(P 246) CTLA4 PATHWAY ACTIVATION IN RADIATION-INDUCED ANGIOSARCOMA: A TRANSCRIPTOMIC RATIONALE FOR IMMUNE CHECKPOINT BLOCKADE

Objective: Radiation-induced breast angiosarcoma (RIBAS) is a rare but aggressive malignancy that arises as a late complication of radiotherapy, with limited effective treatment options. This study aimed to elucidate the molecular distinctions between RIBAS and primary breast angiosarcoma (PBA) and to identify potential therapeutic targets, with a particular focus on immune checkpoint pathways.

Methods: We analyzed gene expression profiles from the GSE49790 dataset, which includes 35 formalin-fixed paraffin-embedded (FFPE) breast angiosarcoma samples, including 10 from patients with PBA and 25 from those with RIBAS. Differential gene expression analysis was performed to identify key regulatory genes. Single-sample gene set enrichment analysis (ssGSEA) was used to assess immune signaling, DNA repair, and oncogenic pathway activity.

Results: CTLA4 was significantly upregulated in RIBAS compared to PBA, indicating heightened immune checkpoint activation. ssGSEA revealed that RIBAS is enriched for T cell and NK cell exhaustion signatures, suggesting a state of immune dysfunction closely associated with elevated CTLA4 expression. In parallel, pathways related to cell cycle progression and DNA damage repair, including PARP-associated and RNA editing/processing nuclease activity, were also upregulated, pointing to increased genomic instability. Together, these findings suggest that RIBAS exhibits a distinct transcriptional landscape characterized by immune exhaustion and active DNA damage response. The concurrent upregulation of CTLA4 and DNA repair pathways implies possible immune-DDR crosstalk, which may contribute to tumor immune evasion and therapeutic resistance, supporting CTLA4 as a rational target for immune checkpoint blockade in this setting.

Conclusion: RIBAS exhibits a distinct transcriptomic profile compared to PBA, with co-enrichment of CTLA4-mediated immunosuppression and DNA repair activity. These findings support CTLA4 as a promising therapeutic target in RIBAS and provide a molecular rationale for future investigation of immune checkpoint blockade in this challenging disease context.