Actionable co-alterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway
Arielle L. Heeke, Joanne Xiu, Filipa Lynce, Paula R. Pohlmann, Gregory A. Vidal, Claudine Isaacs, Sandra M. Swain, Lee S. Schwartzberg, Antoinette R. Tan
INTRODUCTION AND PURPOSE
Homologous recombination deficiency (HRD) is common in breast cancer, with somatic frequencies of 15.6% previously reported1.
Targeted therapies including PARP inhibitors may provide effective and tolerable therapies for patients with breast cancer harboring germline or somatic HRD.
We evaluated the relationship between HRD and the presence of additional mutations that may impact responsiveness to targeted therapies beyond PARP inhibitors in patients with breast cancer.
Comprehensive molecular profiling of 4,647 breast tumors was performed at Caris Life Sciences, Inc using 592-gene Next Generation Sequencing (NGS), average depth 500X.
Complete molecular profiles were retrospectively reviewed to identify pathogenic or presumed pathogenic somatic mutations in the homologous recombination DNA damage repair (HR-DDR) genes ARID1A, ATM, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, KMT2D, MRE11, NBN, RAD50/51/51B, PALB2 & WRN, as well 39 markers that may be associated with treatment response to targeted anti-cancer therapies.
Frequencies of co-alterations (mutation/overexpression) of interest were calculated and compared between breast tumors that had a pathogenic or presumed pathogenic somatic mutation in a gene involved in the HR-DDR pathway (HR-MT) and breast tumors with an intact HR-DDR pathway (HR-WT), and by breast cancer subtype (hormone receptor [hr] positive, HER2 positive, and triple negative).
HRD was identified in 17.9% of the 4,647 evaluable breast tumors and was most commonly seen in HER2 negative disease (hr positive/HER2 negative 18.3%, triple negative 18.2%, hr positive/HER2 positive 15.6%, hr negative/HER2 positive 12.9%). [Table 1/Figure 1a]
Markers of response to immunotherapy [Table 2] were more commonly appreciated among HR-MT breast tumors:
Mean TMB higher for HR-MT tumors across all breast subtypes (9.2mut/Mb HR-MT vs 7.6mut/Mb HR-WT, p=<0.0001), and independent of microsatellite status.
Tumor PD-L1 overexpression more frequent among HR-MT breast tumors (13.2% HR-MT vs 11.0% HR-WT , p=0.08).
Microsatellite instability more common in HR-MT breast tumors (2.1% HR-MT vs 0.2% HR-WT, p=<0.0001), particularly HER2 negative (hr+/HER2- 2.3%, triple negative 1.4%, HER2+ 0%).
Mutations in chromatin remodeling genes more common in HRMT (71.5%), vs HR-WT (9.0%) breast tumors (p=<0.0001)
Frequency of co-alterations associated with response to targeted therapy [Table 4] were similar between HR-MT and HR-WT tumors, with the notable exception of PIK3CA (30.3% HR-WT vs 26.4% HR-MT, p=0.024) and AKT1 (3.7% HR-WT vs 2.1% HR-MT, p=0.021) mutations, which were more common in HR-WT tumors. Additional findings include:
AR overexpression common, particularly in hormone receptor positive tumors (76.9% hr+ vs 24.3% hr- , p=<0.001).
PIK3CA mutations less common in hormone receptor negative tumors (35.9% hr+ vs 20.0% hr-, p=<0.001).
ERBB2 mutations seen in 3.5% of hr+/HER2- and 1.2% of TNBC tumors, and 3.5% of HER2+ tumors.
JAK1/2 mutations were identified in HER2- tumors only.
Frequency of mutations associated with resistance to therapy [Table 5] were similar for HR-MT and HR-WT tumors.
ESR1 mutations seen exclusively in hormone receptor positive tumors.
RB1 mutations more common in TNBC, 7.6% vs 2.7% non-TNBC
In breast cancer, HR-MT is common and is associated with markers of response to immunotherapy.
Co-alterations (mutation/overexpression) were identified in both HR-MT and HR-WT tumors that suggest other targets for treatment.
94.9% of these co-alterations predict responsiveness to currently available treatments