Uterine serous adenocarcinomas (USC) constitute the majority of Type II variants, and about 10% of all endometrial cancers [3]. USC has a higher propensity for lymphovascular invasion, and intraperitoneal as well as extraabdominal spread, than endometrioid carcinoma. It also has a significantly greater incidence of pelvic and para-aortic lymph node metastases [4]. At the time of presentation, approximately 60 to 70 percent of women with USC will have-disease spread outside of the uterus [3]. Overall 1-year-, 2-year-, and 5-year-survival in USC is 84%, 71%, and 54%, respectively. This is compared to a respective overall survival of 94%, 89%, and 80% in endometrioid adenocarcinoma [5]. In a Yale series, there was no survival difference between stage I patients who had 10–50% of the endometrial carcinoma composed of USC compared with those with more than 50% USC [6].

Whereas USC does not share the typical risk factors known to influence its endometrioid counterpart, several unique prognosticators have been identified in this variant. Commonly seen in older, thin, and nulliparous patients, and in African American women, the molecular biology of USC is also distinctive. The tumors, infrequently express estrogen (ER) and progesterone (PR) receptors, are frequently aneuploid, and the majority (90%) are associated with p53 mutations [13]. P53 mutation is known to enhance the aggressiveness of the disease by modulating pathways of proliferation and apoptosis.

It is, therefore, not surprising that erbB2 has been the target of immunotherapy by monoclonal antibodies (mAb) in a number of cancers. Most notably, 25 to 30 percent of breast cancers overexpress erbB2, and have been targeted for mAb therapy. Trastuzumab (Herceptin, Genentech, South San Francisco, Calif) a humanized mAb of the IgG1 family, was approved by the FDA in 1998 for treatment of metastatic breast cancers that overexpress erbB2 in combination with standard chemotherapy.

In a landmark phase III study, of advanced breast cancer, by Slamon et al. [30], trastuzumab was found to reduce the relative risk of death by 20% at a median followup of 30 months in the group of patients who received chemotherapy and trastuzumab compared to the group who received chemotherapy alone. The addition of trastuzumab to either anthracyclines plus cyclophosphamide or a taxane was also associated with a longer time to disease progression, a high rate of objective response, and a longer duration of response [30]. Eligible patients were erbB2 2+ and 3+ overexpressors as determined by immunohistochemistry (IHC). Greater efficacy was noted in IHC 3+ patients compared to the overall population. Subsequently, trastuzumab was consistently shown to significantly improve disease free survival (up to 50%) in multiple other studies when used in combination with multiple other chemotherapies, including taxanes and platinum compounds [31, 32]. The National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 and the North Central Cancer Treatment Group trial N9831 results led to the approval of adjuvant trastuzumab therapy in operable breast cancer. The use of trastuzumab plus chemotherapy in this setting was associated with a 33% reduction in the risk of death (P = 0.015) [33].

A phase II study of single-agent trastuzumab in advanced/recurrent endometrial cancer patients of any histology has recently been reported from the GOG [35]. This study was not able to demonstrate single agent activity of trastuzumab against endometrial carcinoma patients harboring tumors with HER2/neu overexpression. Such results, however, have recently been challenged due to the many shortcomings in the design of the GOG181b study [36]. Moreover, evidence of trastuzumab clinical activity in a handful of heavily pretreated endometrial carcinoma patients has been recently reported as case reports in the medical literature. Consistent with this view, Santin et al. recently reported on two endometrial cancer patients treated with Herceptin. The first case had a stage IIIA platinum refractory G3 endometrioid tumor with IHC 3+ erbB2 overexpression. The second case had a stage IIIC USC that persisted after surgery and adjuvant pelvic as well as extended field radiation. This patient had an IHC 2+ erbB2 overexpression. Both cases received salvage treatment with Herceptin with chemotherapy in the former, and as a single agent in the latter. Both cases achieved significant partial response, stable disease, and a substantial sustained decrease in CA125 [37]. In another case report, Jewell et al. reported similar success with Herceptin therapy in combination with chemotherapy in a 72-year-old patient with stage IIIA grade 2 endometrioid adenocarcinoma that recurred after surgery and adjuvant radiation therapy. The tumor showed IHC 3+ erbB2 overexpression [38]. Finally, Villella et al. reported on two recurrent USC patients with advanced disease and 3+ staining by IHC. When treated with Herceptin, one patient achieved a complete response, and the other had stable disease [39]. Trastuzumab therapy was well tolerated in these patients and, consistent with these results, the single agent use of trastuzumab in a Phase II study of advanced/recurrent endometrial cancer patients by the GOG did not identify any new toxicities or an increased frequency of currently reported toxicities of trastuzumab [35]. In this regard, the major potential toxicities associated with trastuzumab use may include infusion reactions, embryo-fetal toxicity, pulmonary toxicity, and cardiotoxicity. Importantly, the incidence of congestive heart failure and cardiac dysfunction in breast cancer patients have been shown to range from 0.4–3.8% in the major adjuvant trastuzumab trials and to be higher in patients receiving trastuzumab with anthracycline containing chemotherapy regimens [30–33].