title: Tumor immune subtypes distinguish tumor subclasses with clinical implications in breast cancer patients.
abstract: There is strong evidence that the host's cellular immune response is linked to tumor progression, however its impact on patient outcome in breast cancer is poorly understood. The purpose of this study is to define tumor immune subtypes, focusing on cellular immune responses and investigate their prognostic effect in breast cancer patients. Our training (n = 440) and validation cohort (n = 382) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1996. Tumor tissue sections were immunohistochemically stained for CD8 (CTL) and PEN5 (NK cells). Tumor expression of classical and non-classical human leukocyte antigen class I, and tumor-infiltrating Tregs were previously determined. Tumor immune subtypes were constructed based on quantification of these markers and biological rationale. High, intermediate, and low immune susceptible tumor immune subtypes were found, respectively, in 16, 63, and 20 % of patients in the training cohort and 16, 71, and 13 % in the validation cohort. The subtypes showed to be statistically significant prognostic in multivariate analyses for relapse free period (RFP) [p < 0.0001, intermediate versus high: hazard ratio (HR) 1.95; low versus high HR 2.98] and relative survival (RS) (p = 0.006, intermediate versus high HR 3.84; low versus high: HR 4.26). Validation of these outcome analyses confirmed the independent prognostic associations: RFP (p = 0.025) and RS (p = 0.040). The tumor immune subtypes that we present represent a prognostic profile with solid underlying biological rationale and with high discriminative power confirmed in an independent validation cohort. Our results emphasize the importance of tumor immune surveillance in the control of tumor development and, therefore, in determining patient prognosis. Tumor immune subtype profiling is promising for prognosis prediction and the achievement of tailored treatment for breast cancer patients.
authors.affiliation: Departments of Surgery, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.
authors.forename: Esther M
authors.initials: EM
authors.lastname: de Kruijf
authors.forename: Charla C
authors.initials: CC
authors.lastname: Engels
authors.forename: Willemien
authors.initials: W
authors.lastname: van de Water
authors.forename: Esther
authors.initials: E
authors.lastname: Bastiaannet
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Liefers
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000145:classification / Q000276:immunology* / Q000401:mortality*; D016827:CD8 Antigens / Q000032:analysis; D015331:Cohort Studies; D055088:Early Detection of Cancer; D005260:Female; D005500:Follow-Up Studies; D059951:HLA-G Antigens / Q000032:analysis; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D055815:Young Adult; D000097625:HLA-E Antigens
chemical_list: D016827:CD8 Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D000097625:HLA-E Antigens