Fibroblast growth factor receptor-1 protein expression is associated with prognosis in estrogen receptor-positive/human epidermal growth factor receptor-2-negative primary breast cancer

Abstract

Recently, research into the development of new targeted therapies has focused on specific genetic alterations to create advanced, more personalized treatment. One of the target genes, fibroblast growth factor receptor-1 (FGFR1), has been reported to be amplified in estrogen receptor (ER)-positive subtype breast cancer, and is considered one possible mechanism of endocrine resistance through cross-talk between ER and growth factor receptor signaling. We performed a comprehensive analysis of FGFR1 at the levels of gene copy number, transcript and protein expression, and examined the relationships between FGFR1 status and clinicopathological parameters, including prognosis in 307 ER-positive/HER2-negative primary breast cancer patients treated with standard care at our institute. Most notably, a high level of FGFR1 protein expression was observed in 85 patients (27.7%), and was positively associated with invasive tumor size (P = 0.039). Furthermore, univariate analysis revealed that high FGFR1 protein expression was significantly correlated with poor relapse-free survival rate (P = 0.0019, HR: 2.63, 95% confidence interval: 1.17-5.98), and showed a tendency towards an increase in recurrent events if the observation period extended beyond the 5 years of the standard endocrine treatment term. FGFR1 gain/amplification was found in 43 (14.0%) patients, which was only associated with higher nuclear grade (P = 0.010). No correlation was found between FGFR1 mRNA expression levels and any clinicopathological factors. Overall, the level of FGFR1 protein expression may be a biomarker of ER-positive/HER2-negative primary breast cancer with possible resistance to standard treatment, and may be a useful tool to identify more specific patients who would benefit from FGFR-1 targeted therapy.

Keywords: Biomarker; ER-positive/HER2-negative; breast cancer; fibroblast growth factor receptor-1; protein expression.

Figure 1

Intensity score of immunohistochemical staining of fibroblast growth factor receptor‐1 (FGFR1). Score 0: (a) negative staining; (b) score 1: weak staining; (c) score 2: moderate staining; and (d) score 3: strong staining.

Figure 2

Protein expression of fibroblast growth factor receptor‐1 (FGFR1) and survival. Kaplan–Meier plots of the association of FGFR1 protein expression with relapse free survival (RFS) (a) and breast cancer specific survival (BCSS) (b) in estrogen receptor (ER)‐positive/human epidermal growth factor receptor‐2 (HER2)‐negative primary breast cancer. RFS verified by the log‐rank test.

Figure 3

Correlation between fibroblast growth factor receptor‐1 (FGFR1) amplification, mRNA and protein expression. Relationship between FGFR1 gene copy number and mRNA expression level (a), gene copy number and protein expression level (b), and mRNA and protein expression level (c), verified by the Wilcoxon test. The line within each box represents the median value for that group. Whiskers above and below each box show the maximum and minimum values in that group, respectively.