Case Report: Significant Efficacy of Pyrotinib in the Treatment of Extensive Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Cutaneous Metastases: A Report of Five Cases

Breast cancer is one of the most common malignancies among women throughout the world and is the major cause of most cancer-related deaths. Several explanations account for the high rate of mortality of breast cancer, and metastasis to vital organs is identified as the principal cause. Over the past few years, intensive efforts have demonstrated that breast cancer exhibits metastatic heterogeneity with distinct metastatic precedence to various organs, giving rise to differences in prognoses and responses to therapy in breast cancer patients. Bone, lung, liver, and brain are generally accepted as the primary target sites of breast cancer metastasis. However, the underlying molecular mechanism of metastatic heterogeneity of breast cancer remains to be further elucidated. Recently, the advent of novel genomic and pathologic approaches as well as technological breakthroughs in imaging analysis and animal modelling have yielded an unprecedented change in our understanding of the heterogeneity of breast cancer metastasis and provided novel insight for establishing more effective therapeutics. This review summarizes recent molecular mechanisms and emerging concepts on the metastatic heterogeneity of breast cancer and discusses the potential of identifying specific molecules against tumor cells or tumor microenvironments to thwart the development of metastatic disease and improve the prognosis of breast cancer patients.

Most previous studies have found that cutaneous metastases occur infrequently and are rarely present at the time the cancer is initially diagnosed. We studied patients with metastatic cancer to determine the overall frequency of skin metastases, the frequency that these were the first sign of extranodal disease, and the clinical and histologic features of the cutaneous lesions. A 10-year period of tumor registry files was searched for patients with metastatic carcinoma and melanoma. For patients with skin metastases, medical records and pathology reports were also examined. Of 4020 patients with metastatic disease, 420 (10%) had cutaneous metastases; in 306 of them the skin metastases were the first sign of extranodal metastatic Breast cancer and melanoma were the most common. Nodules were the most frequent clinical presentation, although inflammatory, cicatricial, and bullous lesions were also noted. Incisional metastases were common. Histologic findings most frequently revealed adenocarcinoma that was sometimes suggestive of the site of origin. After recognition of skin metastases, mean patient survival ranged from 1 to 34 months depending on tumor type. Cutaneous metastases are not uncommon and frequently are the first sign of extranodal metastatic disease, particularly in patients with melanoma, breast cancer, or mucosal cancers of the head and neck.

Inhibitory receptors have been proposed to modulate the in vivo cytotoxic response against tumor targets for both spontaneous and antibody-dependent pathways. Using a variety of syngenic and xenograft models, we demonstrate here that the inhibitory FcgammaRIIB molecule is a potent regulator of antibody-dependent cell-mediated cytotoxicity in vivo, modulating the activity of FcgammaRIII on effector cells. Although many mechanisms have been proposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we show here that engagement of Fcgamma receptors on effector cells is a dominant component of the in vivo activity of antibodies against tumors. Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin(R)) and rituximab (Rituxan(R)), engaged both activation (FcgammaRIII) and inhibitory (FcgammaRIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential. Mice deficient in FcgammaRIIB showed much more antibody-dependent cell-mediated cytotoxicity; in contrast, mice deficient in activating Fc receptors as well as antibodies engineered to disrupt Fc binding to those receptors were unable to arrest tumor growth in vivo. These results demonstrate that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcgammaRIIB.