Forkhead box M1 (FOXM1) expression predicts disease free survival and may mediate resistance to chemotherapy and hormonotherapy in male breast cancer

Introduction

Male breast cancer is a rare disease that represents less than 1% of all breast cancers [1,2]. Recent, studies on male breast cancer revealed notable differences compared to its female counterpart on the genomic, transcriptomic and proteomic level [3–10]. These findings suggest that male breast cancer should be considered as an entirely separate disease that needs more comprehensive analyses in order to define an optimal clinical management for these patients. Although the biology of female breast cancer is now well defined, knowledge bases of MBC is still incomplete. Thus, the panel of predictive and prognostic factors for male patients with breast cancer remains limited.

The Forkhead box protein M1, FOXM1, belongs to the Forkhead superfamily of transcription factors [11,12]. FOXM1 plays an important role in cell proliferation and cell cycle progression [13]. Furthermore, many studies demonstrated that FOXM1 plays an important role in all cancer hallmarks [14,15] which explains the increasing number of studies indicating that FOXM1 is an important target for cancer therapy that offers promising prospects [16–19]. Moreover, increased expression of FOXM1 has been found in solid tumors including male breast cancer [20] and it was highly correlated with tumor progression, poor prognosis and treatment resistance [21].

However, to date, predictive value of FOXM1 expression in MBC remains unknown. As part of the Understanding Male Breast cancer study (NCT03240510) we sought to investigate the predictive value of FOXM1 expression in male breast cancer.

Materials and Methods

Results

The median age at diagnosis was 66 years (range 30–96). Invasive ductal carcinoma was the predominant histological type representing 97% of the cases (n = 126). Tumor size ranged from 0.5 to 10 cm (median 2). 63.8% of our patients were grade 2 (n = 83) and 59.2% were N+ (n = 77). 45.4% of our patients were classified as luminal A-like (n = 59), 44.6% luminal B-like (n = 58), 5% HER2 enriched (n = 6) and 5% triple negative (n = 7). 93% (n = 121) of patients presented FOXM1 expression, however, only 37% were classified as high FOXM1 expression group (n = 48). In our series, all of our patients had surgery, 36% received adjuvant radiotherapy (n = 48), 31.5% received adjuvant chemotherapy (n = 41), 4.6% received palliative chemotherapy (n = 6) and 36% received adjuvant hormonotherapy (Tamoxifen) (n = 47).

Discussion

Male breast cancer is an uncommon disease that for a long time thought to be identical to female breast cancer. Lately, efforts towards better understanding the biology of male breast cancer are increasing, they outlined the differences hidden behind the similarities between male and female breast cancer [7–10]. Thus, management of male breast cancer should not be extrapolate from research carried out on female patients with breast cancer. Since male breast cancer has a limited biomarker panels, we assessed FOXM1 as a potential predictive biomarker for male breast cancer.

FOXM1 is intimately involved in tumorigenesis since it contributes to tumor initiation and progression, angiogenesis as well as epithelial-mesenchymal transition (EMT) [24–28]. FOXM1 is overexpressed in a wide range of cancers including male breast cancer [20]. Several studies reported that high FOXM1 expression is associated with poor prognosis [29]. In fact, high FOXM1 expression correlates with decreased overall survival, and disease free survival, increased incidence of lymph node metastasis, advanced stage and higher histological grade [21,30,31]. Moreover, we recently demonstrated that FOXM1 is also associated with poor prognosis in male breast cancer [20].

Drug resistance, either acquired or inherent, constitutes a major clinical challenge. The mechanisms underlying drug resistance are multiple and complex, and not fully understood. Therefore, identifying predictive factors to drug resistance is warranted in order to insure an optimal therapeutic management. Numerous studies indicates that FOXM1 induces resistance to treatment [33,34]. Research conducted on cancer cells revealed that FOXM1 expression is correlated with resistance to paclitaxel, anthracycline and cisplatin [34,35]. Furthermore, resistance to hormonotherapy, Herceptin and lapatinib in breast cancer was observed in breast cancer cell lines with high expression of FOXM1 [36,37]. Taken together, these findings showcase the significant role played by FOXM1 in resistance to cancer therapy, and highlight the potential success of FOXM1 targeted therapy.

Despite the fact of the emerging evidence of FOXM1 importance as a predictive marker to drug resistance, the predictive impact of FOXM1 has not been analyzed for male breast cancer so far. We therefore assessed FOXM1 as a potential predictive marker in male breast cancer. In this report conducted on 130 male breast cancer cases, we found that High FOXM1 expression was significantly associated with chemotherapy and endocrine resistance. In fact, patients with high FOXM1 expression presented higher levels of progression under both chemotherapy and hormonotherapy. These results are aligned with literature findings in female breast cancer along with other cancer types [32,33]. Furthermore, FOXM1 expression was identified as an independent predictive factor for disease free survival in male breast cancer patients.

Although the prognostic value of FOXM1 has been established in numerous solid tumors including breast cancer in both genders [29], the use of FOXM1 as a predictive biomarker of response to FOXM1 targeting therapies needs to be clinically validated. In the breast cancer setting, whether it’s in male or female, once targeted therapy anti-FOXM1 is available, it should be evaluated through early pilot studies in different molecular subtypes especially in the most challenging breast cancer subtype triple negative breast cancer (TNBC). Since to date, the treatment of TNBC is essentially based on chemotherapy and lacks targeted therapies, FOXM1 inhibitors may represent new promising therapeutic option.

Our study is limited by the retrospective design; however, these findings demonstrate that FOXM1 may have a reliable predictive significance in male breast cancer and may promote drug resistance. Further explorations are warranted in order to confirm these results.

Conclusions

In recent years, many studies highlighted the predictive value of FOXM1 in a wide range of cancers including female breast cancer but to the best of our knowledge not in male breast cancer. In our study we demonstrated that FOXM1 is a potential novel predictive biomarker in male breast cancer.