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)

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, 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

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.

Figures

Fig. 1
Fig. 1
Examples of the membranous IGF-1R staining in breast tumor tissue sections. Score 0: staining is observed in <10 % of the tumor cells. Score 1+: incomplete staining is observed in >10 % of the tumor cells, Score 2+: weak or moderate complete staining is observed in >10 % of the tumor cells, Score 3+: strong complete staining is observed >10 % of tumor cells. Samples were considered negative if 0 or 1+ was scored, and positive if 2+ and 3+ was given
Fig. 2
Fig. 2
Consort diagram. FFPE formalin-fixed paraffin-embedded, IHC immunohistochemistry, MP Miller and Payne, pCR pathological complete response, SNP single nucleotide polymorphism. *Less tumor specimens available for performing IHC due to pCR of no tumor in the analyzed FFPE slide
Fig. 3
Fig. 3
Membranous IGF-1R expression before and after treatment and the association with pathological response. *P <0.05. IGF-1R insulin-like growth factor 1 receptor, MP Miller and Payne
Fig. 4
Fig. 4
CART analyses of pCR in BC patients treated with TAC chemotherapy. The tree is divided by the SNPs to predict pCR, which has a significant prediction score (AUC 0.613 95 % CI 0.518–0.707, P = 0.040). IGFBP3 insulin-like growth factor binding protein 3, IGF1R insulin-like growth factor 1 receptor, pCR pathological complete response

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