Insulin-like growth factor 2: a poor prognostic biomarker linked to racial disparity in women with uterine carcinosarcoma.

Anne R Van Arsdale,Charles A Leath,David W Doo,Britt K Erickson,Yanhua Wang,Rebecca C Arend,Maria J Cossio,Gary L Goldberg,Gloria S Huang

doi:10.1002/cam4.1335

Abstract

The objective of this study was to investigate the relationship of insulin‐like growth factor 2 (IGF2) expression and survival in women with uterine carcinosarcoma (UCS). Insulin‐like growth factor 2 protein expression was determined by immunohistochemical staining of tumor tissues from 103 patients with UCS. The H‐score (product of staining intensity and percentage positive cells) was quantified for the epithelial cytoplasmic (EC), epithelial nuclear (EN), and malignant stromal compartments. Multivariable Cox proportional hazard regression models were used to examine the relationship of IGF2 levels with progression‐free survival (PFS) and overall survival (OS). Adjusting for stage, race, and adjuvant therapy, PFS and OS were reduced in patients with high IGF2 (H‐score ≥ median) in the EC and EN compartments. Black race was independently associated with reduced PFS and OS in patients with early‐stage disease, and IGF2 levels in the EC were higher in black than in white patients (P = 0.02, Wilcoxon test). In a race‐stratified multivariable analysis, high IGF2 in the epithelial compartments more than doubled the risk of death in black women; HR = 2.43 (95% CI: 1.18–5.01, P = 0.02) for high IGF2 in the EC; and HR = 2.34 (95% CI: 1.25–4.39, P = 0.008) for high IGF2 in the EN. In conclusion, high tumor IGF2 expression is an independent risk factor for reduced PFS and OS in UCS. Black women have elevated tumor IGF2 compared with white women, and decreased survival associated with high IGF2. These findings identify IGF2 as a candidate biomarker for survival linked to racial disparity in women with UCS.

Highlights

Uterine carcinosarcoma (UCS) is a rare but highly aggressive uterine malignancy that accounts for a disproportionate number of endometrial cancer deaths [1]
After controlling for race, stage and adjuvant therapy, high ike growth factor 2 (IGF2) expression in both the epithelial nuclear and cytoplasmic compartments was associated with roughly twice the hazard of progression compared with low IGF2 expression (Epithelial nuclear HR = 1.80, 95% CI: 1.08–2.99, P = 0.02 and epithelial cytoplasmic HR = 2.07, 95% CI: 1.19–3.60, P = 0.01)
After controlling for race, stage and adjuvant therapy, high IGF2 expression in both the epithelial nuclear and cytoplasmic compartments was associated with roughly twice the risk of death compared with low IGF2 expression (Epithelial nuclear HR = 1.86, 95% CI: 1.10–3.15, P = 0.02 and epithelial cytoplasmic HR = 1.98, 95% CI: 1.11–3.54, P = 0.02)

Summary

Introduction

Uterine carcinosarcoma (UCS) is a rare but highly aggressive uterine malignancy that accounts for a disproportionate number of endometrial cancer deaths [1]. These biphasic tumors are composed of carcinomatous and sarcomatous elements originating from a common progenitor cell [2]. Loss of IGF2 imprinting has been observed in UCS tumor tissue [13], and nonislet cell hypoglycemia due to tumor production of incompletely processed forms of pro-IGF2 (“big” IGF2) was previously reported in patients with UCS [14], supporting a potential, unrecognized role of IGF2 in UCS

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