High Hepatocyte Growth Factor Expression in Primary Tumor Predicts Better Overall Survival in Male Breast Cancer

Si-Qi Qiu; Johan van Rooijen; Hilde H. Nienhuis; Bert van der Vegt; Hetty Timmer-Bosscha; Elise van Leeuwen-Stok; Annemiek M. E. Walenkamp; Carolien H. M. van Deurzen; Geertruida H. de Bock; Elisabeth G. E. de Vries; Carolien P. Schröder


Breast Cancer Res. 2020;22(30) 

In This Article


Patient and Tumor Characteristics

In 720 out of the 841 patients, sufficient tumor tissue was available for analysis (Figure 1). Patient and tumor characteristics at the time of diagnosis of these 720 patients are shown in Table 1. The median age at diagnosis of breast cancer was 67 years (IQR, 58–76 years). Almost all patients had ER-positive tumors (98.3%), with 91.0% highly positive. PR positivity was observed in 76.8% and AR positivity in 96.9% of cases. HER2 positivity was present in tumors of 31 patients (4.9%). The majority of patients had a luminal-like breast cancer subtype, with 43.3% luminal A-like and 49.9% luminal B-like HER2−. There were 487 (67.6%) patients that were free from metastasis (M0) at the time of diagnosis. The treatment information of these 487 patients is provided in Additional file 1. The median follow-up for the M0 patients was 6.5 years (range, 0.04–23.8).

Figure 1.

CONSORT diagram of the studied patients, number of patients with available tissue for each marker, and number of M0 patients per marker available for survival analysis. BOOG, Borstkanker Onderzoek Groep; EORTC, European Organisation for Research and Treatment of Cancer; CXCR4, C-X-C chemokine receptor type 4; CXCL12, C-X-C motif chemokine 12; HGF, hepatocyte growth factor; M0, patients without metastases at diagnosis; M1, patients with metastases at diagnosis; Mx, patients with unknown metastatic status at diagnosis

Expression of the Studied Markers in the Primary Tumor

The exact number of tumors tested per marker is shown in Figure 1. Representative images of positive or negative expression for CXCR4, and negative, weak, or strong staining for CXCL12, HGF, and c-MET are shown in Additional file 2. The concordance rates of the percentage/H-score for each TMA core (defined as ≤ 20% difference in percentage or H-score) among the studied markers between the two observers are shown in Additional file 3. The percentage of positive cells for CXCR4 expression and H-score for CXCL12, HGF, and c-MET are demonstrated in Figure 2. The median CXCR4 expression per tumor was 50% (IQR, 18–83%) in the cytoplasm and 11% (IQR, 0–42%) in the nucleus. The median H-score for the CXCL12 expression in the cytoplasm was 100 (IQR, 83–102) and 100 (IQR, 92–107) for the nucleus expression. The median H-scores for HGF and c-MET expression were 106 (IQR, 83–133) and 155 (IQR, 130–180), respectively. Information on the heterogeneity of the studied markers between the cores is provided in Additional file 4, Additional file 5, Additional file 6 and Additional file 7.

Figure 2.

The expression of the studied markers in male breast cancer as assessed by immunohistochemistry. CXCR4 is presented as the percentage of cells with positive staining; CXCL12, HGF, and c-MET are presented as H-score. Each dot represents data for an individual patient. The orange line indicates the median and interquartile range. The dotted line separates markers on its left side presented as the percentage and markers on its right side presented as the H-score. CXCR4, C-X-C chemokine receptor type 4; CXCL12, C-X-C motif chemokine 12; HGF, hepatocyte growth factor

Prognostic Value of the Studied Markers for OS in M0 Patients

The exact number of M0 patients with available data for survival analysis is shown in Figure 1. Both HGF and CXCL12 (cytoplasm) expression by tumor cells were correlated to OS in univariable Cox regression analysis, and HGF remained significant in the multivariable analysis (Figure 3). Median OS was 7.5 years (95% CI, 6.1–8.9) for patients with HGF low-expressing tumors and 13.0 years (95% CI, 9.8–16.2) for those with HGF high-expressing tumors [hazard ratio (HR), 0.64 (95% CI, 0.49–0.84), P = 0.001]. Median OS was 9.1 years (95% CI, 7.7–10.6) for patients with CXCL12 (cytoplasm) low-expressing tumors and 15.3 years (95% CI, 12.3–18.3) for those with CXCL12 (cytoplasm) high-expressing tumors [HR, 0.63 (95% CI, 0.45–0.87), P = 0.005] (Figure 4). In the subgroup analysis, c-MET was correlated to OS in the subgroups with patients older than 65 years at diagnosis, PR low-expressing tumors, luminal B-like HER2− breast cancer subtype, invasive ductal tumors, and histological grade II tumors (see Additional file 8). CXCL12 (nucleus), CXCR4 (cytoplasm), and CXCR4 (nucleus) were not associated with OS in any patient or tumor subgroup in the univariable analysis (see Additional file 9, Additional file 10 and Additional files 11). Based on these findings, we further classified patients according to the expression of HGF and c-MET. The median OS of patients with both HGF and c-MET low-expressing tumors was 6.6 years (95% CI, 5.9–7.3), which was shorter than the OS of the other subgroups (Figure 5). Age at diagnosis, PR, and pT status were the other parameters associated with OS (Figure 3).

Figure 3.

Factors associated with overall survival in M0 patients at diagnosis in univariable (a) and multivariable (b) Cox regression analysis. a HGF, CXCL12 (cytoplasm), age at diagnosis, PR, and pT status are statistically significantly associated with overall survival. b HGF, age at diagnosis, ER, and pT status are independent predictors for overall survival. AR, androgen receptor; CI, confidence interval; CXCR4, C-X-C chemokine receptor type 4; CXCL12, C-X-C motif chemokine 12; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; HR, hazard ratio; ID, invasive ductal; LVI, lymphovascular invasion; M0, no metastasis; PR, progesterone receptor; pT status, pathological tumor status; OT, other types, including invasive lobular, mixed, micropapillary, mucinous, cribriform, tubular, metaplastic, clear cell, and apocrine carcinoma

Figure 4.

Kaplan-Meier analysis for the overall survival of M0 patients at diagnosis classified by HGF and CXCL12 (cytoplasm) tumor expression. CXCL12, C-X-C motif chemokine 12; HGF, hepatocyte growth factor; M0, no metastasis

Figure 5.

Kaplan-Meier analysis for overall survival of M0 patients at diagnosis classified by HGF and c-MET tumor expression. CI, confidence interval; HGF, hepatocyte growth factor; HR, hazard ratio; M0, no metastasis