title: Clinical Impact of Tumor DNA Repair Expression and T-cell Infiltration in Breast Cancers.
abstract: Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol β, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1,269 breast cancers and validated our findings in an independent estrogen receptor-negative (ER-) cohort (n= 279). Patients with tumors that expressed low XRCC1, low ATM, and low BRCA1 were not only associated with high numbers of CD8+tumor-infiltrating lymphocytes, but were also linked to higher grades, high proliferation indexes, presence of dedifferentiated cells, ER-cells, and poor survival (allP≤ 0.01). PD-1+or PD-L1+breast cancers with low XRCC1 were also linked to an aggressive phenotype that was high grade, had high proliferation indexes, contained dedifferentiated cells and ER-(all withPvalues ≤ 0.01), and poor survival (P= 0.00021 andP= 0.00022, for PD-1+and PD-L1+cancers, respectively) including in an independent ER-validation cohort (P= 0.007 andP= 0.047, respectively). We conclude that the interplay between DNA repair, CD8, PD-L1, and PD-1 can promote aggressive tumor phenotypes. XRCC1-directed personalization of immune checkpoint inhibitor therapy may be feasible and warrants further investigation in breast cancer.Cancer Immunol Res; 5(4); 292-9. ©2017 AACR.
authors.affiliation: Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aleskandarany
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Reem
authors.initials: R
authors.lastname: Ali
authors.affiliation: Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Eleanor Grace
authors.initials: EG
authors.lastname: Hodgson
authors.affiliation: Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Suha
authors.initials: S
authors.lastname: Atabani
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: De Souza
authors.affiliation: Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.affiliation: Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom. srinivasan.madhusudan@nottingham.ac.uk.|Department of Oncology, Nottingham University Hospitals, Nottingham, United Kingdom.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D060890:B7-H1 Antigen / Q000378:metabolism; D019313:BRCA1 Protein / Q000378:metabolism; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D046888:Tissue Array Analysis; D047368:Tumor Burden; D000076105:X-ray Repair Cross Complementing Protein 1 / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D061026:Programmed Cell Death 1 Receptor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000076105:X-ray Repair Cross Complementing Protein 1; C492913:BRCA1 protein, human; C423236:CD274 protein, human; C000619371:XRCC1 protein, human