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.

Pathogenic mutation frequency ≤ 1%: AR, BRAF, CCND1, CDKN2A, EGFR, ERBB3, IDH1, IDH2, JAK2, KIT, MET, MTOR, RET, SMARCB1*, SMARCE1*, SMARCA4*, SS18L1*

No mutations: ATR, AURKA/B, BCL7A*, BCL11A/B*, CDK4/6, ERBB4, NTRK1/2/3, PBRM1*, POLE

By IHC (HR-MT vs WT): AR 52.3 (415/794) vs 54.9 (2014/3669) [p=0.18], EGFR 28.6 (4/14) vs 32.4 (36/111) [p=0.77], cMET 11.1 (1/9) vs 5.5 (5/91) [p=0.50]