Gene-fusions are characteristic of a variety of sarcomas and are considered major driver mutations. Prominent examples are EWSR1::FLI1-fusion in Ewing sarcoma, SS18::SSX1/2/4-fusion in synovial sarcoma and NTRK-fusions in infantile fibrosarcoma and other rare neoplasms. Detection of specific gene-fusions is used for histopathological diagnosis, but targeted therapy options are not available for most of these gene-fusions. Exceptions are tumors driven by receptor tyrosine kinase-fusions including NTRK, ALK, ROS1 and RET. In rare cases with NTRK-fusions, targeted therapy has been shown to be highly effective. The use of larotrectinib in NTRK-fusion-positive cancers had a 75% response rate and an ongoing response of 71% in metastasized or irresectable NTRK-fusion-positive cancers after one year of treatment (Drilon et al. 2018). With the increasing use of new technologies, like next-generation sequencing and RNA sequencing, new fusions are detected in sarcomas. Recently, rearranged during transfection (RET)-fusion-associated sarcomas have been reported in a series of six cases (Antonescu et al. 2019). All patients had RET-fusions with an identical break point in exon 12, which retains the tyrosine kinase domain in the fusion oncoprotein. Two patients with a malignant histology had an aggressive course with distant metastasis. We report an highly effective neoadjuvant and adjuvant treatment of a patient with a RET::TRIM33-fusion sarcoma with the selective RET inhibitor selpercatinib.

A 33-year-old male patient presented with a mass within his left triceps brachii muscle, progressive in size over a period of four months. MR imaging revealed a 6.3 × 4.6 × 7.3 cm tumor suspicious of sarcoma (Fig. 1A, B, red arrows). 18F-FDG-PET/CT scan demonstrated intensive glucose hypermetabolism of the lesion (Fig. 1C). No metastases were detected. Biopsy revealed a spindle cell mesenchymal neoplasm, suspicious of fusion-associated unclassified sarcoma (Fig. 2B). Based on our routine diagnostic strategies to submit any unusual or unclassified mesenchymal neoplasm with monomorphic morphology (excluding undifferentiated pleomorphic sarcoma) for targeted RNA sequencing, molecular analysis was performed. Targeted RNA sequencing showed a RET::TRIM33-fusion (Fig. 2A). In this fusion, exons 1–10 of the TRIM33 gene were fused with exons 12–20 of the RET gene including the ring-box-coiled-coil unit of TRIM33 and the protein tyrosine kinase domain of RET. After approval by our molecular tumor board and the sarcoma board, the patient commenced selpercatinib 160 mg twice daily per os. Potential side effects of selpercatinib such as arterial hypertension, liver enzyme elevation, hyponatremia, elongation of QT-time and hemorrhages were monitored by daily blood pressure self-measurements and weekly medical surveillance including electrocardiogram and control of electrolytes. No side effects were detected. Starting at day 3 of the targeted therapy, the patient noticed an obvious shrinkage of the tumor. After 12 days, the tumor had almost completely disappeared on clinical examination. 18F-FDG-PET/CT scan revealed metabolic reduction of 56%, representing a partial response according to PERCIST 1.0 criteria and volume reduction of 45% compared to the initial finding (Fig. 1F). Because of the impressive regression of the tumor, selpercatinib treatment was continued for another 2 weeks. MR imaging demonstrated a further reduction of tumor volume to 4.6 × 1.0 × 4.6 cm (Fig. 1D, E). Due to the change of − 37% of the largest tumor diameter, response evaluation according to RECIST 1.1 is a partial response. However, up to this time, tumor volume had decreased by 90%. On MR-angiography, hypervascularity of the tumor was demonstrated and embolization of the tumor-supplying artery prior to surgery was performed. The sarcoma was resected with wide margins. Histology demonstrated near-total pathological response (ypT1, ypNX, L0, V0, Pn0) with dominant regressive, fibrosclerotic manifestation and minimal (5–10%) vital residual tumor cells. The resection margins were free of tumor (Fig. 2C). Locoregional irradiation with 56 Gy and boost to 65 Gy was applied to the local resection site. Adjuvant selpercatinib at constant dose of 160 mg twice daily per os was continued over a period of 4 weeks.

Fig. 1
figure 1

Well-defined mass (red arrow) within the left triceps brachii muscle (blue arrowheads). The mass is hyperintense on T2-weighted MR imaging (A) and shows strong contrast enhancement (T1-weighted image) (B). MR imaging performed 28 days after treatment initiation. Further shrinkage of the tumor, with solid (red arrow) and diffuse (orange arrow) residual areas (D). Remaining mild, inhomogeneous contrast enhancement (red  and orange arrow) (E). 18F-FDG-PET/CT on initial presentation reveals glucose hypermetabolism of the lesion (SUVmax 6.6) (C). 18F-FDG-PET/CT performed 12 days after treatment initiation with selpercatinib. Markedly reduced glucose hypermetabolism of the tumor (red arrow; SUVmax 2.9, SUVmax of the triceps brachii muscle 0.9) (F)

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Fig. 2
figure 2

Graphical overview of the detected TRIM33::RET-fusion. Exons 1–10 of the TRIM33 gene were fused with exons 12–20 of the RET gene including the protein tyrosine kinase domain of RET (image was created using the public Oviz-Bio platform (https://bio.oviz.org/demo-project/analyses/FusionTransJunc) (A). Biopsy showed a highly cellular neoplasm with monomorphic spindled and ovoid cells (400 × magnification) (B). After 4 weeks of treatment with selpercatinib, extensive fibrosclerotic regressive changes with thrombotic, sclerotic blood vessels and a minimal vital cell count of 5–10% was demonstrated in the resected triceps brachii muscle (400× magnification) (C)

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Tripartite motif-containing 33 or transcriptional intermediary factor 1γ (TRIM33, TIF1γ) protein belongs to the RING type E3 ubiquitin ligase family and regulates TGFß/Smad signaling. It functions either as tumor suppressor or promotor in different cancers (Yu et al. 2019). The RET gene encodes a transmembrane receptor that functions as tyrosine kinase protein. Binding of ligands to the receptor induces receptor dimerization and activation of downstream signaling pathways involved in cell growth, differentiation and development of the nervous system (Adashek et al. 2021; Subbiah et al. 2020). RET-fusions have been identified in several cancer types including 2% of lung carcinomas, 10–20% of thyroid carcinomas and in low frequency in other tumors (Thein et al. 2021). Selpercatinib was highly effective in lung and thyroid cancer treatment (Drilon et al. 2020; Wirth et al. 2020). In lung cancer, the objective response rate (ORR) in second-line treatment after cisplatin-containing therapy was 69% and the median duration of response was 17.5 months. In the first-line treatment, ORR was reported to be 85%. 90% of the responses were ongoing at six months (Drilon et al. 2020). An update of the LIBRETTO-001-study with a longer follow-up, and a higher patient number confirmed a sustained efficacy of selpercatinib in patients with non-small cell lung cancer (Drilon et al. 2022). In RET-mutant medullary thyroid cancer and RET-fusion-positive thyroid cancers with different fusion partners, similar response rates were observed (Wirth et al. 2020).

Because of a locally advanced T2 tumor in our patient with high risk of metastasis, selpercatinib was used as both neoadjuvant and adjuvant treatment. The short-term neoadjuvant therapy was highly efficient since the clinical response was visible after 3 days of treatment. After 12 days, a remarkable reduction in tumor volume and metabolic activity could be demonstrated. After 4 weeks of treatment, a further impressive tumor reduction was observed. Compared to the primary tumor volume, the final reduction in tumor size was 90%. The sarcoma was successfully resected.

To the best of our knowledge, this is the first report of an effective therapy with the selective RET inhibitor selpercatinib in neoadjuvant treatment of a RET-fusion-associated sarcoma. This case emphasizes the need to intensify the search for future targeted therapies in fusion-associated sarcomas.