Actionable co-alterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway

Authors:

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.

METHODS

  • 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).

RESULTS

  • 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

CONCLUSIONS

  • 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

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