford
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004943:Esophagogastric Junction / Q000187:drug effects; D005260:Female; D006801:Humans; D000077341:Lapatinib; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D040901:Proteomics / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C491743:MET protein, human