title: Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial.
abstract: BACKGROUND
  To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or both (THP), or monoclonal antibodies alone (HP).
  
  
  METHODS
  Immune gene mRNA expression (n = 350, 83.8%), lymphocyte infiltration (TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry (n = 305, 73.1%) were correlated with pCRB. We studied five selected genes (IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells (IGG), T cells (CD8A), antigen-presenting cells (MHC2), and to MHC1 genes (MHC1), STAT1 co-expressed genes (STAT1), and interferon-inducible genes (IF-I). Gene expression data from the NOAH trial were used for validation.
  
  
  RESULTS
  TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only.
  
  
  CONCLUSIONS
  The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors.
authors.affiliation: Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bianchini
authors.affiliation: Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: Centrum Onkologii, Warsaw, Poland.
authors.forename: T
authors.initials: T
authors.lastname: Pienkowski
authors.affiliation: Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Im
authors.affiliation: Oncologia Medica, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: G V
authors.initials: GV
authors.lastname: Bianchi
authors.affiliation: Taipei-Veterans General Hospital, National Yang-Ming University, Taipei.
authors.forename: L-M
authors.initials: LM
authors.lastname: Tseng
authors.affiliation: Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan.
authors.forename: M-C
authors.initials: MC
authors.lastname: Liu
authors.affiliation: Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, Valencia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Lluch
authors.affiliation: Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Galeota
authors.affiliation: Fondazione Michelangelo, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Magazzù
authors.affiliation: Hospital Reina Sofia, Córdoba, Spain.
authors.forename: J
authors.initials: J
authors.lastname: de la Haba-Rodríguez
authors.affiliation: Division of Medical Oncology, Seoul National University Hospital Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: D-Y
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Centre des maladies du sein, Hôpital du Saint-Sacrement, CHU de Québec, Québec, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Poirier
authors.affiliation: Hospital Ernesto Dornelles, Porto Alegre, Brazil.
authors.forename: J L
authors.initials: JL
authors.lastname: Pedrini
authors.affiliation: NN Petrov Research Institute of Oncology, St Petersburg, Russia.
authors.forename: V
authors.initials: V
authors.lastname: Semiglazov
authors.affiliation: Fondazione Michelangelo, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Valagussa
authors.affiliation: Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy gianni.luca@hsr.it.
authors.forename: L
authors.initials: L
authors.lastname: Gianni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D000068878:Trastuzumab / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: breast cancer; gene expression; immune system; pertuzumab; predictive marker; trastuzumab