Abstract 2675
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.Table: 867PD
| Main GA subgroups | Genes altered | PMNSGCT | Sem | NS | p-value* |
|---|---|---|---|---|---|
| Total n. | 44 | 22 | 86 | ||
| RAS-RAF pathway | KRAS, NRAS, HRAS, BRAF | 20 (46.4%) | 13 (56.5%) | 44 (51.2%) | 0.584 |
| TP53 pathway | TP53, MDM2 | 36 (81.6%) | 1 (4.3%) | 17 (19.8%) | <0.0001 |
| Cell-cycle pathway | CCND1/2/3, CDK4/6, CDKN2A/B, RB1 | 10 (22.7%) | 12 (52.2%) | 48 (55.8%) | 0.0004 |
| RTK pathway | ERBB2, PDGFRA, KIT, MET, FGFR1/2/3 | 3 (6.8%) | 6 (26.1%) | 6 (6.9%) | >0.99 |
| PI3K pathway | PIK3CA, MTOR, PTEN, AKT1/2 | 19 (43.1%) | 6 (26.1%) | 6 (6.9%) | <0.0001 |
| DDR pathway | BRCA1/2, ATM, CHEK2, MUTYH | 1 (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-High | 0 | 0 | 1 (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/Mb | 3 (6.8) 2 (4.5) | 0 0 | 3 (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
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.
Clinical trial identification
Legal entity responsible for the study
Foundation Medicine Inc.
Funding
Foundation Medicine, Cambridge, MA, USA.
Editorial Acknowledgement
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.