title: Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer.
abstract: BACKGROUND
  Tumor microenvironment of metastasis (TMEM), consisting of direct contact between a macrophage, an endothelial cell, and a tumor cell, has been associated with metastasis in both rodent mammary tumors and human breast cancer. We prospectively examined the association between TMEM score and risk of distant metastasis and compared risk associated with TMEM score with that associated with IHC4.
  
  
  METHODS
  We conducted a case-control study nested within a cohort of 3760 patients with invasive ductal breast carcinoma diagnosed between 1980 and 2000 and followed through 2010. Case patients were women who developed a subsequent distant metastasis; control subjects were matched (1:1) on age at and calendar year of primary diagnosis. TMEM was assessed by triple immunostain and IHC4 by standard methods; slides were read by pathologists blinded to outcome. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusted for clinical variables. A Receiver Operating Characteristic analysis was performed, and the area under the curve was estimated. All statistical tests were two-sided.
  
  
  RESULTS
  TMEM score was associated with increased risk of distant metastasis in estrogen receptor (ER)(+)/human epidermal growth factor receptor (HER2)(-) tumors (multivariable OR high vs low tertile = 2.70; 95% CI = 1.39 to 5.26; P trend = .004), whereas IHC4 score had a borderline positive association (OR10 unit increase = 1.06; 95% CI = 1.00 to 1.13); the association for TMEM score persisted after adjustment for IHC4 score. The area under the curve for TMEM, adjusted for clinical variables, was 0.78. Neither TMEM score nor IHC4 score was independently associated with metastatic risk overall or in the triple negative or HER2(+) subgroups.
  
  
  CONCLUSIONS
  TMEM score predicted risk of distant metastasis in ER(+)/HER2(-) breast cancer independently of IHC4 score and classical clinicopathologic features.
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ). thomas.rohan@einstein.yu.edu.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Rohan
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Xue
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Hung-Mo
authors.initials: HM
authors.lastname: Lin
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Timothy M
authors.initials: TM
authors.lastname: D'Alfonso
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Paula S
authors.initials: PS
authors.lastname: Ginter
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Maja H
authors.initials: MH
authors.lastname: Oktay
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Brian D
authors.initials: BD
authors.lastname: Robinson
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Mindy
authors.initials: M
authors.lastname: Ginsberg
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Glass
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: John S
authors.initials: JS
authors.lastname: Condeelis
authors.affiliation: Affiliation of authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TER, XX, MG); Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY (H-ML); Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (TMD'A, PSG, BDR); Department of Pathology, Montefiore Medical Center, Bronx, NY (MHO); Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (FBG); Center for Health Research, Kaiser Permanente Northwest, Portland, OR (AGG); Department of Oncology, Montefiore Medical Center, Bronx, NY (JAS); Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY (JSC); Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (JGJ).
authors.forename: Joan G
authors.initials: JG
authors.lastname: Jones
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000473:pathology / Q000503:physiopathology; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011379:Prognosis; D012372:ROC Curve; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D015203:Reproducibility of Results; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D059016:Tumor Microenvironment
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human