title: Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01).
abstract: BACKGROUND
  The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid.
  
  
  METHODS
  Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray® RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis.
  
  
  RESULTS
  During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032).
  
  
  CONCLUSIONS
  Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01099436 . Registered April 6, 2010.
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Stefanie
authors.initials: S
authors.lastname: de Groot
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.|Department of Surgery, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Ayoub
authors.initials: A
authors.lastname: Charehbili
authors.affiliation: Department of Medical Oncology, Academic Medical Center, Meibergdreef 9, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands.
authors.forename: Hanneke W M
authors.initials: HW
authors.lastname: van Laarhoven
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Antien L
authors.initials: AL
authors.lastname: Mooyaart
authors.affiliation: Department of Surgery, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: N Geeske
authors.initials: NG
authors.lastname: Dekker-Ensink
authors.affiliation: Department of Radiotherapy, University Medical Center Utrecht, Heidelberglaan 100, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: van de Ven
authors.affiliation: Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Laura G M
authors.initials: LG
authors.lastname: Janssen
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Swen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Department of Medical Oncology, Amphia Hospital, Langendijk 75, P.O. Box 90157, 4800 RL, Breda, The Netherlands.
authors.forename: Joan B
authors.initials: JB
authors.lastname: Heijns
authors.affiliation: Department of Medical Oncology, Deventer Hospital, Nico Bolkesteinlaan 75, P.O. Box 5001, 7400 GC, Deventer, The Netherlands.
authors.forename: Lonneke W
authors.initials: LW
authors.lastname: Kessels
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Tahar
authors.initials: T
authors.lastname: van der Straaten
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Böhringer
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Jacobus J M
authors.initials: JJ
authors.lastname: van der Hoeven
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Hanno
authors.initials: H
authors.lastname: Pijl
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. j.r.kroep@lumc.nl.
authors.forename: Judith R
authors.initials: JR
authors.lastname: Kroep
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1