The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth, proliferation and cell cycle progression and associated with tumor genesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early 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.


Formalin-fixed paraffin-embedded (FFPE) tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression using IHC (n=216) and for analysis of 8 candidate SNPs in genes of the IGF-1 pathway (n=184) using OpenArray® RealTime PCR. Optionally, blood samples were collected immediately before chemotherapy for determination of glucose, insulin, IGF-1, IGF-2 and IGF-BP3. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne (MP) pathologic response were performed using chi square and logistic regression analyses.


High IGF-1R expression was associated with estrogen receptor expression (P=0.001). During chemotherapy, a significant number of the tumors (47.2%) showed a decrease in IGF-1R expression, while in a small number of the 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 analyses (P=0.012) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P=0.008). Moreover, the variant T allele of 3129G>T in IGF-1R (rs2016347) was associated with a better pathological response in multivariate analyses (P=0.032). In addition, high glucose and insulin levels were associated with positive lymph node status before chemotherapy in multivariate analysis (P=0.019) and (P=0.031), respectively.


Neoadjuvant chemotherapy induced changes in the IGF-1R expression in most of the tumors. Absence or diminished expression of IGF-1R after treatment was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF-1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC. These findings may help to select patients who might benefit from (co-)treatment with an IGF-1 pathway inhibitor.

Citation Format: de Groot S, Charehbili A, van Laarhoven HWM, Mooyaart AL, Dekker-Ensink NG, van de Ven S, Janssen LGM, Swen JJ, Smit VTHBM, Heijns JB, Kessels LW, van der Straaten RJHM, Bhringer S, Gelderblom AJ, van der Hoeven JJM, Guchelaar HJ, Pijl H, Kroep JR. Insulin-like growth factor 1 receptor expression and polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: Results from the NEOZOTAC trial (BOOG 2010-01). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-54.