Pi3k Upregulation As A Negative Predictive Factor Of Survival In Her2 Amplified Gastric Cancer Treated With Trastuzumab.

e15567 Background: Use of Trastuzumab accrues significant clinical benefit in the HER2 positive metastatic Gastric Cancer (GC) population. However, many patients do not respond to therapy or develop refractory disease. The identification of potential mechanisms of Trastuzumab resistance may provide a rationale for the development of more effective targeted therapies. Upregulation of the PI3K pathway has been noted as a molecular mechanism of resistance in breast cancer. Our aim was to determine if PI3K activated pathway determined by PTEN loss and/or PI3KCA mutation could be used as a negative predictive factor in a HER2amplified metastatic GC cohort treated with Trastuzumab. Methods: Forty-two formalin-fixed paraffin embedded HER2 amplified GC samples from patients (pts) treated with Trastuzumab-based 1stline chemotherapy were selected. PTEN expression was analyzed with immunohistochemistry and DNA samples were sequenced with the Ion AmpliSeq Cancer Hotspot Panel v2, using the Ion Torrent Personal Genome Machine (PGM) sequencing platform (Life Technologies, Carlsbad, CA, USA). Results: We found PI3K pathway activation in 40.5% (n = 17) of pts: PTEN loss was found in 33.3% (n = 14) and PI3KCA mutation in 11.9% (n = 5). The Kaplan-Meier survival curves displayed a statistically significant difference in overall survival (OS) according to the PI3K pathway status: median OS was 19.5 months in pts without PI3K activation and 14.9 months in pts with PI3K activation (log-rank test, p = 0.042). Cox regression analysis estimated that the PI3K upregulated group had a higher likelihood of death (hazard ratio 2.06, CI 95% 1.01 to 4.20, p = 0.046). After adjustment for RAS and other tyrosine kinase receptors (TKR) alterations, the PI3K status remains as a negative predictive factor only in the non-activated RAS/TKR group (median OS 14.3 vs 19.5 months in patients without PI3K activation, log-rank test, p = 0.047). Conclusions: PI3K pathway activation could be used as a predictive marker for worse outcome in patients with HER2 amplified metastatic gastric cancer treated with trastuzumab. In addition, co-activation of RAS and other TKR in this subgroup may influence the survival benefit of Trastuzumab.