title: Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial.
abstract: OBJECTIVE
  The presence of tumor-infiltrating lymphocytes (TILs) is associated with improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer treated with adjuvant trastuzumab and chemotherapy. The prognostic associations in the neoadjuvant setting of other anti-HER2 agents and combinations are unknown.
  
  
  OBJECTIVE
  To determine associations between presence of TILs, pathological complete response (pCR), and event-free survival (EFS) end points in patients with early breast cancer treated with trastuzumab, lapatinib, or the combination.
  
  
  METHODS
  The NeoALTTO trial (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) randomly assigned 455 women with HER2-positive early-stage breast cancer between January 5, 2008, and May 27, 2010, to 1 of 3 neoadjuvant treatment arms: trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The primary end point used in this study was pCR in the breast and lymph nodes, with a secondary end point of EFS. We evaluated levels of percentage of TILs using hematoxylin-eosin-stained core biopsy sections taken at diagnosis (prior to treatment) in a prospectively defined retrospective analysis.
  
  
  METHODS
  Levels of TILs were examined for their associations with efficacy end points adjusted for prognostic clinicopathological factors including PIK3CA genotype.
  
  
  RESULTS
  Of the 455 patients, 387 (85.1%) tumor samples were used for the present analysis. The median (interquartile range [IQR]) level of TILs was 12.5% (5.0%-30.0%), with levels lower in hormone receptor-positive (10.0% [5.0%-22.5%]) vs hormone receptor-negative (12.5% [3.0%-35.0%]) samples (P = .02). For the pCR end point, levels of TILs greater than 5% were associated with higher pCR rates independent of treatment group (adjusted odds ratio, 2.60 [95% CI, 1.26-5.39]; P = .01). With a median (IQR) follow-up time of 3.77 (3.50-4.22) years, every 1% increase in TILs was associated with a 3% decrease in the rate of an event (adjusted hazard ratio, 0.97 [95% CI, 0.95-0.99]; P = .002) across all treatment groups.
  
  
  CONCLUSIONS
  The presence of TILs at diagnosis is an independent, positive, prognostic marker in HER2-positive early breast cancer treated with neoadjuvant anti-HER2 agents and chemotherapy for both pCR and EFS end points.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00553358.
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium2Department of Pathology, Gasthuis Zusters Antwerpen Hospitals, Antwerp, Belgium.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salgado
authors.affiliation: Institute of Pathology, Charité-Universitätsmedizin, Berlin, Germany4German Cancer Consortium, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Frontier Science (Scotland) Ltd, Grampian View, Kincraig, Kingussie, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Campbell
authors.affiliation: Division of Clinical Medicine and Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Savas
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.affiliation: Val d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Paolo
authors.initials: P
authors.lastname: Nucifero
authors.affiliation: Val d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Aura
authors.affiliation: Breast European Adjuvant Study Team, Institut Jules Bordet, Brussels, Belgium.
authors.forename: Evandro
authors.initials: E
authors.lastname: de Azambuja
authors.affiliation: Department of Obstetrics and Gynecology, Campus Kiel, University Hospital Kiel, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.affiliation: GlaxoSmithKline Oncology, Collegeville, Pennsylvania.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Ellis
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Piccart-Gebhart
authors.affiliation: Centre de Recherche en Epidémiologie et Santé des Populations, INSERM U1018, Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Université Paris-Sud, Villejuif, France.
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.affiliation: Frontier Science (Scotland) Ltd, Grampian View, Kincraig, Kingussie, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Bradbury
authors.affiliation: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.affiliation: Division of Clinical Medicine and Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077341:Lapatinib; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D016017:Odds Ratio; D016016:Proportional Hazards Models; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012074:Remission Induction; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D000068878:Trastuzumab / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human