Abstract P5-08-16: MTAP deletion and synthetic lethality-based drug development for metastatic breast cancer (MBC)
Authors: Pusztai Lajos , Danziger Natalie , Sokol Ethan S , Pavlick Dean C , Graf Ryon , Ramkissoon Shakti , Huang Richard SP , Decker Brennan J , Ross Jeffrey S 
Published: March 2022

Background: Homozygous deletion of the MTAP gene (MTAPdel) results in arginine accumulation in tumor cells and is currently being used for patient selection in clinical trials testing novel inhibitors in several tumor types. Methods: 7,308 clinically advanced ductal and lobular breast cancers (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 up to 114 loci. PD-L1 tumor cell expression was determined by IHC (Ventana SP142 immunocyte scoring assay used in 81% or Dako 22C3 tumor cell scoring assay used in 19%). ER and PR staining as reported by treating facility was available for a subset of 1,204 cases. HER2 status for these cases was assigned based on the presence of ERBB2 amplification (amp). All cases were of known lobular (ILC) or ductal (IDC) subtype. Results: 212 (2.9%) MBC featured MTAPdel. When compared to MTAPintact MBC, MTAPdel MBC were younger (p=.004) and less often of lobular subtype (p&lt;.0001). They were less frequently ER and PR positive and more frequently triple negative (TNBC) (both p&lt;.0001). ERBB2 amp frequencies were similar. The GA/tumor were similar when CDKN2A/B del (near universally present on MTAPdel cases) are excluded from analysis. Of non-targetable GA, TP53 GA were more frequent in MTAPdel MBC. In the MTAPintact group, ESR1 GA were more common, likely reflecting use of hormonal therapy given the greater frequency of ER/PR+ cases, and RB1 GA were similarly more frequent possibly reflecting use of cell cycle inhibitors. CDH1 GA reflected the greater ILC frequency in the MTAPintact group. For the currently targetable GA, the MTAPdel MBC featured more frequent BRCA1 and PTEN GA and the MTAPintact MBC had more ERBB2 non-amplification GA, PIK3CA and CCND1 GA. The immunotherapy predictive biomarkers microsatellite instability (MSI) and tumor mutational burden (TMB) were similarly low in both groups, but CD274 (PD-L1) amplification and PD-L1 expression were higher in the MTAPdel patients. Conclusions: MTAPdel MBC differs significantly from MTAPintact MBC in routine clinical features and GA impacting both targeted and immunotherapies. Given the current early and mid-stage development of MTA2 and PRMT5 inhibitors that exploit a synthetic lethality pathway for MTAPdel cancer, further study of selecting MTAPdel MBC for clinical trials appears warranted.

MTAPIntact MBCMTAPdel MBC P valueNumber of Cases7096212Age (median + range)59 (22-89+)54 (25-89)Age (mean)58.155.6=.004ILC Prevalence15.2%1.4%&lt;.0001ER+69.2%*49%^&lt;.0001PR+49.1%*34%^&lt;.0001HER2+ (ERBB2 amplification +)7.8%7.4%NSTNBC27.1%*45.3%^&lt;.0001GA/tumor with CDKN2A/B excluded6.16.6NSUntargetable GACDKN2A3.1%100%&lt;.0001CDKN2B1.3%97.4%&lt;.0001TP5352.1%62.4%=.004ESR18.5%3.7%=.011RB17.3%1.1%&lt;.0001CDH114.5%1.1%&lt;.0001Potentially Targetable GAERBB2 non-amplification3.0%0%=.003PIK3CA36.6%23.3%=.001CCND117.8%0.5%&lt;.0001BRCA13.7%10.1%&lt;.0001BRCA24.2%5.8%NSFGFR113.4%11.1%NSPTEN13.2%22.8%=.0002NF16.4%8.5%NSImmunotherapy BiomarkersCD274 amplification1.4%3.2%=.03MSI-H&lt;1%&lt;1%NSMedian TMB2.52.5NSTMB ≥ 10 mut/Mb7.9%5.1%NSPD-L1 Low3.9% (of 2895 cases)13% (of 92 cases)=.0004PD-L1 High0.7% (of 2895 cases)0% (of 92 cases)NS*Based on 1,014 cases ^Based on 190 cases

Citation Format: Lajos Pusztai, Natalie Danziger, Ethan S Sokol, Dean C Pavlick, Ryon Graf, Shakti Ramkissoon, Richard SP Huang, Brennan J Decker, Jeffrey S Ross. MTAP deletion and synthetic lethality-based drug development for metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-16.