title: Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients.
abstract: BACKGROUND
  T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date.
  
  
  METHODS
  Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival.
  
  
  RESULTS
  In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1).
  
  
  CONCLUSIONS
  The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.
authors.affiliation: Cancer Research UK Cambridge Institute Departments of Pathology Oncology, University of Cambridge, Cambridge.
authors.forename: H R
authors.initials: HR
authors.lastname: Ali
authors.affiliation: Cancer Research UK Cambridge Institute Oncology, University of Cambridge, Cambridge.
authors.forename: E
authors.initials: E
authors.lastname: Provenzano
authors.affiliation: Cancer Research UK Cambridge Institute Oncology, University of Cambridge, Cambridge Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Dawson
authors.affiliation: Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge.
authors.forename: F M
authors.initials: FM
authors.lastname: Blows
authors.affiliation: Cancer Research UK Cambridge Institute Oncology, University of Cambridge, Cambridge Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge.
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.affiliation: Oncology, University of Cambridge, Cambridge Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge Strangeways Research Laboratory, Cambridge.
authors.forename: M
authors.initials: M
authors.lastname: Shah
authors.affiliation: Oncology, University of Cambridge, Cambridge Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge.
authors.forename: H M
authors.initials: HM
authors.lastname: Earl
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry.
authors.forename: C J
authors.initials: CJ
authors.lastname: Poole
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry.
authors.forename: L
authors.initials: L
authors.lastname: Hiller
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry.
authors.forename: J A
authors.initials: JA
authors.lastname: Dunn
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, The University of Birmingham, Birmingham.
authors.forename: S J
authors.initials: SJ
authors.lastname: Bowden
authors.affiliation: University of Leeds and Leeds Cancer Research UK Centre, St James' Institute of Oncology, Leeds, UK.
authors.forename: C
authors.initials: C
authors.lastname: Twelves
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Canada and Biomarker and Companion Diagnostics, Edinburgh Cancer Research Centre, Edinburgh Department of Histopathology and School of Molecular Medical Sciences, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: J M S
authors.initials: JM
authors.lastname: Bartlett
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia; Integrative Oncology Department, British Columbia Cancer Agency, Vancouver.
authors.forename: S M A
authors.initials: SM
authors.lastname: Mahmoud
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia; Integrative Oncology Department, British Columbia Cancer Agency, Vancouver.
authors.forename: E
authors.initials: E
authors.lastname: Rakha
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia; Integrative Oncology Department, British Columbia Cancer Agency, Vancouver.
authors.forename: I O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Gao
authors.affiliation: Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: T O
authors.initials: TO
authors.lastname: Nielsen
authors.affiliation: Oncology, University of Cambridge, Cambridge Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge Strangeways Research Laboratory, Cambridge.
authors.forename: P D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Cancer Research UK Cambridge Institute Oncology, University of Cambridge, Cambridge Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge carlos.caldas@cruk.cam.ac.uk.
authors.forename: C
authors.initials: C
authors.lastname: Caldas
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008875:Middle Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism / Q000473:pathology; D011237:Predictive Value of Tests; D011980:Receptors, Progesterone / Q000378:metabolism; D016019:Survival Analysis; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D000068456:Clinical Studies as Topic; D015337:Multicenter Studies as Topic
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011980:Receptors, Progesterone
keywords: breast cancer; chemotherapy; inflammation; lymphocytes; molecular subtypes