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

person Arielle Lutterman Heeke Levine Cancer Institute, Atrium Health, Charlotte, NC info_outline Arielle Lutterman Heeke, Joanne Xiu, Filipa Lynce, Paula Raffin Pohlmann, Gregory A. Vidal, Claudine Isaacs, Sandra M. Swain, Lee S. Schwartzberg, Antoinette R. Tan

Authors person Arielle Lutterman Heeke Levine Cancer Institute, Atrium Health, Charlotte, NC info_outline Arielle Lutterman Heeke, Joanne Xiu, Filipa Lynce, Paula Raffin Pohlmann, Gregory A. Vidal, Claudine Isaacs, Sandra M. Swain, Lee S. Schwartzberg, Antoinette R. Tan Organizations Levine Cancer Institute, Atrium Health, Charlotte, NC, Caris Life Sciences, Phoenix, AZ, Division of Hematology/Oncology, Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, West Cancer Center, Memphis, TN, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC, University of Tennessee Health Sciences Center, Memphis, TN Abstract Disclosures Research Funding Pharmaceutical/Biotech Company 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. HR-MT (%, +/total) HR WT (%, +/total) p-value PIK3CA 26.4 (217/823) 30.3 (1150/3792) 0.02 tumor PD-L1 (IHC) 13.2 (104/788) 11 (405/3677) 0.08 ESR1 8.2 (67/820) 7.9 (298/3790) 0.77 RB1 4.9 (37/754) 4.4 (150/3442) 0.51 AKT1 2.1 (17/817) 3.7 (140/3789) 0.02 ERBB2 2.8 (23/831) 2.6 (100/3812) 0.81 ARID2* 1.3 (10/796) 0.5 (20/3671) 0.03 JAK1 1.1 (9/796) 0.2 (7/3657) 0 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]