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Poster Discussion session - Genitourinary tumours, non prostate

2675 - Comprehensive genomic profiling (CGP) of chemotherapy-resistant, primary mediastinal nonseminomatous germ cell tumors (PMNSGCT)


20 Oct 2018


Poster Discussion session - Genitourinary tumours, non prostate


Translational Research

Tumour Site

Malignant Germ-Cell Tumours of the Adult Male


Andrea Necchi


Annals of Oncology (2018) 29 (suppl_8): viii303-viii331. 10.1093/annonc/mdy283


A. Necchi1, G. Bratslavsky2, R.J. Corona2, J. Chung3, S.Z. Millis3, L.M. Gay4, J.A. Elvin3, J. Vergilio3, S. Ramkissoon3, E. Severson3, S. Daniel3, J.K. Killian3, S.M. Ali3, A.B. Schrock3, V.A. Miller3, J.S. Ross5

Author affiliations

  • 1 Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milan/IT
  • 2 Medical Oncology, Upstate Medical University, 13210 - Syracuse/US
  • 3 Genetics, Foundation Medicine, Inc., Cambridge/US
  • 4 Pathology, Foundation Medicine, 02141 - Cambridge/US
  • 5 Medicine, SUNY Upstate Medical University, Syracuse/US

Abstract 2675


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.


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.Table: 867PD

Main GA subgroupsGenes alteredPMNSGCTSemNSp-value*
Total n.442286
RAS-RAF pathwayKRAS, NRAS, HRAS, BRAF20 (46.4%)13 (56.5%)44 (51.2%)0.584
TP53 pathwayTP53, MDM236 (81.6%)1 (4.3%)17 (19.8%)<0.0001
Cell-cycle pathwayCCND1/2/3, CDK4/6, CDKN2A/B, RB110 (22.7%)12 (52.2%)48 (55.8%)0.0004
RTK pathwayERBB2, PDGFRA, KIT, MET, FGFR1/2/33 (6.8%)6 (26.1%)6 (6.9%)>0.99
PI3K pathwayPIK3CA, MTOR, PTEN, AKT1/219 (43.1%)6 (26.1%)6 (6.9%)<0.0001
DDR pathwayBRCA1/2, ATM, CHEK2, MUTYH1 (2.3%)3 (13.0%)12 (13.9%)0.060
Mean GA per tumor (standard deviation)4.0 (2.5)2.9 (2.6)4.0 (2.7)>0.99
MSI-High001 (1.2)>0.99
Median TMB (mut/Mb, range)2.4 (0-55.7)1.8 (0-6.3)2.7 (0-23.4)>0.99
TMB ≥10-20 mut/Mb TMB ≥20 mut/Mb3 (6.8) 2 (4.5)0 03 (3.5) 1 (1.2)>0.99 >0.99

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


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.


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.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine Inc.


Foundation Medicine, Cambridge, MA, USA.

Editorial Acknowledgement


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.

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