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

• Published in: Breast cancer research and treatment 2018-08, Vol.171 (1), p.21-31
• Main Authors: Telli, M. L., Stover, D. G., Loi, S., Aparicio, S., Carey, L. A., Domchek, S. M., Newman, L., Sledge, G. W., Winer, E. P.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; B7-H1 Antigen - antagonists & inhibitors; Biomarkers; Biomarkers, Tumor; Biotechnology; Breast cancer; Cancer metastasis; Cancer research; Care and treatment; Chemotherapy; Clinical outcomes; Disease Susceptibility; DNA Damage; DNA Repair; Drug approval; Female; Gene Expression Regulation, Neoplastic; Gene mutation; Genes, BRCA1; Genes, BRCA2; Genetic recombination; Germ-Line Mutation; Homologous Recombination; Humans; Immunity; Immunity - immunology; Immunomodulation; Medical schools; Medicine; Medicine & Public Health; Metastasis; Molecular Targeted Therapy; Oncology; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Review; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - metabolism
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-018-4807-x

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.