title: Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial.
abstract: The aim of this work was to evaluate the impact of (and relative contribution of) tumor-related and immune-related diversity of HER2-positive disease on the response to neoadjuvant chemotherapy plus anti-HER2 agents.
  
  
  
  The CherLOB phase II study randomized 121 HER2-positive breast cancer patients to neoadjuvant chemotherapy plus trastuzumab, lapatinib or both. Tumor samples from diagnostic core biopsy were centralized. Tumor-infiltrating lymphocytes (TILs) were evaluated on H&E slides. Intrinsic subtyping was carried out using the research-based 50-gene prediction analysis of a microarray (PAM50) subtype predictor. Immune-related gene signatures were also evaluated.
  
  
  
  Continuous Str-TILs and It-TILs were significantly associated with pCR [OR 1.03, 95% CI 1.02-1.05 (P < 0.001) and OR 1.09, 95% CI 1.04-1.15 (P < 0.001) for Str-TILs and It-TILs, respectively]. According to PAM50, the subtype distribution was as follows: HER2-enriched 26.7%, Luminal A 25.6%, Luminal B 16.3%, Basal-like 14% and Normal-like 17.4%. The highest rate of pCR was observed for the HER2-enriched subtype (50%), followed by Basal-like, Luminal B and Luminal A (χ(2) test, P = 0.026). Immune gene signatures significantly associated with pCR in univariate analyses were identified: most of them maintained a significant association with pCR in multivariate analyses corrected for PAM50 subtypes, whereas TILs did not.
  
  
  
  In this study, both tumor-related and immune-related features contribute to the modulation of pCR after neoadjuvant chemotherapy plus anti-HER2 agents. Immune signatures rather than TILs added significant prediction of pCR beyond PAM50 intrinsic subtypes.
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua Division of Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy mariavittoria.dieci@unipd.it.
authors.forename: M V
authors.initials: MV
authors.lastname: Dieci
authors.affiliation: Translational Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona Translational Genomic and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Prat
authors.affiliation: Center for Genome Research, University of Modena and Reggio Emilia, Modena.
authors.forename: E
authors.initials: E
authors.lastname: Tagliafico
authors.affiliation: Translational Genomic and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona.
authors.forename: L
authors.initials: L
authors.lastname: Paré
authors.affiliation: Division of Pathology, Modena University Hospital, Modena.
authors.forename: G
authors.initials: G
authors.lastname: Ficarra
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliera ASMN, IRCCS, Reggio Emilia.
authors.forename: G
authors.initials: G
authors.lastname: Bisagni
authors.affiliation: Department of Medical and Surgical Sciences of Mother, Child and Adult, University of Modena and Reggio Emilia, Modena.
authors.forename: F
authors.initials: F
authors.lastname: Piacentini
authors.affiliation: U.O. Multidisciplinare di Patologia Mammaria, AO. Istituti Ospitalieri di Cremona, Cremona, Italy.
authors.forename: D G
authors.initials: DG
authors.lastname: Generali
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua Division of Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Conte
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua Division of Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Guarneri
mesh_terms: D000328:Adult; D000368:Aged; D062005:Biopsy, Large-Core Needle; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D000077341:Lapatinib; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D046228:Microarray Analysis; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D011960:Receptors, Estrogen / Q000235:genetics; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: HER2; PAM50; breast cancer; immune signatures; neoadjuvant; tumor-infiltrating lymphocytes