Trastuzumab targeted on HER2 has been shown to confer overall survival benefit adding to fluoropyrimidine (Fp) plus CDDP in HER2-positive advanced gastric cancer (AGC). HER2 is known to make the formation of heterodimer with EGFR(HER1), HER3 and HER4. HER2 containing heterodimer activates the common downstream of HER family such as MAPK pathway via RAS. RAS and BRAF status has been established as predictive biomarkers for anti EGFR treatment in metastatic colorectal cancer. However it remains unclear that the implications for these status and HER2 targeted treatment in AGC. In this study we attempted to assess the relationship with the efficacy of trastuzumab including treatment and mutational status of HER family signaling pathway.
Out of 100 patients received Fp plus CDDP with trastuzumab as 1st-line between March 2011 and November 2015, total 77 patients with sufficient specimen for DNA extraction were enrolled in this analysis. Multiplex genotyping of HER family common downstream was performed on archival samples using Luminex Assay (MEBGEN and GENOSEARCH Mu-PACK, MBL) for KRAS and NRAS including exon 2, 3 and 4, PIK3CA and BRAF. Tumor response was re-assessed by the investigator retrospectively by RECIST1.1.
KRAS mutation of exon2 was detected in only 6 patients of 77 patients (7.8 %). No mutations were found in NRAS, PIK3CA and BRAF in this HER2 positive AGC series. An overall RR and the disease control rate (DCR) in KRAS wild type (WT) vs. mutant type (MT) were following, RR; 66.2% vs. 16.7%, DCR; 87.3% vs. 66.7%, respectively (CR2/0, PR 45/1, SD 15/3, PD 9/2). The median PFS and OS in KRAS WT vs. MT were as followed, 8.9 months (m) vs. 3.6 m and 20.8 m vs. 10.3 m, respectively. KRAS MT showed extremely shorter PFS and OS compared with KRAS WT (P = 0.00008 and 0.0008).
Our data suggested HER2-positive AGC harbored KRAS mutation at the low frequency. KRAS mutation might predict poor prognosis as receiving HER2 targeted treatment. Further investigation was warranted to confirm the predictive value of KRAS status in HER2-positive AGC treated with trastuzumab to fluoropyrimidine plus CDDP. We will present additional analysis of KRAS amplification in this cohort at the convention.
Clinical trial identification
Legal entity responsible for the study
Japanese Foundation for Cancer Research
All authors have declared no conflicts of interest.