The addition of
trastuzumab to
chemotherapy regimen is the standard of care for
human epidermal growth factor receptor 2 (HER2)-positive advanced
gastric cancer; however, most patients eventually acquire
trastuzumab resistance. Although some resistance mechanisms to
trastuzumab-based regimens have been proposed, further understanding is required for developing therapeutic strategies to overcome the resistance. In the present work, we attempted to determine the possible resistance mechanism to
trastuzumab in a patient with HER2-positive stage IV gastric
adenocarcinoma. In this study, we first report the
nucleotide change c.1899-1G>A at the intron 15 acceptor splice site promoting exon 16 deletion of HER2 as the potential mechanism of
trastuzumab resistance in HER2-positive gastric
adenocarcinoma. KEY POINTS: The combination of
trastuzumab with
chemotherapy is considered to be the standard
therapy for HER2-positive advanced
gastric cancer (GC), but most of the patients eventually acquire
trastuzumab resistance. The mechanisms of resistance to
trastuzumab in GC are poorly characterized. To the best of the authors' knowledge, this study is the first to implicate HER2 c.1899-1G>A, which results in exon 16 skpping, as the acquired resistance mechanism to
trastuzumab in HER2-positive gastric
adenocarcinoma. This work provides insights into the potential molecular mechanism of
trastuzumab resistance, which is crucial in developing effective therapeutic strategies for HER2-positive GC patients refractory to
trastuzumab.