Actionable coalterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway.

Abstract

3132 Background: Homologous recombination (HR) deficient breast tumors may have genomic alterations that suggest responsiveness to targeted therapies other than PARP inhibitors. Methods: Comprehensive molecular profiles of 4,647 breast tumors performed at Caris Life Sciences using 592-gene NGS (average read depth 500X) were reviewed to identify somatic pathogenic mutations in HR genes ARID1A, ATM, ATRX, BAP1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, KMT2D, MRE11, NBN, RAD50/51/51B & PALB2, as well 41 markers associated with treatment response. Results: Overall, 17.9% of breast tumors have HR mutations (HR-MT, 831/4647). HR-MT is seen most in HER2– disease [hormone receptor (hr)+/HER2– (18.3%, n=2183), TNBC (18.2%, n=1568), hr–/HER2+ (12.9%, n=217)]. Mean TMB is higher for HR-MT tumors across subtypes (9.2 mut/Mb vs 7.6 WT, p=<0.0001) & independent of MS status. HR-MT hr–/HER2+ tumors are more likely to have PD-L1 overexpression (25% vs 13.1% hr–/HER2+ WT, p=0.10), whereas MSI is more prevalent in HR-MT HER2– (hr+/HER2– 2.3%, TNBC 1.4%, HER2+ 0%). Mutations in chromatin remodeling genes (*) are more common in HR-MT. Additional co-alterations are outlined in the Table. Conclusions: In breast cancer, HR-MT is associated with HER2– disease & markers of response to immunotherapy. Clinical trials combining HRD targeted agents & immunotherapy are underway & could be enriched through comprehensive molecular profiling. Mutations were identified in both HR-MT & HR WT tumors that suggest other targets for treatment. [Table: see text]