title: Association of Depressed Anti-HER2 T-Helper Type 1 Response With Recurrence in Patients With Completely Treated HER2-Positive Breast Cancer: Role for Immune Monitoring.
abstract: OBJECTIVE
  There is a paucity of immune signatures identifying patients with human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancer (IBC) at risk for treatment failure following trastuzumab and chemotherapy.
  
  
  OBJECTIVE
  To determine whether circulating anti-HER2 CD4-positive (CD4+) T-helper type 1 (Th1) immunity correlates with recurrence in patients with completely treated HER2-positive IBC.
  
  
  METHODS
  Hypothesis-generating exploratory translational analysis at a tertiary care referral center of patients with completely treated HER2-positive IBC with median (interquartile range) follow-up of 44 (31) months. Anti-HER2 Th1 responses were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II-promiscuous peptides via interferon-γ (IFN-γ) enzyme-linked immunospot assay.
  
  
  METHODS
  T-helper type 1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFCs]/106 cells). Anti-HER2 Th1 responses in treatment-naive patients (used as an immunologic baseline) were compared with those in patients completing trastuzumab and chemotherapy; in the latter group, analyses were stratified by recurrence status. Recurrence was defined as any locoregional or distant breast event, or both. Cox regression analysis estimated the instantaneous hazard of recurrence (ie, disease-free survival [DFS]) stratified by anti-HER2 Th1 responsivity.
  
  
  RESULTS
  In 95 women with HER2-positive IBC (median [range] age, 49 [24-85] years; 22 treatment-naive, 73 treated with trastuzumab and chemotherapy), depressed anti-HER2 Th1 responsivity (recurrence, 2 of 25 [8%], vs nonrecurrence, 40 of 48 [83%]; P < .001), mean (SD) repertoire (0.1 [0.1] vs 1.5[0.2]; P < .001), and mean (SD) cumulative response (14.8 [2.0] vs 80.2 [11.0] SFCs/106 cells; P < .001) were observed in patients incurring recurrence (n = 25) compared with patients without recurrence (n = 48). After controlling for confounding, anti-HER2 Th1 responsivity remained independently associated with recurrence (P < .001). This immune disparity was mediated by anti-HER2 CD4+T-bet+IFN-γ+ (Th1)-not CD4+GATA-3+IFN-γ+ (Th2) or CD4+CD25+FoxP3+ (Treg)-phenotypes, and not attributable to immune incompetence. When stratifying trastuzumab plus chemotherapy-treated patients by Th1 responsivity, Th1-nonresponsive patients demonstrated a worse DFS (median, 47 vs 113 months; P < .001) compared with Th1-responsive patients (hazard ratio, 16.9 [95% CI, 3.9-71.4]; P < .001).
  
  
  CONCLUSIONS
  Depressed anti-HER2 Th1 response is a novel immune correlate to recurrence in patients with completely treated HER2-positive IBC. These data underscore a role for immune monitoring in patients with HER2-positive IBC to identify vulnerable populations at risk of treatment failure.
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia.
authors.forename: Jashodeep
authors.initials: J
authors.lastname: Datta
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia.
authors.forename: Megan
authors.initials: M
authors.lastname: Fracol
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: McMillan
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia.
authors.forename: Erik
authors.initials: E
authors.lastname: Berk
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Xu
authors.affiliation: Division of Medical Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia.
authors.forename: Noah
authors.initials: N
authors.lastname: Goodman
authors.affiliation: Division of Medical Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.affiliation: Division of Medical Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia3Department of Epidemiology and Biostatistics, Hospital of the University of Pennsylvania, Philadelphia.
authors.forename: Angela
authors.initials: A
authors.lastname: DeMichele
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia4Rena Rowen Breast Center, Hospital of the University of Pennsylvania, Philadelphia.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Czerniecki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D015166:Monitoring, Immunologic; D009364:Neoplasm Recurrence, Local; D015143:Philadelphia; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D062606:Tertiary Care Centers; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D000068878:Trastuzumab / Q000627:therapeutic use*; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human