title: Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression.
abstract: Based on the hypothesis that impaired glucose metabolism might be associated with survival outcomes independently of overt diabetes, we sought to investigate the prognostic value of routinely used glycemic parameters in a prospective study of breast cancer (BC) patients.
  
  
  
  Fasting blood glucose, insulin and HbA1c levels, and insulin resistance (assessed by the Homeostasis Model Assessment [HOMA] index) at diagnosis were evaluated in 286 nondiabetic BC patients (249 with primary cancer, 37 with metastatic) with respect to those parameters' possible associations with clinicopathological features and survival outcomes. As a control group, 143 healthy women matched in a 2:1 ratio for age, blood lipid levels, and body mass index were also investigated.
  
  
  
  Fasting blood glucose level (mean ± SD: 99 ± 26 vs. 85 ± 15 mg/dL), insulin level (median: 10.0 vs. 6.8 μIU/mL), and HOMA index (median: 2.2 vs. 1.4), but not HbA1c level, were significantly elevated in BC patients compared with control subjects. Receiver operating characteristics analysis showed comparable areas for blood glucose and insulin levels, and HOMA index (ranging from 0.668 to 0.671). Using a cutoff level of 13 μIU/mL, insulin had the best specificity (92%) and sensitivity (41%), was significantly associated with disease stage, and acted as a negative prognostic marker of progression-free survival (hazard ratio: 2.17; 95% confidence interval: 1.13-4.20) independently of menopausal status, disease stage, hormone receptor status, and human epidermal growth factor receptor 2 and Ki67 expression.
  
  
  
  These results suggest that insulin determination might provide prognostic information in BC and support the hypothesis that lifestyle and/or pharmacological interventions targeting glucose metabolism could be considered to improve survival outcome of selected BC patients.
  
  
  
  Pretreatment insulin levels may represent a biomarker of adverse prognosis in nondiabetic women with breast cancer, independently of other well-established prognostic factors (i.e., stage, hormone receptors, HER2/neu, and Ki67). This finding has important implications, because it provides the rationale for lifestyle or insulin-targeting pharmacologic interventions as a means of improving breast cancer outcomes not only in early stages, but also in advanced-stage breast cancer patients with aggressive tumor phenotypes (HER2-negative hormone-resistant, or triple-negative breast cancer), in which treatments are still challenging. The possibility of using insulin as a biomarker to guide insulin-targeted interventions also should be taken into account.
authors.affiliation: San Raffaele Roma Open University, Rome, Italy patrizia.ferroni@sanraffaele.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferroni
authors.affiliation: Interinstitutional Multidisciplinary Biobank, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy Department of Systems Medicine, Medical Oncology, Tor Vergata Clinical Center, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Riondino
authors.affiliation: Department of Systems Medicine, Medical Oncology, Tor Vergata Clinical Center, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Laudisi
authors.affiliation: Department of Systems Medicine, Medical Oncology, Tor Vergata Clinical Center, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Portarena
authors.affiliation: Department of Systems Medicine, Medical Oncology, Tor Vergata Clinical Center, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Formica
authors.affiliation: Interinstitutional Multidisciplinary Biobank, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy.
authors.forename: Jhessica
authors.initials: J
authors.lastname: Alessandroni
authors.affiliation: Interinstitutional Multidisciplinary Biobank, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: D'Alessandro
authors.affiliation: Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
authors.affiliation: Department of Pathology, San Giovanni Hospital-Addolorata, Rome, Italy.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Costarelli
authors.affiliation: Department of Surgery, San Giovanni Hospital-Addolorata, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cavaliere
authors.affiliation: San Raffaele Roma Open University, Rome, Italy Interinstitutional Multidisciplinary Biobank, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Guadagni
authors.affiliation: Department of Systems Medicine, Medical Oncology, Tor Vergata Clinical Center, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Roselli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D003920:Diabetes Mellitus / Q000097:blood* / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006442:Glycated Hemoglobin / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000235:genetics; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D018719:Erb-b2 Receptor Tyrosine Kinases; C517652:hemoglobin A1c protein, human; C508053:ERBB2 protein, human
keywords: Breast cancer; Insulin; Insulin resistance; Prognostic value