SUNY Upstate Medical University, Syracuse, NY
Michael Basin , Rebecca A Sager , Dean C. Pavlick , Andrea Necchi , Philippe E. Spiess , Roger Li , Ashish M. Kamat , Petros Grivas , Liang Cheng , Douglas I. Lin , Jeffrey S. Ross , Alina Basnet , Gennady Bratslavsky , Joseph M Jacob
Background: Activating DNA sequence genomic alterations (GA) in the FGFR3 gene including short variant (SV) mutations and kinase domain activating gene rearrangements/fusions (RE-FUS) are known drivers and relevant precision treatment targets for pts with UC. THOR trial showed a significant overall survival benefit with erdafitinib (FGFR inhibitor) vs (taxane or vinflunine) in patients (pts) with advanced UCB or UTUC. PROOF-302 trial showed higher frequency of FGFR3 GA in UTUC (30%) vs UCB (13%). We sought to explore differences in frequency of FGFR3 alterations and the genomic landscapes of FGFR3-altered UCB and UTUC. Methods: 10,402 UCB and 2,325 UTUC (combined ureter and renal pelvis) underwent hybrid capture-based comprehensive genomic profiling (CGP) using a hybrid capture-based to assess all classes of GA and measure MSI status, TMB level, genomic ancestry, genomic signature, germline mutations and HRD score. PD-L1 was determined by IHC (Dako 22C3 using the TPS system. Results were compared using the Fisher Exact method with the Benjamini-Hochberg adjustment. Results:FGFR3mut+ status was significantly more frequent in UTUC than in UBC (24.9% vs 17.7%; p<.0001) (Table). UCB pts were more often male than UTUC (P=.0003). Age (71-72 yrs), EUR ancestry (85%) and GA/tumor (8.9-9.0) were similar. The number of GA/case and the frequency of EUR ancestry were similar. Targetable GA in ERBB2 and PIK3CA were more frequent in FGFR3mut+ UBC vs FGFR3mut+ UTUC. GA in PTEN, TSC1 and MTAP currently associated with clinical trials were similar in UBC and UTUC. The KEGG ERBB and VEGF signaling pathways were more frequently identified in UCB (p=0.036) and the MMR pathway more frequently identified in UTUC (p=0.014). The HRD signature was similar in both groups (2.3-3.1%). Anti-PD(L)1 putative biomarkers included a significantly higher frequency of MSI-high status in UTUC vs UCB but no significant difference in TMB or PD-L1 expression levels. Conclusions: Although histologically similar, the genomic landscape of FGFR3mut+ UTUC has notable differences with FGFR3mut+ UCB. Limitations include lack of clinical data annotation. The findings may impact of clinical trial designs for UCB and UTUC, including evaluating combinations of anti-FGFR3 with other agents.
UCB (10402 cases) | UTUC (2325 cases) | P-value | |
---|---|---|---|
sex (% male) | 71.2% | 61.7% | 0.0003 |
ERBB2 | 7.2% | 4.1% | 0.042 |
MTAP | 45.9% | 43.1% | NS |
PIK3CA | 28.8% | 22.6% | 0.019 |
TERT | 79.8% | 69.6% | <.0001 |
TP53 | 31.1% | 27.2% | NS |
MSI-high | 1.8% | 5.4% | <.0001 |
Median TMB | 5.2 | 5 | NS |
PD-L1 low positive | 18.0% | 29.4% | NS |
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Abstract Disclosures
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