Abstract 710P
Background
NEBC is a rare malignancy associated with unique histology and aggressive clinical course. We performed CGP on a series of 92 clinically advanced NEBC and compared the landscape of genomic alterations (GA) to a matched series of 3,393 conventional urothelial bladder carcinomas (UCB).
Methods
All cases underwent hybrid-capture based CGP to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA. PD-L1 expression was determined by tumor cell (TC) expression on IHC (Dako 22C3). The diagnosis of NEBC was confirmed by central pathology review.
Results
The ages and gender distributions were similar in both NEBC and UBC. NEBC had significantly higher frequencies of inactivating mutations in RB1 and TP53 and lower frequencies of CDKN2A/B deletions than UBC. For potentially ‘targetable’ GA, UBC had higher frequencies of GA in FGFR3, ERBB2, TSC1, and MTAP but lower frequencies of PTEN GA than NEBC. DDR GA were extremely rare in both groups. NEBC and UBC had similar rates of high TMB with >35% of cases featuring TMB ≥ 10 mut/Mb. Although both groups had similar rates of low-level PD-L1 expression (1-49% TC staining), UBC featured a significantly higher frequency of high level (≥50% TC staining) of PD-L1 expression. Table: 710P
| NEBC | UBC | P value | |
| Number of Cases | 92 | 3,595 | |
| Males/Females | 80%/20% | 75%/25% | NS |
| Median age (range) | 69 (34-89) | 70 (16-89) | NS |
| Top ‘Untargetable’ GA | |||
| RB1 | 82% | 21% | <.0001 |
| TP53 | 89% | 60% | <.0001 |
| TERT | 75% | 77% | NS |
| ARID1A | 22% | 25% | NS |
| CDKN2A/B | 2%/2% | 38%/30% | <.0001 |
| Top ‘Potentially Targetable’ GA | |||
| PIK3CA | 22% | 23% | NS |
| PTEN | 13% | 4% | .0004 |
| TSC1 | 0% | 9% | .0003 |
| ERBB2 | 2% | 17% | <.0001 |
| FGFR1 | 8% | 4% | NS |
| FGFR2 | 1% | 1% | NS |
| FGFR3 | 1% | 18% | <.0001 |
| MTAP | 1% | 25% | <.0001 |
| BRCA2 | 7% | 3% | NS |
| anti-PD(L)1 Biomarkers | |||
| MSI High Status | 0% | <1% | NS |
| Median TMB | 7.5 | 6.3 | |
| TMB≥10/20 mut/Mb | 39%/10% | 36%/12% | NS |
| PD-L1 Low/High Positive | 14%/0% (21 cases) | 20%/19% (131 cases) | .03 |
Conclusions
When compared with UBC, NEBC features a unique GA profile on CGP. NEBC is characterized by higher RB1 and TP53 GA frequencies and significantly fewer potentially “targetable” therapy options, such as inhibitors of FGFR, HER2, MTOR and MAT2A/PRMT5. The higher rate of inactivating RB1 GA in NEBC could support evaluation of novel agents targeting this pathway. UBC and NEBC have similar rates of TMB high status, suggesting that ICPI efficacy in NEBC could mirror the high response rate seen in UBC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Foundation Medicine Inc.
Disclosure
A. Necchi: Financial Interests, Personal, Research Grant: Merck Share & Dohme; Financial Interests, Personal, Other, Consulting fees: Merck Sharp & Dohme; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, Consulting fees: Roche; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca; Financial Interests, Personal, Research Grant: Bayer; Financial Interests, Personal, Research Grant: Amgen; Financial Interests, Personal, Research Grant: Novartis. P. Grivas: Financial Interests, Personal, Invited Speaker, Consulting fees: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Invited Speaker, Consulting fees: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Invited Speaker, Consulting fees: Clovis Oncology; Financial Interests, Institutional, Research Grant: Clovis Oncology; Financial Interests, Institutional, Research Grant: Bavarian nordic; Financial Interests, Institutional, Research Grant: Debiopharm; Financial Interests, Institutional, Research Grant: Immunomedics; Financial Interests, Institutional, Research Grant: OncoGenex Pharmaceuticals; Financial Interests, Personal, Other, Consulting fees: Bayer; Financial Interests, Personal, Other, Consulting Fees: Genentech; Financial Interests, Personal, Other, Consulting fees: GlaxoSmithKline; Financial Interests, Personal, Other, Consulting fees: Merck; Financial Interests, Personal, Other, Consulting fees: Mirati; Financial Interests, Personal, Other, Consulting fees: Pfizer; Financial Interests, Personal, Other, Consulting fees: QED Therapeutics; Financial Interests, Personal, Other, Consulting fees: EMD Serono; Financial Interests, Personal, Other, Consulting fees: Exelixis; Financial Interests, Personal, Other, Consulting fees: F. Hoffman La Roche; Financial Interests, Personal, Other, Consulting fees: Foundation Medicine Inc.; Financial Interests, Personal, Other, Consulting fees: Genzyme; Financial Interests, Personal, Other, consulting fees: Heron Therapeutics; Financial Interests, Personal, Other, Consulting Fees: Janssen; Financial Interests, Personal, Other, consulting fees: Seattle Genetics. P.E. Spiess: Non-Financial Interests, Personal, Leadership Role: NCCN Panel on bladder and penile cancer; Non-Financial Interests, Personal, Leadership Role: Global Society of Rare GU Tumors. S. Millis: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. B. Decker: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. N.A. Danziger: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La-Roche LTd. J.S. Ross: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. All other authors have declared no conflicts of interest.