Clinical significance of ERBB2 exon 16 skipping: analysis of a real-world retrospective observational cohort study

BACKGROUND: ERBB2 exon 16 skipping is an alternatively spliced isoform of ERBB2, which was reported to lead to oncogenic activation of ERBB2 and could potentially cause tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) in case studies. In this study, we aimed to evaluate the frequency of ERBB2 exon 16 skipping in a large patient cohort and its function in cancer development. METHODS: A total of 38 680 Chinese patients with cancer whose tumour specimens and/or circulating cell-free DNA underwent targeted nextgeneration sequencing of cancer-related genes were retrospectively reviewed. Clinicopathological features and treatment history of patients harbouring ERBB2 exon 16 skipping were evaluated. RNA-sequencing was performed to validate the presence of exon 16 skipping in ERBB2 at the transcriptional level. RESULTS: ERBB2 exon 16 skipping is rare and was identified in a total of 18 patients (0.046% of total patients), including 12 lung cancers, which were caused by large fragment deletion spanning the whole or partial region of exon 16 (13/18, 72.2%) and/or splice site variants (6/18, 33.3%). The majority of these variants have not been previously reported and three of them were confirmed by RNA-sequencing. Among the 12 patients with lung cancer, 9 had coexisting activating EGFR mutations (exon 19 deletions or L858R) and received prior-treatment with epidermal growth factor receptor TKIs. Further analysis of matched pre-treatment and post-treatment samples in three EGFR-mutated NSCLC patients confirmed that ERBB2 exon 16 skipping was newly acquired on resistance to TKI therapies. In 6 out of 18 patients, including colorectal, gastric and ovarian cancers, there were no mutations in known cancer driver genes detected, indicating that ERBB2 exon 16 skipping might be the oncogenic driver in these patients. CONCLUSIONS: Our data suggest that ERBB2 exon 16 skipping is another mechanism of TKI resistance in EGFR-mutated patients with lung cancer, in addition to its role of being an oncogenic driver in other solid malignancies.