(P 412) UNCOVERING HER2 OVEREXPRESSION IN SOFT TISSUE SARCOMAS (STS): INSIGHTS FROM THE CANCER GENOME ATLAS (TCGA)

Objective: HER2 (ERBB2) is a transmembrane receptor belonging to the EGFR family, known to play a pivotal role in tumorigenesis. HER2 expression in STS, while less prevalent than in epithelial cancers, is a therapeutic target with the development of Antibody–Drug Conjugates (ADC). This is particularly true in select subtypes such as synovial sarcoma (SS). Multiple studies have demonstrated variable expression in SS, with some reports indicating overexpression in 30% of cases. Gene amplification is rare. Importantly, the relationship between HER2 mRNA and protein levels may be inconsistent, and membrane localization is not always detectable. These findings underscore the therapeutic potential of HER2-directed strategies in a defined subset of STS and support further clinical investigation. We evaluated HER2 mRNA expression in STS from TCGA data.

Methods: Amp defined by either CNV (Affymetrix single nucleotide polymorphism [SNP] 6.0 array data) or transcriptome (RNA-Seq_v2, log2-transformed RNA-Seq by expectation maximization [RSEM] normalized values) via cBioPortal. Query for amp of “ERBB2” gene was performed on 255 samples of STS from the TCGA Sarcoma PanCancer Atlas (Cohort 1) and on 34 samples from the ICGC TGCA Nature 2020 dataset (Cohort 2).

Results: Cohort 1 (255 patients) included undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), synovial sarcoma (SS), leiomyosarcoma (LMS), dedifferentiated liposarcoma (DDLPS), and malignant peripheral nerve sheath tumor (MPNST). HER-2 overexpression was observed in 5 out of 10 SS cases (50%), 1 out of 25 MFS cases (4%), 1 out of 100 LMS cases (1%), 1 out of 59 DDLPS cases (2%), 1 out of 50 UPS cases (2%), and in 4 out of 9 MPNST cases (44%).Cohort 2 included 34 STS samples, comprising 19 DDLPS and 15 LMS. No ERBB2 amplification or overexpression was detected in either subtype (0%).

Conclusion: Overexpression of HER2 has been identified in specific subtypes, such as SS and MPNST, suggesting its potential as a therapeutic target. Our findings emphasize the need for further investigation of HER2 in STS, including IHC analysis and clinical trials with ADCs such as Trastuzumab-deruxtecan, in pursuit of cutting-edge therapies to improve outcomes in STS.