Integrated clinical and genomic analysis of mediastinal germ cell tumors (GCT) with somatic transformation (SM): A multi-institutional cohort study.

5029 Background: SM of GCT is a rare but lethal entity largely described in the context of testicular primaries. The distinct clinical and genomic features of SM that arise from anterior mediastinum are less defined. Methods: A multi-institutional study was conducted by integrating data from Indiana University and the MD Anderson Cancer Center, including patients(pts) with SM arising from mediastinal GCT treated between 2016 and 2025. Electronic health records were queried to obtain clinical, pathologic and genomic data when available. SM was classified as “de novo” if detected prior to disease relapse; all others were “evolved”. In the absence of elevated markers or concomitant GCT elements, isochromosome12p testing confirmed GCT ancestry. Descriptive statistics were used. Cox regression and Kaplan Meier analysis were used for overall survival(OS) and reverse KM for follow-up. OS measured from the time of transformation to date of last follow-up. The study was under protocol PA16-0736. Results: 40 pts were identified. All were male; median age at GCT diagnosis was 25 yrs (IQR:22-35); First detection of SM was by diagnostic biopsy in 14(35%) instances and surgical excision in 24(60%). Sarcoma was the most common histology detected in 33(82%), notably rhabdomyosarcoma and angiosarcoma- 8(20%) each. More than one SM pathology in 6(15%) pts and hematolymphoid SM was detected in 4(10%). Of 23/40 (57%) pts with genomic testing, 17(74%) were performed on the primary specimens, 5(22%) on metastatic deposits and 1(4%) on peripheral blood. TP53 and PTEN/AKT pathway mutations were seen in 16(70%) and 14(61%) respectively. De novo SM was seen in 32(80%). 9(28%) had baseline metastatic disease. Elevated AFP and beta-hCG in 28/32(84%) and 14/32(44%); 6(19%) were marker negative. 24(75%) received conventional GCT regimens. All marker negative pts had histology-driven therapy. Response data in Table. 26(81%) received surgical consolidation. For full cohort, median follow-up was 2.9 yrs, 2yr OS- 62%(95%CI:46.9-81.9) and 5yr OS- 52%(95%CI: 35.6-75.4). For de novo SM, surgical consolidation was associated with longer survival (mOS 8 yrs vs 0.6 yrs, HR-0.09, 95%CI:0.02-0.3, p-0.0003). Conclusions: The vast majority of mediastinal SM are sarcomas, that can be detected de novo. Conventional tumor markers are frequently elevated at presentation and may reflect concomitant non-teratoma GCT. TP53 and PTEN/AKT pathway mutations characterize the most common alterations and can be detected in primary and metastatic specimens. Response to first-line therapy GCT Therapy (n= 24) (%) Histology driven therapy (n=7) (%) Complete Remission (without resection) 4 (17) 1 (14) Partial Remission 8 (34) 3 (42) Stable Disease 5 (22) 2 (29) Progressive Disease 6 (26) 1(14) Not available 1 (4) Marker Response Elevated at presentation 23 (96) 1 (14) Normalization of markers 15 (63) 1 (14)