Abstract 1393P
Background
SPOP encodes the speckle-type POZ protein that may act as a tumor suppressor by promoting the degradation of DAXX, SRC3, and Hedgehog effectors GLI2 and GLI3. Recent evidence suggests that SPOP mutation in CAPC may be associated with prolonged response to novel hormonal therapies.
Methods
12,254 CAPC cases underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3) with TPS 1-49% = low expression and TPS > 50% = high expression.
Results
1,030 (8.4%) of CAPC were SPOPmut. All (100%) of the SPOPmut were short variant base substitutions with the F113L (23.8%), F133V (15.9%), F102C (11.2%) and F102V (6.9%) the most frequent GA. Compared to SPOPwt CAPC, SPOPmut CAPC featured almost no TMPRSS2-ERG fusions (2.3% v 35.8%; p<.0001) and had significantly lower rate of AR amplification (12.0% v 7.2%; p=.0001). SPOPmut CAPC had significantly lower frequencies of GA in cell cycle regulatory genes (CDK12, CCND1, TP53 and RB1), MTOR pathway GA (PTEN 16.5% v 33.6%; p<.0001) and DDR genes including BRCA2 (6.5% v 9.6%; p=.0013). APC GA were significantly more frequent in SPOPmut CAPC (26.8% v 7.4%; p=.0001). In contrast, biomarkers associated with immune-oncology (IO) drug response were more frequent in SPOPmut than SPOPwt including MSI high status (4.04% v 2.63%; p=.012), TMB > 10 mut/.Mb (7.30% v 4.68%; p=.003), TMB > 20 mut/Mb (4.27% v 2.90%; p=.017), PD-L1 low expression (33.3% v 9.9%; p<.0001) and high expression (8.33% v 0.8%; p,.0001).
Conclusions
SPOP mutation occurs in a moderate number of CAPC cases and is associated with fewer TMPRSS2:ERG fusions, AR amplifications, cell cycle GA and MTOR pathway GA and higher frequencies of IO drug efficacy biomarkers including MSI, TMB and PD-L1 status. Further consideration of SPOP status in CAPC especially for planning hormonal and IO drug treatments appears warranted.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Foundation Medicine Inc.
Disclosure
P. Grivas: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck, Bristol Myers Squibb, Clovis Oncology, EMD Serono, Seattle Genetics, Pfizer, Janssen, Genzyme, Mirati Therapeutics, Exelixis, Genentech/Roche, GlaxoSmithKline, Immunomedics, Dyania Health, Infinity Pharmaceuticals, QED Therapeutics, 4D Pharma PLC; Financial Interests, Personal, Other, consulting: Foundation Medicine; Financial Interests, Institutional, Invited Speaker: Pfizer, Clovis Oncology, Bavarian Nordic, Immunomedics, Bristol Myers Squibb, Debiopharm Group, Merck, QED Therapeutics, GlaxoSmithKline, Mirati Therapeutics. A. Necchi: Financial Interests, Institutional, Research Grant: Merck, AstraZeneca, Ipsen, BMS, Gilead; Financial Interests, Personal, Invited Speaker: Roche, Janssen, Bayer, Astellas, AstraZeneca, Merck, Clovis Oncology; Financial Interests, Invited Speaker: Incyte, Pfizer; Non-Financial Interests, Leadership Role: Global society of Rare Genitourinary Tumors (GSRGT). N.A. Danziger: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La-Roche Ltd. D.C. Pavlick, H. Tukachinsky, R. P. Graf: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: Roche. J.S. Ross: Financial Interests, Personal, Full or part-time Employment, Medical Director: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. All other authors have declared no conflicts of interest.