Abstract 305P
Background
With an increase of targeted therapies for MBC patients, an understanding of resistant mechanisms is crucial. Prior to the use of cell cycle inhibitors, mutations in the retinoblastoma cell cycle inhibitory gene (RB1) were rare while ESR1 mutations were common. Increasingly, activating alterations in the other pathways are described including rare fusions. A genomic analysis of primary untreated samples and post-treatment metastatic samples was done, and in another set of patients, we analyzed patients with both tissue and ctDNA samples.
Methods
Genomic analysis was performed using DNA extracted from 51 primary breast tumors (PBx) and 51 metastatic breast cancer tumors (MBx) using CGP by hybrid-capture sequencing (FoundationOne®CDx). Samples were analyzed for all classes of genomic alterations, tumor mutational burden, and microsatellite instability. ER staining by IHC were extracted from pathology report IHC results. PD-L1 expression was determined by IHC (Ventana SP142). Additional ctDNA samples were analyzed for some patients using CGP (FoundationOne®Liquid)).
Results
The MBxs were enriched for alterations in ESR1 (p<0.001) and RB1 (p=0.027) yet similar for TP53 and PIK3CA. All cases with RB1 alterations had ESR1 alterations, yet only two also had PIK3CA alterations. No PBx had concurrent ESR1 and PIK3CA alterations, but 7 MBx (14%) had co-mutation of the two genes. MBx had an observed but not statistically significant increase in amplification of FGFR1 and its ligands FGF3/ FGF4/FGF19. Short variants in ERBB2 were seen in both PBx and MBx. No cases were MSI-TMB >10 mut/Mb was rare and PD-L1 expression levels were similar in both cohorts. The samples with additional ctDNA samples suggested increased polyclonal variants, including rare fusions.
Conclusions
Sequential CGP in our ER+ MBC cohort showed the expected resistant mutations as well as patterns of co-mutations and alterations in other pathways such as FGFR. ctDNA testing also identified polyclonal variants and events not seen in tissue. These findings suggest both tissue and liquid CGP can provide insights into mechanisms of resistance in the treatment of HR+ MBC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
K. McGregor: Full/Part-time employment: Foundation Medicine. J.S. Ross: Advisory/Consultancy: Celsius Therapeutics; Leadership role, Research grant/Funding (institution), Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine. N.A. Danziger: Full/Part-time employment: Foundation Medicine. E.S. Sokol: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine. J. Venstrom: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine. J.H. Chung: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine. J. Lee: Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. B. Alexander: Leadership role, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche; Research grant/Funding (institution): Celgene; Research grant/Funding (self): Eli Lilly; Research grant/Funding (institution): Puma. A.B. Schrock: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. H. Tukachinsky: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine.