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

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.