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


In this unique cohort of male breast cancer patients, we identified HGF expression in the primary tumor to be an independent predictor for better OS in the non-metastatic setting. In addition, high expression of CXCL12 in the cytoplasm of tumor cells in the primary tumor was associated with better OS.

Remarkably, the prognostic value of HGF and c-MET is contradictory to the findings in female breast cancer. In female breast cancer, HGF and c-MET have been identified as a predictor for worse outcomes and are associated with a high Ki-67 labeling index.[14,16–19] This led to the hypothesis that HGF acts as a mitogen in female breast cancer.[32] In our cohort in male breast cancer, we identified HGF to be an independent prognostic factor for better OS.

The prognostic value of the CXCL12 expression in male breast cancer is comparable with the findings in female breast cancer reported in the literature.[33,34] In female breast cancer, the cytoplasmic expression of CXCL12 was associated with better disease-free survival and OS.[33,34] These results are confirmed by a recently published meta-analysis, which included 8 studies with a total of 2205 patients.[35] Four of these studies (N = 953) measured the CXCL12 protein expression which was positively correlated with disease-free survival and OS.

The remarkable difference in the prognostic value of HGF and c-MET compared to female breast cancer might result from differences in tumor and environment biology between male and female breast cancer. This is in line with a recent study of DNA sequencing analysis on 1943 cancer-related genes in 135 patients with male breast cancer, which demonstrated differences in the genomic landscape between male and female breast cancers. Somatic mutations in homologous recombination deficiency-related genes were more prevalent in male breast cancer compared to female breast cancer, whereas TP53 somatic mutations were less frequent.[36] Currently, it becomes clear that some important markers in breast cancer biology can play a different role in male compared to female breast cancer. When dependency patterns of key oncoproteins were compared between 134 male and 728 female breast cancer tissues, some similar patterns were observed for both genders, such as p53 and hypoxia-inducible factor 1-alpha.[8] However, also clear differences were identified. For example, the expression of PR showed in female breast cancer a continuous dependency on cytokeratin 8/18, cyclin D1, B cell lymphoma 2 (Bcl-2), and cyclin-dependent kinase inhibitor p21.[8] In male breast cancer, however, PR showed no dependency on these markers, indicating that PR is subject to effects from other markers.[8] AR had a stronger effector function in males compared to female tumors.[8] Results from the 21-gene breast recurrence score, used to characterize the molecular features of breast cancer, also indicate distinct differences in male compared to female breast cancer. Men below 40 years of age had a higher recurrence score compared to females while above 60 years men had a larger proportion with a low recurrence score.[10] Therefore, although differences between male and female breast cancer become apparent, the crosstalk among predominant biologic pathways and their function in males is not well understood, including that of the HGF/c-MET signaling.

In female breast cancer, HGF/c-MET promotes cell proliferation, migration, and invasion by HGF binding-induced c-MET activation of the phosphoinositide 3-kinase/Akt pathway and the Erk/mitogen-activated protein kinase cascade.[14] Furthermore, high expression of HGF or c-MET was associated with higher histological tumor grade and worse patient outcomes.[16,19] In the present study, higher expression of both HGF and c-MET was associated with improved OS. One possible factor contributing to this difference might be the age difference between male and female breast cancer patients. Preclinical evidence suggests that with advancing age, the tumor stroma exhibits alterations, such as decreased interferon signaling and antigen presentation. These changes may influence the proliferative effects of the tumor microenvironment.[37] The influence of age on the tumor microenvironment needs to be further elucidated but might lead to new insight into the dynamics of the tumor microenvironment.

Our study has limitations. First, due to its retrospective nature, data of some patient and tumor characteristics are missing. Nevertheless, the number of M0 patients excluded for the OS analysis was limited, and therefore, a significant impact on our findings appears unlikely. Second, currently, there is no widely accepted standardized methodology for immunohistochemical staining and the scoring of the studied markers. This may create bias in interpreting the data. These issues can be addressed in the prospective Male Breast Cancer Program prospective part (NCT01101425), which has finalized the inclusion and of which analyses are ongoing.