title: Tumor-Infiltrating Lymphocytes: A Predictive and Prognostic Biomarker in Neoadjuvant-Treated HER2-Positive Breast Cancer.
abstract: OBJECTIVE
  We elucidated the value of tumor-infiltrating lymphocytes (TIL) as an independent predictor for pathologic complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting.
  
  
  METHODS
  We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; ≥ 60% TILs), and correlated with pCR rate and DFS.
  
  
  RESULTS
  In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared with non-LPBC types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, P = 0.002; LPBC: OR 2.02, P = 0.002) and multivariate analyses (10% TILs: OR 1.1, P = 0.014; LPBC: OR 1.87, P = 0.009). This effect was also detectable in the trastuzumab-treated (10% TILs: OR 1.12, P = 0.018; LPBC: OR 2.08, P = 0.013) but not in the lapatinib-treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple-positive breast cancer, TILs are of more prognostic relevance than pCR.
  
  
  CONCLUSIONS
  We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions. Clin Cancer Res; 22(23); 5747-54. ©2016 AACR.
authors.affiliation: Institut für Pathologie, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ingold Heppner
authors.affiliation: Klinik für Gynäkologie und Geburtshilfe, Helios Klinikum Berlin Buch, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.affiliation: Institut für Pathologie, Charité Universitätsmedizin, Berlin, Germany. carsten.denkert@charite.de.|German Cancer Consortium (DKTK), Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Institut für Pathologie, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Berit M
authors.initials: BM
authors.lastname: Pfitzner
authors.affiliation: German Breast Group (GBG) Forschungs GmbH, Neu-Isenburg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Lederer
authors.affiliation: Institut für Pathologie, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schmitt
authors.affiliation: Klinik für Gynäkologie und Geburtshilfe, UK-SH, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.affiliation: Frauenklinik, UK Erlangen, Erlangen, Germany.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.affiliation: Onkologie Bethanien, Frankfurt am Main, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Tesch
authors.affiliation: Klinik für Frauenheilkunde und Geburtshilfe, UKF, Frankfurt am Main, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Solbach
authors.affiliation: MCD, Luisenkrankenhaus Düsseldorf, Düsseldorf, Germany.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Rezai
authors.affiliation: Brustzentrum, SRH Waldklinikum Gera, Gera, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zahm
authors.affiliation: Brustzentrum, St. Barbara Klinik, Hamm-Heessen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Holms
authors.affiliation: Onkologische Gemeinschaftspraxis, Coesfeld, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Glados
authors.affiliation: Klinik für Frauenheilkunde und Geburtshilfe, Klinikum Chemnitz, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Krabisch
authors.affiliation: Gynäkologie, Johanna-Etienne-Krankenhaus, Neuss, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Heck
authors.affiliation: Frauenklinik, St. Vincenz Krankenhaus, Limburg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Ober
authors.affiliation: Pathologie, SRH Waldklinikum Gera, Gera, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Lorenz
authors.affiliation: Institut für Pathologie, St. Barbara Klinik, Hamm-Heessen, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Diebold
authors.affiliation: Zentrum für Histopathologie, Chemnitz, Germany.
authors.forename: Jörg-Olaf
authors.initials: JO
authors.lastname: Habeck
authors.affiliation: German Breast Group (GBG) Forschungs GmbH, Neu-Isenburg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D011379:Prognosis; D011446:Prospective Studies; D011799:Quinazolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab / Q000627:therapeutic use; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human