Carcinosarcomas, also known as Mixed Mullerian Tumors (MMT), of the female genital tract are rare tumors that most commonly arise in the uterus, followed by the ovaries, fallopian tubes, and the vagina [1
]. The pathogenesis of carcinosarcomas remains under debate, but an increasing body of evidence supports the origin of both elements from a common epithelial cell line that undergoes sarcomatous dedifferentiation, rather than two independent progenitors [2
]. Carcinosarcomas are histologically comprised of malignant epithelial and mesenchymal components and may be classified based on the nature of their mesenchymal elements. Tumors with "homologous" mesenchymal components differentiate towards tissues physiologically native to the primary site (e.g. leiomyosarcoma component), while heterologous tumors contain mesenchymal components that are physiologically foreign to the primary site (e.g. chondrosarcoma component).
Uterine cancer is the most prevalent gynecologic malignancy and the 4th
most prevalent cancer among United States women, with an estimated 43,470 new cases and 7,950 cancer-related deaths in 2010 [3
]. Carcinosarcomas comprise 2-5% of all uterine malignancies and have an estimated recurrence rate of 40-60% [4
], with approximately 35% of patients having extra-uterine disease at diagnosis. Although surgical debulking is the mainstay of treatment, the high rate of tumor recurrence and a poor median survival of 16-40 months after diagnosis suggest a need for improved adjuvant treatment [5
Cancer of the ovary is the 9th
most common malignancy and the 5th
leading cause of cancer-related death among U.S. women, with an estimated 28,880 new cases and 13,850 associated deaths in 2010 [3
]. Carcinosarcomas comprise less than 1-2% of these tumors [4
], with most individuals having nodal metastases at diagnosis and 75% of women being found to have stage III or IV disease at surgical staging. Ovarian carcinosarcoma portends a worse prognosis than uterine carcinosarcoma, with a median survival rate of 8-32 months and recurrence rates of 50-100% [4
]. Cytoreductive surgery followed by combination platinum-based chemotherapy appears to confer the best survival benefits, with attendant notable morbidity risks and continued dismal long-term survival data.
There is a clear need to better understand the molecular basis of carcinosarcomas and to develop more effective treatment modalities against these aggressive tumors. Trop-2 (also referred to as EGP-1, TACSTD2, M1S1, and GA733-1) is a monomeric transmembrane cell surface glycoprotein that was originally identified in human placental trophoblastic tissue. It is expressed by several human epithelial cancers but has limited expression in normal human cells [7
]. Little is known about the physiologic role of Trop-2 and the nature of its role as an oncogene remains unclear. Trop-2 has been implicated in activation of the ERK/MAPK pathway, leading to downstream alterations in cell proliferation, migration, invasion, and survival [8
]. Clinically, Trop-2 overexpression has been associated with increased tumor invasiveness and decreased overall survival in multiple types of human carcinomas. Our group has previously identified Trop-2 overexpression in serous ovarian cancer and uterine serous papillary carcinoma (USPC), two notably aggressive, treatment-resistant gynecologic malignancies. We have also identified Trop-2 as an independent marker for decreased survival in patients with epithelial ovarian carcinomas [9
The differential expression of Trop-2 in cancers compared to normal tissue, its association with clinically important tumor behavior, and its histologic accessibility as a transmembrane receptor make it an attractive target for immunotherapy. Importantly, a murine monoclonal antibody (mAb), mRS7, generated by hybridoma technology against Trop-2, has been shown to be effective as a radiolabeled, as well as drug- and toxin-conjugated, immunotherapeutic agent in xenograft cancer models [11
]. In this study we aimed to investigate the potential of hRS7, a humanized anti-Trop-2 monoclonal antibody, in the treatment of uterine and ovarian carcinosarcomas.