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• W2896482403 abstract "Background: Locally advanced and metastatic PMNSGCT are highly aggressive tumors, most of which become refractory to platinum-based chemotherapy. No effective salvage therapy has been identified for these patients (pts). In this study, we performed CGP on a series of 44 PMNSGCT and compared the results with chemorefractory, metastatic pure seminomatous (Sem) and non-seminomatous (NS) testicular GCT. Methods: Archival tissues from 44 chemotherapy-treated PMNSGCT, 22 Sem and 86 NS were sequenced by an FDA-approved hybrid-capture based CGP (FoundationONE) at a CLIA-certified laboratory. Microsatellite instability (MSI) was determined on 114 loci and tumor mutational burden (TMB, reported as mutations [mut]/Mb) was determined on 1.1 Mbp of sequenced DNA. Results: The PMNSGCT pts (43M/1F) had a similar median age as the NS which was significantly younger than the Sem pts (P = 0.007). Yolk sac differentiation was most frequent in PMNSGCT (39%). The mean GA/tumor was similar in all 3 GCT subtypes. Notable differences in GA in PMNSGCT vs NS included significantly higher TP53 pathway GA (81.6% vs 19.8%; p < 0.0001) and PIK3CA pathway GA (43.1% vs 6.9%; P < 0.0001) and lower cell-cycle pathway GA (22.7% vs 55.8%; P = 0.0004) [Table]. PMGCT featured more frequent targetable GA in BRAF (7%), ERBB2 and NTRK1-3 (2% both) than PS or NS. KRAS GA frequencies were similar in all the 3 groups. There were no MSI-H PMNSGCT cases. The mean TMB in PMNSGCT was similar to the Sem and NS tumors, but there were more TMB ≥10 and ≥20 mut/Mb in the PMNSGCT group. Clinical examples of PMNSGCT responding to targeted therapy and immunotherapy will be presented. Conclusions: The array of GA in PMNSGCT were similar to those from testicular NS, with a higher frequency of yolk sac differentiation, TP53 GA and slightly increased opportunities for targeted therapies (BRAF, ERBB2 and NTRK1) and immunotherapies (4.5% with TMB ≥20 mut/Mb). Further study of precision treatments for this orphan disease appear warranted.Table: 867PDMain GA subgroupsGenes alteredPMNSGCTSemNSp-value*Total n.442286RAS-RAF pathwayKRAS, NRAS, HRAS, BRAF20 (46.4%)13 (56.5%)44 (51.2%)0.584TP53 pathwayTP53, MDM236 (81.6%)1 (4.3%)17 (19.8%)<0.0001Cell-cycle pathwayCCND1/2/3, CDK4/6, CDKN2A/B, RB110 (22.7%)12 (52.2%)48 (55.8%)0.0004RTK pathwayERBB2, PDGFRA, KIT, MET, FGFR1/2/33 (6.8%)6 (26.1%)6 (6.9%)>0.99PI3K pathwayPIK3CA, MTOR, PTEN, AKT1/219 (43.1%)6 (26.1%)6 (6.9%)<0.0001DDR pathwayBRCA1/2, ATM, CHEK2, MUTYH1 (2.3%)3 (13.0%)12 (13.9%)0.060Mean GA per tumor (standard deviation)4.0 (2.5)2.9 (2.6)4.0 (2.7)>0.99MSI-High001 (1.2)>0.99Median TMB (mut/Mb, range)2.4 (0-55.7)1.8 (0-6.3)2.7 (0-23.4)>0.99TMB ≥10-20 mut/Mb TMB ≥20 mut/Mb3 (6.8) 2 (4.5)0 03 (3.5) 1 (1.2)>0.99 >0.99Abbreviations: DDR: DNA-damage response and repair genes; GA: genomic alterations; IQR: interquartile range; MSI: microsatellite instability; TGCT: testicular germ cell tumors; TMB: tumor mutational burden; Mut: mutations; NS: not significant. *Fisher’s exact test or t-test Open table in a new tab Abbreviations: DDR: DNA-damage response and repair genes; GA: genomic alterations; IQR: interquartile range; MSI: microsatellite instability; TGCT: testicular germ cell tumors; TMB: tumor mutational burden; Mut: mutations; NS: not significant. *Fisher’s exact test or t-test Legal entity responsible for the study: Foundation Medicine Inc. Funding: Foundation Medicine, Cambridge, MA, USA. Disclosure: J. Chung, S.Z. Millis, L.M. Gay, J.A. Elvin, J-A. Vergilio, S. Ramkissoon, E. Severson, S. Daniel: Employee: Foundation Medicine Inc. J.K. Killian, S.M. Ali, A.B. Schrock, V.A. Miller, J.S. Ross: Employee: Foundation Medicine Inc. All other authors have declared no conflicts of interest." @default.
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• W2896482403 date "2018-10-01" @default.
• W2896482403 modified "2023-09-27" @default.
• W2896482403 title "Comprehensive genomic profiling (CGP) of chemotherapy-resistant, primary mediastinal nonseminomatous germ cell tumors (PMNSGCT)" @default.
• W2896482403 doi "https://doi.org/10.1093/annonc/mdy283.076" @default.
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