title: Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial.
abstract: BACKGROUND
  We have previously shown the prognostic importance of tumor-infiltrating lymphocytes (TILs) in newly diagnosed triple-negative breast cancer (TNBC) using tumor samples from a large clinical trial cohort. In this study, we aimed to validate these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease (HER2+).
  
  
  METHODS
  A prospective-retrospective study was conducted using samples from the FinHER adjuvant, phase III trial that enrolled 1010 early-stage BC patients, 778 of whom were HER2-nonamplified. Those with HER2+ disease (n = 232) were randomized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy. Two pathologists independently quantified stromal TILs in 935 (92.6%) available slides. The primary end point of distant disease-free survival (DDFS) and interactions with trastuzumab were studied in Cox regression models.
  
  
  RESULTS
  Confirming our previous findings, in TNBC (n = 134) each 10% increase in TILs was significantly associated with decreased distant recurrence in TNBC; for DDFS the hazard ratio adjusted for clinicopathological factors: 0.77; 95% confidence interval (CI) 0.61-0.98, P = 0.02. In HER2+ BC (n = 209), each 10% increase in lymphocytic infiltration was significantly associated with decreased distant recurrence in patients randomized to the trastuzumab arm (DDFS P interaction = 0.025).
  
  
  CONCLUSIONS
  Higher levels of TILs present at diagnosis were significantly associated with decreased distant recurrence rates in primary TNBC. These results confirm our previous data and further support that TILs should be considered as a robust prognostic factor in this BC subtype. We also report for the first time an association between higher levels of TILs and increased trastuzumab benefit in HER2+ disease. Further research into why some TN and HER2+ BCs can or cannot generate a host antitumor immune response and how trastuzumab can favorably alter the immune microenvironment is warranted.
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne,Australia sherene.loi@petermac.org.
authors.forename: S
authors.initials: S
authors.lastname: Loi
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium Service de Biostatistique et D'Epidemiology, Gustave Roussy, Universite Paris-Sud, Villejuif, France.
authors.forename: S
authors.initials: S
authors.lastname: Michiels
authors.affiliation: Department of Anatomical Pathology, Institut Jules Bordet, Brussels, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Salgado
authors.affiliation: Department of Anatomical Pathology, Institut Jules Bordet, Brussels, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Sirtaine
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Jose
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Fumagalli
authors.affiliation: Department of Oncology, Tampere University Hospital, Tampere.
authors.forename: P-L
authors.initials: PL
authors.lastname: Kellokumpu-Lehtinen
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Helsinki.
authors.forename: P
authors.initials: P
authors.lastname: Bono
authors.affiliation: Cancer Center, Kuopio University Hospital, Kuopio, Finland.
authors.forename: V
authors.initials: V
authors.lastname: Kataja
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Desmedt
authors.affiliation: Department of Medicine, Institut Jules Bordet, Brussels, Belgium.
authors.forename: M J
authors.initials: MJ
authors.lastname: Piccart
authors.affiliation: German Breast Group, Neu-Isenburg.
authors.forename: S
authors.initials: S
authors.lastname: Loibl
authors.affiliation: Charité University Hospital, Institute of Pathology, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Immunology in Cancer and Infection Laboratory, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute; School of Medicine, University of Queensland, Herston, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Helsinki.
authors.forename: H
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Sotiriou
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis; D017024:Chemotherapy, Adjuvant; D005260:Female; D005387:Finland; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D000068878:Trastuzumab; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D000068878:Trastuzumab
keywords: TILs; biomarkers trastuzumab efficacy; breast cancer; lymphocytic infiltration; prediction; prognosis