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Molecular characterization of HER2-positive (HER2+) metastatic gastric and gastro-esophageal junction cancer patients (mGC): Identification of resistance mechanisms to trastuzumab-based therapy (TTZ)

Date

08 Oct 2016

Session

Poster Display

Presenters

Maria Alsina

Citation

Annals of Oncology (2016) 27 (6): 207-242. 10.1093/annonc/mdw371

Authors

M. Alsina1, C. Hierro2, J. Sastre3, R. Guardeño4, C. Lopez5, E. Pineda6, E. Aranda7, J.L. Manzano8, M. Galán9, F. Longo10, L. Visa11, S. Landolfi12, J. Jimenez13, J. Sperinde14, A. Pandiella15, J. Tabernero1, J. Hernandez-Losa12, J. Arribas13, M. Scaltriti16, P. Nuciforo17

Author affiliations

  • 1 Medical Oncology, Vall Hebron University Hospital and VHIO-Vall d’Hebron Institute of Oncology, 08035 - Barcelona/ES
  • 2 Medical Oncology, Vall Hebron University Hospital and VHIO-Vall d’Hebron Institute of Oncology, Barcelona/ES
  • 3 Oncology Department, Clínico San Carlos Hospital, Madrid/ES
  • 4 Medical Oncology, Catalan Institute of Oncology (ICO)-Hospital Universitari Josep Trueta, Girona/ES
  • 5 Medical Oncology, Hospital Universitario Marques de Valdecilla, Santander/ES
  • 6 Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona/ES
  • 7 Medical Oncology, Reina Sofía Hospital, University of Córdoba, Maimonides Institute of Biomedical Research (IMIBIC). Spanish Cancer Network (RTICC), Instituto de Salud Carlos III,, 14004 - Cordoba/ES
  • 8 Medical Oncology, Catalan Institute of Oncology (ICO Badalona), Hospital Germans Trias i Pujol, Badalona/ES
  • 9 Medical Oncology, Institut Català d'Oncologia Hospital Duran i Reynals, Barcelona/ES
  • 10 Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid/ES
  • 11 Department Medical Oncology, University Hospital del Mar, 08003 - Barcelona/ES
  • 12 Pathology, Vall d`Hebron University Hospital Institut d'Oncologia, 08015 - Barcelona/ES
  • 13 Molecular Oncology Group, Vall d’Hebron Institute of Oncology, 08035 - Barcelona/ES
  • 14 Laboratory Corporation Of America Holdings, Monogram Biosciences, San Francisco/US
  • 15 Pathology, Centro de Investigación del Cáncer-IBMCC University of Salamanca-CSIC, Salamanca/ES
  • 16 Pathology, Memorial Sloan-Kettering Cancer Center, New York/US
  • 17 Molecular Oncology Group, Vall d’Hebron Institute of Oncology, Barcelona/ES
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Resources

Abstract 4014

Background

mGC represents the 3rd leading cause of cancer death worldwide. Chemotherapy is efficient but limited, overall survival (OS) of mGC patients (pts) remains poor. Almost 40% of them harbor ERK and PIK3CA-pathway gene amplifications (amp). HER2+ mGC patients benefit from TTZ, however response is seen in 

Methods

We analyzed baseline biopsies of 105 HER2+ mGC pts from 10 Spanish hospitals. All pts received TTZ. Median follow up was 13 months (m), 22m for alive pts. We evaluated Cyclin E/D1 and PIK3CA amp (Fluorescence In Situ Hybridation), expression of cyclin E/D1, PTEN, HER3 and p95HER2 (Immunohistochemistry-IHC), HER2 and p95HER2 quantification (VeraTag® fluorescence assays), and PIK3CA mutations (mut) (Sanger sequencing).

Results

The median age of pts was 65 years (63-67), 75% men. Location of primary tumor was gastric (57%) and gastro-esophageal (43%). The most common histologies were intestinal (74%) and diffuse (13%). Predominant metastatic locations were liver (33%), lymph nodes (30%), peritoneum (14%) and lung (10%). Median OS was 12.8m (10.6-15.4). Median progression-free survival was 7.3m (6.7-7.9). Amp (gene/CEP ≥2) were found in cyclin E (21%) and cyclin D1 (15%). A positive correlation between amp/overexpression was detected for cyclin E (p 

Conclusions

To our knowledge, this is the largest molecular characterization of HER2-positive mGC pts. Whereas levels of HER2 have been associated with intrinsic sensitivity to TTZ, cyclin E amp/overexpression has been described as a TTZ resistance mechanism in breast cancer. Final survival analysis will shed light of the real role of these molecular alterations in HER2+ mGC.

Clinical trial identification

Legal entity responsible for the study

VHIO Vall d'Hebron University Institute of Oncology

Funding

VHIO Vall d'Hebron University Institute of Oncology

Disclosure

J. Tabernero: Consultant/Advisory role: Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, Sanofi, Symphogen, Takeda, Taiho. All other authors have declared no conflicts of interest.

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