Screening of TROP2, Nectin-4, and HER2 in osteosarcomas: In pursuit of a target.

Abstract

e23511 Background: Osteosarcoma (OS), the most common malignant bone tumor, primarily affects adolescents and young adults and is associated with poor outcomes. This highlights the need for prognostic and predictive biomarkers and novel therapeutic targets. Trophoblast cell surface antigen 2 (TROP2) is a glycoprotein that facilitates the transmission of intracellular calcium signals, while Nectin-4 is a transmembrane protein that plays a vital role in cell-to-cell adhesion. Research has shown that the upregulation of those genes contributes to tumor cell proliferation and metastasis. Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein and oncogene amplified in various malignancies. Nectin-4 overexpression in OS has been demonstrated to enhance tumor cell proliferation and migration by activating the PI3K/AKT signaling pathway. Although TROP2 and Nectin-4 are recognized as targets for antibody-drug conjugates (ADCs) which have received approval in urothelial and breast cancers, there is still a lack of understanding regarding their significance in OS. Similarly, although HER2 expression has been studied in several malignancies and agents targeting HER2 are approved for breast and gastric carcinoma, its importance in OS has not been investigated. Methods: Our study aimed to assess the expression of TROP2, Nectin-4 and HER2 in OS and their clinicopathological correlations. We first examined publicly available data from The Cancer Genome Atlas (TCGA) to investigate genetic alterations of these genes in OS. Next we retrospectively analyzed samples from OS patients diagnosed between 2015 and 2021 and treated at our center using immunohistochemistry (IHC) for TROP2, Nectin-4 and HER2. Results: Nectin-4 alterations, including amplifications and elevated mRNA expression, were present in 15% of TCGA OS samples, while TROP2 displayed genetic alterations in 16% and HER2 presented mRNA expression alterations in 18%. Although there were no correlations between TROP2 or Nectin-4 levels and overall survival, tumors with expression of either marker exhibited a significantly higher tumor mutational burden (TMB) (q < 0.001) and mutation count (q < 0.001). In our study, IHC for TROP2 and HER2 returned negative results in all samples, while two out of ten patients (20%) showed positive Nectin-4 membrane staining. Both patients had extraskeletal OS with lung metastases; one presented with de novo metastatic disease, while the other experienced progression of lung metastases following adjuvant chemotherapy. Conclusions: With the limitations of the small sample size, our findings suggest that Nectin-4 and TROP2 are expressed in a subset of OS patients and may be more prevalent in tumors with a higher TMB. While further studies are necessary to evaluate the expression rates of these markers in OS, their potential value as therapeutic targets for ADCs and combinations with immune checkpoint inhibitors is noteworthy.