Proteomics-derived basal biomarker DNA-PKcs is associated with intrinsic subtype and long-term clinical outcomes in breast cancer

Karama Asleh,Torsten O Nielsen,Nazia Riaz,Dongxia Gao,Samuel C Y Leung,Meenakshi Anurag,Angela S Cheng

doi:10.1038/s41523-021-00320-x

Abstract

Precise biomarkers are needed to guide better diagnostics and therapeutics for basal-like breast cancer, for which DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has been recently reported by the Clinical Proteomic Tumor Analysis Consortium as the most specific biomarker. We evaluated DNA-PKcs expression in clinically-annotated breast cancer tissue microarrays and correlated results with immune biomarkers (training set: n = 300; validation set: n = 2401). Following a pre-specified study design per REMARK criteria, we found that high expression of DNA-PKcs was significantly associated with stromal and CD8 + tumor infiltrating lymphocytes. Within the basal-like subtype, tumors with low DNA-PKcs and high tumor-infiltrating lymphocytes displayed the most favourable survival. DNA-PKcs expression by immunohistochemistry identified estrogen receptor-positive cases with a basal-like gene expression subtype. Non-silent mutations in PRKDC were significantly associated with poor outcomes. Integrating DNA-PKcs expression with validated immune biomarkers could guide patient selection for DNA-PKcs targeting strategies, DNA-damaging agents, and their combination with an immune-checkpoint blockade.

Highlights

While gene expression profiling has refined breast cancer prognosis and helped guide treatment choices[1,2,3], few advancements have been made in identifying practical biomarkers that can aid in tailoring treatments for the aggressive basal-like intrinsic subtype of breast cancer[4,5,6].The gene expression-defined basal-like breast cancer subtype is currently clinically approximated by triple-negative immunohistochemical (IHC) status, characterized by combined negativity for estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor-2 (Her[2])
The median follow-up for the University of British Columbia (UBC) cohort was 12.7 years; tumors with high expression of DNA-PKcs were found to be significantly associated with lower breast cancer-specific survival (HR 2.04, 95% CI 1.19–3.52, p = 0.01) when compared to cases with low DNA-PKcs (Fig. 2c)
We found that low DNA-PKcs expression concurrent with the presence of stromal TILs correlated with superior survival in the core basal tumors (HR 0.42, 95% CI 0.22–0.78; p = 0.005) (Fig. 4a)

Summary

Introduction

The gene expression-defined basal-like breast cancer subtype is currently clinically approximated by triple-negative immunohistochemical (IHC) status, characterized by combined negativity for estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor-2 (Her[2]). This IHC definition identifies a group with a heterogeneous biology[7,8,9] that consists of at least four major molecular subgroups termed basal immune activated, basal immune suppressed, mesenchymal and luminal androgen receptor[10,11]. A mass spectrometry-based analysis performed by the Clinical Proteomic Tumor Analysis Consortium group using fresh frozen materials from 122 TCGA breast cancer specimens reported DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to be the most specific biomarker for the basal-like subtype[12,13]

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Conclusion