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Insulin-like growth factor receptor polymorphism defines clinical outcome in estrogen receptor-positive breast cancer patients Q1 treated with tamoxifen


Winder, T; Giamas, G; Wilson, P M; Zhang, W; Bohanes, P; Ning, Y; Gerger, A; Stebbing, J; Lenz, H-J (2014). Insulin-like growth factor receptor polymorphism defines clinical outcome in estrogen receptor-positive breast cancer patients Q1 treated with tamoxifen. Pharmacogenomics Journal, 14:28-34.

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.

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.

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8 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2014
Deposited On:04 Mar 2015 15:40
Last Modified:05 Apr 2016 19:04
Publisher:Nature Publishing Group
ISSN:1470-269X
Publisher DOI:https://doi.org/10.1038/tpj.2013.8
PubMed ID:23459444

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