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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01099436 . Registered April 6, 2010.

• Authors: Stefanie de Groot, Ayoub Charehbili, Hanneke W M van Laarhoven, Antien L Mooyaart, N Geeske Dekker-Ensink, Saskia van de Ven, Laura G M Janssen, Jesse J Swen, Vincent T H B M Smit, Joan B Heijns, Lonneke W Kessels, Tahar van der Straaten, Stefan Böhringer, Hans Gelderblom, Jacobus J M van der Hoeven, Henk-Jan Guchelaar, Hanno Pijl, Judith R Kroep, Dutch Breast Cancer Research Group
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 18 Issue 1 Pg. 3 (Jan 06 2016) ISSN: 1465-542X [Electronic] England
• PMID: 26738606 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• IGF1R protein, human
• Receptors, Somatomedin
• Receptor, IGF Type 1

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols
• Biomarkers, Tumor
• Breast Neoplasms (drug therapy, genetics, pathology)
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Association Studies
• Humans
• Middle Aged
• Neoadjuvant Therapy
• Polymorphism, Single Nucleotide
• Prognosis
• Receptor, IGF Type 1
• Receptors, Somatomedin (biosynthesis, genetics)