Study Identifies HER2 Expression as Potential Target in Rare Sarcoma Patients

Researchers at a specialized and certified sarcoma center have evaluated HER2 protein expression as a possible therapeutic target in desmoplastic small round cell tumors, an exceptionally rare and aggressive malignancy characterized by scarce clinical evidence and limited treatment options. The retrospective study evaluated patients whose diagnoses were molecularly confirmed by the detection of the pathognomonic EWSR1::WT1 fusion gene, examining their clinical characteristics, treatment approaches, and responses to targeted therapeutic interventions.

Desmoplastic small round cell tumors, commonly abbreviated as DSRCT, present substantial management challenges due to their aggressive clinical trajectory and a lack of established therapy regimens. To explore alternative therapeutic avenues, the investigation sought to characterize both the typical clinical course and therapeutic approaches administered to patients at the center, with a particular focus on whether HER2 expression could serve as an actionable target for antibody-drug conjugate treatments.

The study cohort comprised eleven identified patients with molecularly confirmed disease. Among these individuals, the median age at presentation was 22 years, with an age range spanning from 5 to 63 years. Male patients represented the vast majority of the cohort, accounting for 81.8 percent of the individuals assessed during the retrospective review of clinical characteristics and surgical outcomes.

Laboratory evaluation of tumor tissue included immunohistochemistry to assess HER2 protein expression alongside fluorescence in situ hybridization to test for gene amplification. The immunohistochemistry assessments demonstrated that HER2 protein was present in a considerable proportion of the cases, even though every tumor in the series tested negative for HER2 amplification via fluorescence in situ hybridization.

Specifically, immunohistochemistry analysis revealed a score of 0 in three patients, representing 27.3 percent of the cohort, while an additional three patients showed 1+ expression, also accounting for 27.3 percent. Five patients, or 45.5 percent of the group, demonstrated 2+ HER2 expression. None of the evaluated tumors exhibited 3+ HER2 expression, confirming that moderate protein levels occurred entirely in the absence of genetic amplification.

Based on these findings, clinicians administered off-label treatment with the HER2-directed antibody-drug conjugate trastuzumab deruxtecan to two extensively pretreated patients whose tumors exhibited 2+ immunohistochemistry expression and negative fluorescence in situ hybridization results. Both patients experienced initial radiological responses following the initiation of the targeted conjugate regimen.

The subsequent clinical courses diverged between the two treated individuals, reflecting the severe nature of the underlying disease. One patient experienced disease progression following the initial response and ultimately died. In contrast, the second patient maintained disease control after receiving more than ten cycles of trastuzumab deruxtecan therapy, achieving ongoing stabilization without substantial additional toxicity despite undergoing chronic dialysis.

The authors concluded that while desmoplastic small round cell tumors maintain an aggressive course with high unmet medical needs, HER2 protein expression is present in a notable subset of non-amplified tumors. The objective responses documented in two patients provide a hypothesis-generating signal that supports further systematic investigation into HER2-directed antibody-drug conjugates for this rare malignancy.

Subject of Research: HER2 expression and targeted antibody-drug conjugate therapy in desmoplastic small round cell tumors

Article Title: HER2 as a treatment target in desmoplastic small round cell tumors (DSRCT): a retrospective study in a certified sarcoma center

Article References: Deinzer, C. K. W., Benzler, K., Zender, L., Ladurner, R., Rottscholl, R., & Strohäker, J. (2026). HER2 as a treatment target in desmoplastic small round cell tumors (DSRCT): a retrospective study in a certified sarcoma center. Journal of Cancer Research and Clinical Oncology. https://doi.org/10.1007/s00432-026-06668-6

Image Credits: AI Generated

DOI: 10.1007/s00432-026-06668-6

Keywords: HER2 expression, desmoplastic small round cell tumors, DSRCT, trastuzumab deruxtecan, T-DXd, EWSR1::WT1 fusion, sarcoma research, immunohistochemistry, fluorescence in situ hybridization, antibody-drug conjugates, off-label therapy, rare cancer, targeted oncology, clinical oncology, sarcoma center, retrospective study