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, HER3 and HER4. HER2 containing heterodimer activates the common downstream of HER family such as MAPK pathway via RAS and PI3K pathway. RAS and PIK3CA mutations has been well known as predictive biomarkers for anti EGFR treatment in colorectal cancer and anti HER2 treatment in breast 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 treatments and mutational status of molecules in HER family signaling pathway.
Out of over 500 AGC between March 2011 and November 2015 we chose 100 patients (pts) received Fp plus CDDP with trastuzumab as 1st-line, finally total 77 pts with sufficient specimen for DNA extraction were enrolled in this analysis. Multiplex genotyping of common downstream in HER family 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. KRAS amplification was measured by quantitative real-time reverse transcription- polymerase chain reaction. The relative level of KRAS mRNA was normalized by HPRT-1 mRNA. We assessed the relationship between gene or mRNA status and clinical outcomes. Tumor response was re-assessed by the investigator retrospectively by RECIST1.1.
KRAS mutation of exon2 was detected in only 6 patients of 77 pts (7.8%). No mutations were found in NRAS, PIK3CA and BRAF in this HER2 positive AGC series. KARS amplification was detected in 16 pts (20.1%) (cut-off > 3.0). 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 low response rate and extremely shorter PFS and OS compared with KRAS WT. On the other hands, KRAS amplification did not affect the clinical outcomes.
Our data suggested HER2-positive AGC harbored KRAS mutation at the low frequency. KRAS mutation was strong prognostic and might predict the lack of benefit as receiving HER2 targeted treatment. Further investigation was warranted to confirm the predictive value of KRAS status in HER2-positive AGC receiving trastuzumab to fluoropyrimidine plus CDDP.
Clinical trial identification
Legal entity responsible for the study
Ethical Guidelines for Medical Research on Humans
Grant for research from Setsuro Fujii Memorial - The Osaka Foundation for Promotion of Fundamental Medical Research
E. Shinozaki: Honoraria from Taiho, Merck Serono, Takeda, Chugai, Yakult, Ono, Bayer and Lilly. All other authors have declared no conflicts of interest.