Abstract 690P
Background
We compared the genomic alteration (GA) landscape of VHL mutated (VHLmut) and VHL wild type (VHLwt) ccRCC.
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).
Results
Of 948 cases of clinically advanced ccRCC, 708 (75%) were VHLmut and 240 (25%) were VHLwt. The ages and gender distributions of both groups were similar (Table). Significant differences in currently “untargetable” GA included higher frequencies of SETD2 in the VHLmut ccRCC (P=.04) and higher TERT GA in the VHLwt ccRCC (P=.007). VHLmut and VHLwt ccRCC featured similar frequencies of potentially targetable GA except for MTAP deletions (investigational target of MAT2A and PRMT5 inhibitors in clinical trials), which were identified more frequently in VHLwt ccRCC (P=.03). For GA potentially associated with immune checkpoint inhibitor (ICPI) efficacy, PBRM1 GA were significantly more frequent in VHLwt than VHLmut ccRCC (P<.0001). ccRCC cases featured low TMB levels with only 1-2% of cases having TMB ≥ 10 mut/Mb. Both VHLmut and VHLwt ccRCC often had low positive PD-L1 expression (1-49% TC staining) but rarely high positive staining (≥ 50% TC staining). Table: 690P
| VHLmut ccRCC | VHLwt ccRCC | Significance | |
| Number of Cases | 708 | 240 | |
| Males/Females | 71%/29% | 71%/29% | NS |
| Median age (range) | 62 (17-89+) | 63 (24-87) | NS |
| Top ‘Untargetable’ GA | |||
| SETD2 | 29% | 22% | P=.04 |
| KDM5C | 16% | 14% | NS |
| BAP1 | 14% | 15% | NS |
| TP53 | 13% | 14% | NS |
| CDKN2A | 11% | 15% | NS |
| CDKN2B | 9% | 13% | NS |
| TERT | 7% | 13% | P=.007 |
| Top ‘Potentially Targetable’ GA | |||
| PTEN | 13% | 12% | NS |
| TSC1 | 6% | 4% | NS |
| PIK3CA | 5% | 5% | NS |
| MTAP | 5% | 9% | P=.03 |
| NF2 | 2% | 4% | NS |
| MET | 1% | 3% | NS |
| BRCA2 | 1% | 2% | NS |
| ICPI Response and Resistance GA | |||
| PBRM1 | 13% | 38% | P<.0001 |
| CD274 | <1% | <1% | NS |
| STK11 | 0% | 0% | NS |
| ICPI Biomarkers | |||
| MSI High Status | 0% | 0% | NS |
| Median TMB | 2.5 | 2.5 | NS |
| TMB≥10 mut/Mb | 1% | 2% | NS |
| PD-L1 Low/High Positive | 28%/4% (274 cases) | 36%/5% (99 cases) | NS |
Conclusions
VHLmut ccRCC and VHLwt ccRCC have similar clinical characteristics but differ in other GAs, which may impact potential clinical trial treatment selection. Further study of ccRCC based on VHL mutation status in the clinical trial setting appears warranted.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Foundation Medicine Inc.
Disclosure
P. Grivas: Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Other, Consulting fees: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: AstraZeneca; Financial Interests, Institutional, Research Grant: Clovis Oncology; Financial Interests, Personal, Other, Consulting Fees: Clovis Oncology; Financial Interests, Institutional, Research Grant: Bavarian nordic; Financial Interests, Institutional, Research Grant: Debiopharm; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: OncoGenex Pharmaceuticals; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Personal, Other, Consulting Fees: Bayer; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Personal, Other, Consulting fees: Genentech; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Personal, Other, Consulting fees: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Personal, Other, Consulting fees: Merck; Financial Interests, Institutional, Research Grant: 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 Ltd; 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. 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. E. Sokol: 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.