title: Immune Signatures Following Single Dose Trastuzumab Predict Pathologic Response to PreoperativeTrastuzumab and Chemotherapy in HER2-Positive Early Breast Cancer.
abstract: Recent data suggest that intrinsic subtype and immune cell infiltration may predict response to trastuzumab-based therapy. We studied the interaction between these factors, changes in immune signatures following brief exposure to trastuzumab, and achievement of pathologic complete response (pCR) to subsequent preoperative trastuzumab and chemotherapy in HER2-positive breast cancer.
  
  
  
  In patients enrolled on two multicenter trials (03-311 and 211B), tumor core biopsies were obtained at baseline and after brief exposure to single-agent trastuzumab or nab-paclitaxel. Gene expression profiles were assessed to assign PAM50 subtypes, measure immune cell activation, and were correlated with response.
  
  
  
  The pCR rate was significantly higher in HER2-enriched tumors in the Discovery, 03-311 (36%, P = 0.043) dataset, as compared with other subtypes, which validated in 211B (50%, P = 0.048). Significant increases in a signature of immune cell admixture (Immune Index) were observed only following brief exposure to trastuzumab in HER2-enriched tumors (Discovery/03-311, P = 0.05; Validation/211B, P = 0.02). Increased Immune Index was predictive of response after brief exposure (03-311, P = 0.03; 211B, P = 0.04), but not at baseline, in addition to increased expression of a CD4(+) follicular helper T-cell signature (03-311, P = 0.05; 211B, P = 0.04). Brief exposure to trastuzumab significantly increased gene expression of the T-cell marker PD-1 in HER2-enriched tumors (Discovery/03-311, P = 0.045) and PD-1 positivity by IHC (Validation/211B, P = 0.035).
  
  
  
  Correlations between pCR rates, increases in Immune Index and markers of T-cell activity following brief exposure to trastuzumab in HER2-enriched tumors provide novel insights into the interaction between tumor biology, antitumor immunity, and response to treatment, and suggest potential clinically useful biomarkers in HER2(+) breast cancers. Clin Cancer Res; 22(13); 3249-59. ©2016 AACR.
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio. lyndsay.harris@case.edu vxv89@case.edu.
authors: Vinay
authors: V
authors: Varadan
authors: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors: Hannah
authors: H
authors: Gilmore
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Kristy L S
authors: KL
authors: Miskimen
authors: Curis, Inc., Lexington, Massachusetts.
authors: David
authors: D
authors: Tuck
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors: Shikha
authors: S
authors: Parsai
authors: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors: Amad
authors: A
authors: Awadallah
authors: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors: Ian E
authors: IE
authors: Krop
authors: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors: Eric P
authors: EP
authors: Winer
authors: Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
authors: Veerle
authors: V
authors: Bossuyt
authors: City of Hope National Medical Center, Duarte, California.
authors: George
authors: G
authors: Somlo
authors: Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
authors: Maysa M
authors: MM
authors: Abu-Khalaf
authors: Lifespan Comprehensive Cancer Center, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors: Mary Anne
authors: MA
authors: Fenton
authors: Women and Infants Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors: William
authors: W
authors: Sikov
authors: Case Western Reserve University School of Medicine, Cleveland, Ohio. lyndsay.harris@case.edu vxv89@case.edu.
authors: Lyndsay N
authors: LN
authors: Harris
mesh_terms: D000418:Albumins / Q000627:therapeutic use; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000627:therapeutic use; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000068878:Trastuzumab / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000418:Albumins; D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D017239:Paclitaxel; D061026:Programmed Cell Death 1 Receptor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C520255:130-nm albumin-bound paclitaxel; C105992:PDCD1 protein, human