Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma

Abstract

Introduction: GP88 (progranulin) has been implicated in tumorigenesis and resistance to anti-estrogen therapies for estrogen receptor positive (ER+) breast cancer. Previous pathological studies showed that GP88 is expressed in invasive ductal carcinoma (IDC), but not in normal mammary epithelial tissue, benign lesions or lobular carcinoma. Based on these results, the present study examines GP88 prognostic significance in association with recurrence and death risks for ER+ IDC patients.

Methods: Two retrospective multi-site clinical studies examined GP88 expression by immunohistochemistry (IHC) analysis of paraffin-embedded breast tumor tissue sections from ER+ IDC patients (lymph node positive and negative, stage 1 to 3) in correlation with patients' survival outcomes. The training study established a GP88 cut-off value associated with decreased disease-free (DFS) and overall (OS) survivals. The validation study verified the GP88 cut-off value and compared GP88 prognostic information with other prognostic factors, particularly tumor size, grade, disease stage and lymph node status in multivariate analysis.

Results: GP88 expression is associated with a statistically significant increase in recurrence risk for ER+ IDC patients. The training study established that GP88 3+ score was associated with decreased DFS (P = 0.0004) and OS (P = 0.0036). The independent validation study verified that GP88 3+ score was associated with a 5.9-fold higher hazard of disease recurrence and a 2.5-fold higher mortality hazard compared to patients with tumor GP88 < 3+. GP88 remained an independent risk predictor after considering age, ethnicity, nodal status, tumor size, tumor grade, disease stage, progesterone receptor expression and treatments.

Conclusions: The survival factor GP88 is a novel prognostic biomarker, predictive of recurrence risk and increased mortality for non-metastatic ER+ IDC patients. Of importance, our data show that GP88 continues to be a prognostic factor even after five years. These results also provide evidence that GP88 provides prognostic information independent of tumor and clinical characteristics and would support prospective study to examine whether GP88 expression could help stratify patients with ER+ tumors for adjuvant therapy.

Figures

Figure 1

Immunohistochemical staining for GP88 expression in paraffin- embedded invasive ductal carcinoma tissue sections. Representative photomicrographs of breast cancer tissue sections from ER+ IDC showing various GP88 expression 0, 1+, 2+, and 3+, respectively are provided.

Figure 2

Kaplan-Meier estimates for disease-free survival and overall survival by GP88 scores in the training study. GP88 expression for the 267 ER+ IDC cases was examined by IHC and reported as GP88 scores of 0, 1+, 2+ and 3+. Kaplan-Meier estimates for DFS (A) and OS (B) were determined for each GP88 score group. The difference between the curves was estimated by the log-rank test.

Figure 3

Kaplan-Meier estimates for disease-free survival and overall survival by GP88 scores in the validation study. GP88 scores for cases examined were grouped as GP88 < 3+ and GP88 = 3+. Kaplan-Meier survival estimates for DFS and OS were established for the two GP88 groups. A: DFS in high (GP88 = 3+) and lower GP88 score (GP88 < 3+) groups in the training study. B: DFS in high and low GP88 score groups in the validation study. C: OS in high and low GP88 score groups in the training study. D: OS in high and low GP88 score groups in the validation study. E-F: Kaplan-Meier survival estimates for DFS were established for the two GP88 groups in the validation study separated by lymph node status. E: DFS for high and low GP88 groups of lymph node negative cases. F: DFS for high and low GP88 scores of lymph node positive cases.