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


Breast cancer in men is a rare disease. Although only 0.5–1% of all breast cancers occur in men, the incidence is slowly rising.[1,2] Generally, male breast cancer has more favorable tumor characteristics than female breast cancer, such as lower tumor grade, a higher incidence of estrogen receptor (ER) expression, and a lower incidence of human epidermal growth factor receptor 2 (HER2) expression.[1,3] On the other hand, male patients present with higher stages of disease at first diagnosis than women.[1,4] Although the outcome in male breast cancer is similar compared to women after correction for age and stage, in general, survival improvement in men is still lagging behind.[1,4–7] Due to the lack of survival data from randomized trials in male breast cancer, treatment strategies for this disease are largely based upon data from studies of treatment for female breast cancer. In recent years, it becomes clear that the male breast cancer biology may have distinct properties compared to females.[8–11] Therefore, a better understanding of the breast tumor characteristics in men may help to improve treatment strategies for male breast cancer.

The tumor microenvironment in female breast cancer is now recognized as a critical participant in determining the tumor biology. In this environment, the stromal cell-derived factor-1 (SDF1, also known as CXCL12)/the C-X-C chemokine receptor type 4 (CXCR4) axis as well as the hepatocyte growth factor (HGF)/c-MET axis play a role in promoting tumor progression and metastasis, as demonstrated in ex vivo cell experiments and in vivo mouse models of breast cancer.[12–14] The HGF/c-MET axis induces several biological responses in cancer cells, which lead to cell migration, matrix degradation, invasiveness, and induction of angiogenesis.[15] Moreover, overexpression of CXCR4, HGF, and c-MET in primary breast cancer is associated with worse patient outcomes in females.[14,16–20] Treatments targeting CXCR4 and c-MET in female metastatic breast cancer studied in early-phase clinical trials were tolerated well, and partial response and stable disease were observed.[21–24]

However, whether the CXCL12/CXCR4 and the HFG/c-MET axis hold similar significance in male breast cancer is unknown. These microenvironment factors are of interest because the host/environment in male breast cancer will likely be different from female breast cancer.

In order to gain more insight into the male breast cancer tumor and environment biology, we studied a large male breast cancer cohort from The Netherlands. This cohort is part of the international EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425). We aimed to explore the tumor expression of HGF, c-MET, CXCL12, and CXCR4 and their correlation with patient overall survival (OS).