IGFBP ratio confers resistance to IGF targeting and correlates with increased invasion and poor outcome in breast tumors
Menée sur une cohorte de 76 patientes atteintes d'un cancer du sein, puis in vitro, cette étude suggère que le rapport entre les niveaux d'expression de IGFBP-5 et IGFBP-4 pourrait servir de biomarqueur pour prédire la réponse à une thérapie ciblée anti-IGF-1R
Purpose: To improve the significance of insulin-like growth factor binding protein 5 (IGFBP-5) as a prognostic and potentially predictive marker in breast cancer patients. Experimental Design: Increased IGFBP-5 expression was identified in MCF-7 cells resistant (MCF-7R4) to the IGF-1R/InsR inhibitor, BMS-536924 and its role examined by targeted knockdown and overexpression in multiple experimental models. Protein expression of IGFBP-5 was measured by immunohistochemistry in a cohort of 76 breast cancer patients to examine correlative associations with invasive tumor fraction and outcome. The utility of a combined IGFBP-5/IGFBP-4 (BPR) expression ratio was applied to predict anti-IGF-1R/InsR response in a panel of breast cancer lines and outcome in multiple breast tumor cohorts. Results: IGFBP-5 knockdown decreased BMS-536924 resistance in MCF-7R4 cells, while IGFBP-5 overexpression in MCF-7 cells conferred resistance. When compared to pathologically normal reduction mammoplasty tissue, IGFBP-5 expression levels were upregulated in both invasive and histologically normal adjacent breast cancer tissue. In both univariate and multivariate modeling, metastasis-free survival (MFS), recurrence free survival (RFS), and overall survival (OS) were significantly associated with high IGFBP-5 expression. Prognostic power of IGFBP-5 was further increased with the addition of IGFBP-4 where tumors were ranked based upon IGFBP-5/IGFBP-4 expression ratio (BPR). Multiple breast cancer cohorts confirm that BPR (high vs. low) was a strong predictor of RFS and OS. Conclusion: IGFBP-5 expression is a marker of poor outcome in breast cancer patients. An IGFBP-5/IGFBP-4 expression ratio may serve as a surrogate biomarker of IGF pathway activation and predict sensitivity to anti-IGF-1R-targeting.
Clinical Cancer Research , résumé, 2012