Abstract 1710P
Background
Homozygous deletion of MTAP causes intracellular arginine accumulation enabling anti-tumor effects of MTA2/PRMT5 inhibitors via a synthetic lethality mechanism.
Methods
7,301 cases of MBC underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and MSI status was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3).
Results
208 (2.84%) of CABC featured MTAP loss. MTAP loss patients were younger (p=.002) and were more frequently ER- (30% v 50%; p<.0001), triple negative (TNBC) (47% v 27%; p<.0001) and less frequently HER2+ (2% v 8%; p=.0001) than MTAP intact MBC. Lobular histology and CDH1 mutations were more frequent in MTAP intact (14%) than MTAP loss MBC (p<.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p<.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% v 4%; p<.0001). There was no clear pattern for predictive Immuno-Oncology (IO) drug biomarkers with higher TMB > 20 mut/Mb levels found in the MTAP intact MBC (p<.0001) and higher PD-L1 low expression (1-49%% TPS) in the MTAP loss MTAP (p=.002) CABC cases. Table: 1710P
| Cases with MTAP intact | Cases with MTAP loss | ||
| Number | 7093 | 208 | |
| Mean age* | 57.8 | 54.5 | |
| ER+/PR+ Status by IHC** | 70.0%/ 49.0% | 50.00%/29.90% | |
| HER2+ Amplification by CGP* | 7.80% | 1.92% | |
| TNBC Status* | 27.00% | 47.28% | |
| TP53* | 51.70 | 61.30 | |
| CDKN2A** | 3.10 | 100.00 | |
| CDKN2B** | 1.30 | 96.70 | |
| CDH1* | 14.30 | 0.90 | |
| PTEN* | 13.10 | 21.70 | |
| PIK3CA** | 36.8 | 23.60 | |
| BRCA1** | 3.70 | 9.90 | |
| ERBB2 amplification* | 7.80 | 1.92 | |
| ERBB2 sequence mutation* | 11.20 | 6.60 | |
| EGFR * | 2.60 | 5.20 | |
| MSI High | Frequency | 0.03% | 0.05% |
| cases tested | 7077 | 205 | |
| TMB > 10%/>20% | 7.84%/7.40% | 5.32%/0.96% | |
| PD-L1 Positive IC expression (Dako 22C3) | Low (1-49%)* | 11.45% | 42.90% |
| High (> 50%) | 2.86% | 0.00% |
*Significant (P<0.05), **(P<0.0001).
Conclusions
MTAP loss is associated with ER-, HER2- and TNBC status, features a distinctive GL with potential to impact both targeted and immunotherapies and enables emerging clinical trials testing MTA2 and PRMT5 inhibitors for patients with CABC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Foundation Medicine Inc.
Disclosure
E.S. Sokol: Financial Interests, Personal, Full or part-time Employment, Employee: Foundation Medicine; Financial Interests, Personal, Stocks/Shares, Stocks and stock options: Roche. D.C. Pavlick: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: Roche. M. Levy: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: Roche. 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, Medical Director: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. A. Sivapiragasam: Financial Interests, Personal, Advisory Role: Pfizer, Puma Oncology, Blueprint Medicines, Immunomedics. All other authors have declared no conflicts of interest.