Metastatic Metaplastic Breast Cancer Successfully Treated with Adriamycin and Cisplatin

Abstract

Metaplastic breast cancer (MBC) is characterized by the histological presence of a mixture of epithelial and mesenchymal-like elements. However, MBC responds poorly to chemotherapy. Due to its rarity, there is no well-defined treatment for MBC. Herein, we report the case of a 56-year-old woman who underwent a mastectomy and was diagnosed with MBC with osseous differentiation classified as pT4N0M1. After the operation, she was treated with adriamycin and cisplatin, which are standard osteosarcoma treatments, resulting in a partial response. However, to determine the proper chemotherapy treatment, knowledge of the metaplastic elements of the tumor is required.

Introduction

Metaplastic breast cancer (MBC) is characterized by the histological presence of ductal carcinoma cells, mixed with areas of diverse morphological phenotypes displaying spindle, squamous, chondroid, or osseous differentiation (1,2). MBC is rare, comprising less than 1% of all breast cancers, is large in size, and has a high incidence of a triple-negative phenotype compared to invasive ductal carcinoma (IDC) (3-5). Approximately 10% of the cases are at stage IV at the time of diagnosis (6,7), and MBC has a poor response to chemotherapy compared with IDC (3,8). The 3-year overall survival for patients with metastatic MBC is only 15%, significantly lower than that for other IDCs (4). We herein report the case of a 56-year-old woman who had metastatic MBC with osseous cell differentiation. As a result of the predominant tumor being similar to osteosarcoma, she was treated with adriamycin and cisplatin, the standard treatments for osteosarcoma, and exhibited a partial response (PR). As far as we know, this is the first report of MBC metastases with osseous cell differentiation treated with adriamycin and cisplatin.

Case Report

A 56-year-old postmenopausal woman noticed a mass in her left breast in March 2018 and went to the Kure Medical Center for an evaluation in September 2018. She had no past medical history, family history of cancer, or history of childbirth or pregnancy. She had an Eastern Cooperative Oncology Group performance status of 0. She was not obese and had no signs of cachexia. Physical examination revealed a mass of approximately 20×10 cm that was invading the skin with ulceration, and partially necrotic in her left breast (Fig. 1). The superficial axillary lymph nodes were not enlarged. Laboratory data revealed that carcinoembryonic antigen and cancer antigen 15-3 levels were not elevated. Ultrasonography showed multiple low-absorption cysts with no significant bloodstream signals inside the mass. Computed tomography (CT) revealed a mass measuring 19×11×8 cm with central necrosis and calcification and few bilateral solid lesions in the lungs (Fig. 2). There were no significantly enlarged lymph nodes or evidence of distant metastasis. A needle biopsy was performed; however, we could not diagnose the tumor. The axillary lymph node was not dissected because an intraoperative frozen biopsy specimen from the tumor revealed only a sarcoma-like component. The deep margin in the mastectomy stump also tested negative. Pathological examination revealed an osteosarcoma-like component in approximately 60% of the tumor (Fig. 3a), an undifferentiated pleomorphic sarcoma-like component in approximately 30% of the tumor, and an angiosarcoma-like component in a minor portion of the tumor. In addition, carcinoma-like components were identified in approximately 10% of the tumor (Fig. 3b). The carcinoma-like tumor cells were positive for p63 (monoclonal antibody, DAK-p63; Dako, Carpinteria, USA) and focally positive for anti-cytokeratin (monoclonal antibody, CAM5.2; BD Biosciences, San Jose, USA) and anti-human cytokeratin (monoclonal antibody, AE1/AE3; Dako, Carpinteria, USA). Vimentin (polyclonal antibody, V9; Dako, Tokyo, Japan) was positive in both the sarcoma and carcinoma-like tumor cells. She was finally diagnosed with metaplastic carcinoma with osseous differentiation. Immunohistochemically, the tumor cells were negative for the estrogen receptor (monoclonal antibody, SP1; Roche Diagnostics, Tokyo, Japan), progesterone receptor (monoclonal antibody, 1E2; Roche Diagnostics, Tokyo, Japan), and c-erbB-2 oncoprotein (polyclonal antibody; Dako, Carpinteria, USA). The pathological stage was pT4bN0M1 (PUL), stage IV (although the solid lung lesions were not biopsied, there was a noticeable growth in the lesion size at the time of follow-up). After the surgery, fluorodeoxyglucose positron emission tomography (FDG-PET)-CT revealed swelling and an accumulation in the left axillary lymph node that was not detected before the surgery. FDG-PET-CT also revealed accumulation in the solid bilateral lung lesions and the tumors were increased in size compared to that of the initial examination (Fig. 4a-c).

Figure 1.

Tumor presentation before surgery.

Figure 2.

Computed tomography image before surgery. (a) Tumor with necrosis and calcification, and (b) bilateral solid lesions in the lungs.

Figure 3.

(a, b) Hematoxylin and Eosin staining. (a) The tumor was mostly composed of osteosarcoma-like components and (b) occasional carcinoma-like tumor cells (arrows).

Figure 4.

(a-c) Positron emission tomography-computed tomography and computed tomography. (a, b) The tumor spread to an axillary lymph node and bilateral lungs; (c) the tumor increased in size when compared to the initial examination.

Since the majority of the tumor had an osteosarcoma-like component, therapy was initiated to target the osteosarcoma. She was treated with 20 mg/m²/day adriamycin for 3 days and 100 mg/m² cisplatin at 21-day intervals, a standard anti-sarcoma chemotherapy. After two cycles, a 38% PR, according to the Response Evaluation Criteria in Solid Tumors criteria, was observed in January 2019 (Fig. 5). After four cycles, lung and lymph node metastases maintained PR; however, the regimen was discontinued due to grade 2 renal impairment (based on the Common Terminology Criteria for Adverse Events) and complete atrioventricular block. The chemotherapy treatment was then changed to eribulin, used for recurrent or chemo-refractory soft tissue sarcomas. After two treatment cycles, CT revealed disease progression with multiple new lung metastases. Subsequently, she was treated with pazopanib, also used for recurrent or chemo-refractory soft tissue sarcomas. Two months later, pazopanib administration was discontinued due to nausea. After that, she was diagnosed with dyspnea, and a follow-up CT scan revealed disease progression with an increase in the size and number of lung metastases and new metastases in the pericardium and liver. Ultrasonic echocardiography revealed a significant decline in heart function. She received palliative care and died of MBC approximately 12 months after the initiation of treatment.

Figure 5.

The metastasis decreased in size after treatment with adriamycin and cisplatin.

Discussion

MBC is a heterogeneous disease in which malignant epithelial and malignant stromal features can be found. Approximately 10% of cases have metastases at the time of diagnosis, and about 50% of cases experience disease recurrence (6,7,9,10). Due to the rarity of MBC, there are no guidelines for the treatment of metastasis or disease recurrence. Most MBCs (69-77%) are classified as triple-negative breast cancers (TNBC); that is, the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor are negative, as in this case (4,11), making them ineligible for hormonal treatment. Therefore, MBC is frequently treated with the chemotherapy usually used in TNBC; however, only 10-21.8% of patients respond to chemotherapy (8,12). Compared to IDC, MBC often has a different gene expression associated with epithelial to mesenchymal transition and relatively rapid distant metastatic spread. These differences lead to increased resistance to chemotherapy (13). MBC often lacks EP300, and downregulation of EP300 results in the epithelial to mesenchymal transition. Moreover, the lack of EP300 results in a resistance to paclitaxel. Therefore, taxane-based treatments, often used for TNBC with recurrence or metastases, are usually ineffective for MBC (14).

In this case, the patient was treated with adriamycin and cisplatin, which is the standard treatment for osteosarcoma (15), because of the predominant osseous differentiation. Adriamycin and cisplatin are among the therapeutic options for TNBC. However, the treatment outcome is not statistically significant compared to that with adriamycin and cyclophosphamide, which are considered the standard regimen for TNBC (16). Although the patient experienced a PR, she could not continue this regimen due to renal dysfunction and complete atrioventricular block. Similarly, there is a case report of a patient with recurrent MBC with cartilaginous and osseous differentiation, who received a sarcoma-based regimen (ifosfamide at 1.8 mg/m² and etoposide 100 mg/m²) targeting its sarcomatous features. This patient also experienced a PR (17). In this case, pathological examination revealed a metaplastic carcinoma consisting of not only osseous differentiation but also undifferentiated pleomorphic sarcoma cells and angiosarcoma cells. Pathological examination revealed that the tumor cells were undifferentiated and highly aggressive. Although undifferentiated pleomorphic sarcoma and angiosarcoma are rare and standard chemotherapy has not yet been defined, adriamycin is effective for both sarcomas (18,19).

As far as we know, this is the first report of MBC treated with adriamycin and cisplatin. This case suggests that chemotherapy should be selected based on the metaplastic elements of the tumor.

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. This study has been approved by the research ethics committee of Kure Medical Center and Chugoku Cancer Center.

The authors state that they have no Conflict of Interest (COI).