title: Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study.
abstract: BACKGROUND
  There is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC).
  
  
  METHODS
  Three hundred four TNBC patients with residual disease after NACT were retrospectively identified in three different hospitals. Hematoxylin and eosin-stained slides from surgical postchemotherapy specimens were evaluated for intratumoral (It-TIL) and stromal (Str-TIL) TIL. Cases were classified as High-TIL if It-TIL and/or Str-TIL >60%.
  
  
  RESULTS
  TIL were assessable for 278 cases. Continuous It-TIL and Str-TIL variables were strong prognostic factors in the multivariate model, both for metastasis-free [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.77-0.96, P = 0.01 and HR 0.85, 95% CI 0.75-0.98, P = 0.02 for Str-TIL and It-TIL, respectively] and overall survival (HR 0.86, 95% CI 0.77-0.97, P = 0.01 and HR 0.86, 95% CI 0.75-0.99, P = 0.03 for Str-TIL and It-TIL, respectively). The 5-year overall survival rate was 91% (95% CI 68% to 97%) for High-TIL patients (n = 27) and 55% (95% CI 48% to 61%) for Low-TIL patients (HR 0.19, 95% CI 0.06-0.61, log-rank P = 0.0017). The major prognostic impact of TIL was seen for patients with large tumor burden following NACT (residual tumor >2 cm and/or node metastasis). In all but one High-TIL case, It-TIL and Str-TIL values were lower on the prechemotherapy sample.
  
  
  CONCLUSIONS
  The presence of TIL in residual disease after NACT is associated with better prognosis in TNBC patients. This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new prognostic marker to select patients at high risk of relapse.
authors.affiliation: INSERM Unit U981, Institut Gustave Roussy, Villejuif, France; Department of Oncological and Surgical Sciences, University of Padua, Padua; Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova.
authors.forename: M V
authors.initials: MV
authors.lastname: Dieci
authors.affiliation: Early Drug Development for Innovative Therapies Division, Department of Medicine, Istituto Europeo di Oncologia, Milano.
authors.forename: C
authors.initials: C
authors.lastname: Criscitiello
authors.affiliation: INSERM Unit U981, Institut Gustave Roussy, Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Goubar
authors.affiliation: Department of Pathology, Istituto Europeo di Oncologia, Milano; Faculty of Medicine, University of Milan, Milano.
authors.forename: G
authors.initials: G
authors.lastname: Viale
authors.affiliation: Department of Oncological and Surgical Sciences, University of Padua, Padua; Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova.
authors.forename: P
authors.initials: P
authors.lastname: Conte
authors.affiliation: Department of Oncological and Surgical Sciences, University of Padua, Padua; Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova.
authors.forename: V
authors.initials: V
authors.lastname: Guarneri
authors.affiliation: Division of Pathology, Modena University Hospital, Modena, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ficarra
authors.affiliation: Departments of Medical Biology and Pathology.
authors.forename: M C
authors.initials: MC
authors.lastname: Mathieu
authors.affiliation: INSERM Unit U981, Institut Gustave Roussy, Villejuif, France; Medical Oncology, Institut Gustave Roussy, Villejuif.
authors.forename: S
authors.initials: S
authors.lastname: Delaloge
authors.affiliation: Department of Oncological and Surgical Sciences, University of Padua, Padua; Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova.
authors.forename: G
authors.initials: G
authors.lastname: Curigliano
authors.affiliation: INSERM Unit U981, Institut Gustave Roussy, Villejuif, France; Medical Oncology, Institut Gustave Roussy, Villejuif; Faculty of Medicine, Paris Sud University, Kremlin-Bicêtre, France. Electronic address: fabrice.andre@igr.fr.
authors.forename: F
authors.initials: F
authors.lastname: Andre
mesh_terms: D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D047368:Tumor Burden
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
keywords: breast cancer; neoadjuvant chemotherapy; triple negative; tumor lymphocytes