title: Identification of stromal ColXα1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer.
abstract: BACKGROUND
  The influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.
  
  
  METHODS
  We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.
  
  
  RESULTS
  Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.
  
  
  CONCLUSIONS
  Increased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.
authors.affiliation: Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA. alex_brodsky@brown.edu.|Department of Pathology, Rhode Island Hospital and Lifespan Medical Center, Providence, RI, 02903, USA. alex_brodsky@brown.edu.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Brodsky
authors.affiliation: Department of Pathology, Women and Infants Hospital, Warren Alpert Medical School of Brown University, Providence, USA.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Yang
authors.affiliation: Molecular Biology, Cell Biology, & Biochemistry, Brown University, Providence, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schorl
authors.affiliation: Department of Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA.
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Fenton
authors.affiliation: Department of Surgery, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Graves
authors.affiliation: Program in Women's Oncology, Women and Infants Hospital, Warren Alpert Medical School of Brown University, Providence, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Sikov
authors.affiliation: Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA.
authors.forename: Murray B
authors.initials: MB
authors.lastname: Resnick
authors.affiliation: Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA. ywang6@lifespan.org.|Department of Pathology, Rhode Island Hospital and Lifespan Medical Center, Providence, RI, 02903, USA. ywang6@lifespan.org.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology*; D024121:Collagen Type X / Q000235:genetics / Q000302:isolation & purification*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics*; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D024121:Collagen Type X; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human
keywords: Collagen; HER2-positive breast cancer; Neoadjuvant chemotherapy; Tumor infiltrating lymphocytes; Tumor microenvironment