Abstract 282P
Background
MTAP loss has emerged as a potential biomarker for novel PRMT5 inhibitors in a variety of malignancies. We queried whether MTAP GA loss would impact the genomic alteration (GA) landscape in clinically advanced ERBB2 altered MBC.
Methods
1,644 ERBB2 amplified or mutated clinically advanced MBC underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Ventana SP142 or Dako 22C3).
Results
50 (3%) of ERBB2 altered MBC featured MTAP loss (MTAP-) and 1,594 (97%) were MTAP intact (MTAP+). Ages were similar in both groups as were the GA/tumor when the co-deleted CDKN2A/B GA were excluded in the comparison. Co-deleted CDKN2A/B was far more common in MTAP- ERBB2+ cases (P<.0001). MTAP+ ERBB2+ MBC featured a lower frequency of ERBB2amp and a higher frequency of ERBB2mut than the MTAP- ERBB2+ cases (p=.07). PIK3CA mutations were more frequent in MTAP+ cases (P=.03) whereas both BRCA1 and BRAF GA were more frequent in MTAP- cases (both P=.02). Biomarker GA impacting immune checkpoint inhibitor treatment efficacy and resistance were mostly similar in both MTAP- and MTAP+ cases although PD-L1 expression was significantly more frequent in the MTAP- ERBB2+ cases (P<.0001). Table: 282P
| MTAP Loss | MTAP Intact | P Value | |
| Cases | 50 | 1594 | |
| Age (range in years) | 59 (32-85) | 58 (21-89+) | NS |
| ERBB2 Status | |||
| ERBB2 amplified | 78% | 67% | NS |
| ERBB2 sequence mutation | 16% | 28% | =.07 |
| Both | 6% | 5% | NS |
| Endocrine Rx Related | |||
| CDH1 | 10% | 16% | NS |
| ESR1 | 0% | 6% | NS |
| AR | 0% | 2% | NS |
| Cell Cycle Regulation | |||
| CDKN2A/B | 100%/94% | 26%/11% | <.0001 |
| CCND1 | 20% | 19% | NS |
| CDK4/6 | 0% | 4%/2% | NS |
| MTOR GA | |||
| PIK3CA | 26% | 40% | =.03 |
| PTEN | 8% | 4% | NS |
| NF1 | 6% | 8% | NS |
| HRD Related | |||
| BRCA1 | 8% | 2% | =.02 |
| BRCA2 | 0% | 3% | NS |
| PALB2 | 2% | 1% | NS |
| ATM | 2% | 3% | NS |
| Other Kinase targets | |||
| FGFR1 | 12% | 11% | NS |
| FGFR2 | 0% | 2% | NS |
| EGFR | 0% | 2% | NS |
| KIT | 0% | 1% | NS |
| MET | 0% | 1% | NS |
| BRAF | 6% | 1% | =.02 |
| IO Drug Biomarkers | |||
| MSI High | 0% | <1% | NS |
| TMB Median | 3.8 | 3.8 | NS |
| TMB > 10 mut/Mb | 16% | 14% | NS |
| PD-L1 IHC Positive | 10% | 5% | <.0001 |
| CD274 (PD-L1) amp | 0% | 1% | NS |
| STK11 GA | 0% | 1% | NS |
| MDM2 amp | 2% | 4% | NS |
Conclusions
Deletion of MTAP, a biomarker linked to selection of PRMT5 drugs in clinical trials employing a synthetic lethality mechanism is rare in ERBB2 altered MBC. Further study of the potential to employ PRMT5 inhibitors in patients ERBB2 driven MBC that has become refractory to anti-HER2 treatments appears warranted.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Foundation Medicine Inc.
Disclosure
N.A. Danziger: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La-Roche Ltd. K. Mcgregor: 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.