Insulin-like growth factor receptor polymorphism defines clinical outcome in estrogen receptor-positive breast cancer patients treated with tamoxifen.

Abstract

Compelling evidence points to a key role for insulin-like growth factor 1 (IGF1) signaling in breast cancer development and progression. In addition, IGF1 receptor (IGF1R) expression has been correlated and functionally linked with estrogen receptor (ER) signaling. Recent translational studies support a cross talk between IGF1R and ERα at different levels and data suggest enhanced IGF1R signaling as a causative mechanism of tamoxifen (TAM) resistance. We tested whether functional germline variations in the IGF pathway are associated with clinical outcome in ER-positive primary invasive breast cancer patients, who were treated with surgery and adjuvant TAM. Tissue samples of 222 patients with ER+ primary invasive breast cancer, who had undergone surgery at Charing Cross Hospital, London, UK between 1981 and 2003, were analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue samples and six functional IGF1 pathway polymorphisms were analyzed using direct DNA sequencing and PCR-restriction fragment length polymorphism. In multivariable analysis, patients with primary invasive breast cancer carrying IGF1R_rs2016347 G allele had a significantly increased risk of early tumor progression (hazard ratio (HR) 2.01; adjusted P=0.004) and death (HR 1.84; adjusted P=0.023) compared with patients carrying G/T or T/T, independent of established clinicopathological determinants. This association remained significant after adjusting for multiple testing. In addition, we were able to demonstrate that IRS1_rs1801123 and IGFBP3_rs2854744 were significantly associated with lymph node involvement and tumor size, respectively. We provide the first evidence for IGF1R_rs2016347 as an independent prognostic marker for ER+ breast cancer patients treated with TAM and support a rational for combined treatment strategies.

• Authors: T Winder, G Giamas, P M Wilson, W Zhang, D Yang, P Bohanes, Y Ning, A Gerger, J Stebbing, H-J Lenz
• Journal: The pharmacogenomics journal (Pharmacogenomics J) Vol. 14 Issue 1 Pg. 28-34 (Feb 2014) ISSN: 1473-1150 [Electronic] United States
• PMID: 23459444 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Estrogen
• Selective Estrogen Receptor Modulators
• Tamoxifen
• Receptor, IGF Type 1

Topics

• Amplified Fragment Length Polymorphism Analysis
• Breast Neoplasms (drug therapy, genetics, pathology, surgery)
• Chemotherapy, Adjuvant
• Combined Modality Therapy
• Disease-Free Survival
• Female
• Humans
• Multivariate Analysis
• Neoplasm Invasiveness
• Polymorphism, Single Nucleotide
• Receptor, IGF Type 1 (genetics)
• Receptors, Estrogen (antagonists & inhibitors, metabolism)
• Selective Estrogen Receptor Modulators (administration & dosage, therapeutic use)
• Tamoxifen (administration & dosage, therapeutic use)