Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Abstract

Purpose Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. Methods We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Results Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. Conclusions HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

Prevention of DNA Replication Stress by CHK1 Leads to Chemoresistance Despite a DNA Repair Defect in Homologous Recombination in Breast Cancer

“…Therefore, the established methods to successfully identify HR deficient tumors should be extended by the detection of CHK1 activation. This could be made possible by extending BRCA1/2 testing by genes of the intra S-phase damage response or the combined detection of RAD51 with RPA in S-phase cells [25,26,58].…”

Pan-cancer characterization of immune-related lncRNAs identifies potential oncogenic biomarkers

“…20a). Moreover, homologous recombination deficiency (HRD) remains an important biomarker and a potentially effective adjunct to enhance immunogenicity of tumors 46 . We compared the HRD scores across different subtypes.…”

Low-Dose and Long-Term Olaparib Treatment Sensitizes MDA-MB-231 and SUM1315 Triple-Negative Breast Cancers Spheroids to Fractioned Radiotherapy

“…Thereby, a in silico transcriptomic comparison was carried out. These analyses highlighted in MDA-MB-231 the overexpression of AURKA, a gene exhibiting cell cycle regulation function and known as a biomarker of PARPi sensitivity [36][37][38][39]. Therefore, this specific overexpression of AURKA could partially explain the increased sensitivity to the co-treatment of MDA-MB-231 model compared to SUM1315 model.…”