414P - Landscape of ERBB2 mutations in advanced cancers (AC) using circulating tumor DNA (ctDNA) next-generation sequencing (NGS) in Asia and Middle East (AME)

Background

ERBB2 activating mutations (ERBB2m) are oncogenic drivers or resistance mechanisms in many cancer types and are targets for anti-ERBB2 therapies. ERBB2m can be identified by NGS of either tumor tissue or ctDNA. The prevalence of ERBB2m and associated co-alterations using ctDNA NGS in AC from AME is unknown.

Methods

We reviewed results of Guardant360 (Guardant Health, Inc) ordered for patients with AC from AME as part of routine clinical practice through June 2023. This comprehensive genomic profiling assay identifies single-nucleotide variants, insertions, deletions, fusions, and amplifications; for ERBB2, all exons are evaluated. Samples were analyzed at a CLIA-certified, CAP-accredited laboratory in California.

Results

Among 10,416 samples analyzed, the prevalence of ERBB2m was 3.8%. For samples with ERBB2m, 58% were from women, median patient age was 63 years (range, 23-116), and median variant allele frequency was 1.5% (range, 0.01-68.1). Prevalence was highest in breast cancer (BC; 7.6%), gynecological cancers (4.0%) and lung cancer (LC; 3.8%). The most common mutations occurred in exon 20 (53%), exon 19 (14%), and exon 8 (12%). The most frequent ERBB2m types were exon 20 insertions (E20i; 44%), S310F (10%), and V777L (7%). Thirteen E20i variants were identified, with A775_G776insYVMA (61%) and G776delinsVC (14%) the most common. In LC, the most prevalent alterations were E20i (73%) followed by other mutations in the tyrosine kinase domain (TKD; 12%), extracellular domain (ECD; 10%), and juxta-membrane/transmembrane domain (JMD; 5%). In contrast, for BC the prevalence of TKD mutations was highest (75%), followed by ECD (10%), JMD (9%) and E20i (6%). For GI cancers, the distribution of ERBB2m was TKD (39%), ECD (37%), JMD (22%), and E20i (4%). The most frequent co-mutations were in TP53 (62.4%), EGFR (12.2%), and PIK3CA (19%). Concurrent gene amplifications included EGFR (15.4%), ERBB2 (8%), and PIK3CA (8%). MSI-high was observed in 15 samples.

Conclusions

Comprehensive ctDNA NGS can identify ERBB2m including complex insertions and co-alterations that may inform therapeutic decisions for patients with AC in AME.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Dawood: Financial Interests, Personal, Advisory Board: Guardant Health. N. Sandhir, S. Hsing: Financial Interests, Personal, Full or part-time Employment: Guardant Health. All other authors have declared no conflicts of interest.