Relationship in gene amplification between <i>ERBB2</i> and other oncogenes: Implications for the therapeutic efficacy of trastuzumab (Tmab)-based chemotherapy (CTx) in HER2 positive gastric cancer.

468 Background: This study aimed to elucidate the molecular characteristics, focusing on the co-amplification of ERBB2 and other oncogenes, and to investigate their impact on treatment efficacy in HER2 positive GC. Methods: We conducted a phase 2 clinical trial (UMIN 00017602) evaluating the efficacy of S-1, oxaliplatin, and Tmab. Next-generation sequencing was performed using the TS-170 (Illumina). Results: 32 patients were enrolled, of whom 6 (19%) were IHC2+/FISH+. The median progression-free survival (PFS) and overall survival (OS) were 11.8 and 28.8 months. ERBB2 amplification with a cut-off value of 2.84 was present in 84.4% with a median copy number (CN) of 9.3 (range 2.4-76.6). Amplification of oncogenes other than ERBB2 , such as KRAS, FGFR2, MET, and CCNE1, was observed in 87.5%, and the median CN of the highest CNs among oncogenes other than ERBB2 was 7.8 (range 2.4-22.9). Eventually co-amplification was observed in 75%, and CNs of ERBB2 and other oncogenes showed an inverse correlation (r=0.345, p=0.058). In all tumors having ERBB2 CN ≥ 7.25 obtained by the ROC analysis, CN of ERBB2 was the highest among oncogenes ( ERBB2 dominant). Conversely, in 92% of the tumors having ERBB2 CNs &lt; 7.25, CNs of oncogenes other than ERBB2 was higher than ERBB2 ( ERBB2 non-dominant) (p&lt;0.001). Moreover, the highest CN of the oncogenes other than ERBB2 was higher in tumors with ERBB2 CNs &lt; 7.25 than that with ERBB2 CNs ≥ 7.25 (median 12.6 vs 6.4 p=0.018). Patients with ERBB2 non-dominant tumors showed significantly shorter PFS (median 6.9 vs 17.0 months, HR 6.40, p=0.001) and OS (median 14.8 vs 35.5 months, HR 2.72, p=0.016) and numerically lower response rate (63.6 vs 90.0%, p=0.151) compared with those with ERBB2 dominant tumors. Conclusions: Most patients had co-amplification of ERBB2 and other oncogenes, and the dominance of oncogene amplification in the tumor was associated with treatment efficacy of Tmab-based CTs in HER2 positive GC. These results suggest that the dominance of oncogene CNs within the tumor may determine tumor drivenness and influence treatment efficacy.