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

This is the authors' abstract. We don't add key points for this paper.

Purpose Desmoplastic small round cell tumors (DSRCT) are exceptionally rare and aggressive sarcomas with limited therapeutic options and scarce clinical evidence. We aimed to characterize the clinical course and treatment of patients with molecularly confirmed DSRCT and to investigate HER2 expression as a potential therapeutic target, including real-world experience with trastuzumab deruxtecan (T-DXd). Methods We retrospectively analyzed patients with DSRCT treated at our specialized and certified sarcoma center. Diagnosis was confirmed by detection of the pathognomonic EWSR1::WT1 fusion. Clinical characteristics, treatment strategies, surgical outcomes, HER2 immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) results were assessed. Clinical outcomes of patients receiving T-DXd were reviewed. Results Eleven patients were identified (median age 22 years, range 5–63; 81.8% male). HER2 IHC was 0 in three patients (27.3%), 1 + in three (27.3%), and 2 + in five (45.5%); none showed 3 + expression, and all tumors were FISH-negative. Two extensively pretreated patients with HER2 IHC 2+/FISH-negative tumors received off-label treatment with T-DXd and demonstrated initial radiological responses. One patient experienced subsequent progression and died, whereas the second maintained disease control after more than 10 cycles despite chronic dialysis and without substantial additional toxicity. Conclusions This molecularly confirmed cohort highlights the aggressive clinical course and substantial unmet therapeutic need in DSRCT. HER2 protein expression was observed in a considerable proportion of tumors despite the absence of HER2 amplification. Responses to T-DXd in two HER2 IHC 2+/FISH-negative patients provide a hypothesis-generating clinical signal supporting further investigation of HER2-directed antibody–drug conjugates in DSRCT.