Obstetrics and Gynecology International an autocrine fashion in the individual cells or a paracrine fashion in the surrounding tissue. Ligand binding results in dimerization of the receptor either with a twin receptor (homodimerization) or with one of its siblings (heterodimer- ization). This leads to phosphorylation of the intracellular tyrosine kinase residues which serve as docking sites for various eﬀectors and transcription factors that ultimately modulate various biological responses, such as proliferation, survival, migration, and diﬀerentiation. Diﬀerent ligands bind speciﬁc receptors based on their binding aﬃnities. This results in a variety of dimerization combinations and, in turn, activation of diverse intracellular pathways. It is note- worthy that erbB2 has no deﬁned ligand and, due to its con- formation design, is the preferred dimerization partner of all other erbB receptors. Furthermore, an erbB2 heterodimer is characterized by a stronger and more diverse signaling potential than other erbB dimers [21]. erbB2 overexpression was, indeed, found in various cancers (including breast, ovarian, and endometrial) to be associated with cancer cell proliferation, poor survival, and resistance to therapy [12, 22–25]. 5. Trastuzumab 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. Whereas Trastuzumab is alleged to inhibit downstream signal transduction, ultimately modulating proliferation and apoptosis, its principal mechanism of action is believed to be through recruiting host immune cells (Natural Killer cells), and setting oﬀ an antibody-dependent cell-mediated cy- totoxicity (ADCC) process [26–28]. This is dependent on receptor overexpression. Based on the breast cancer model, primary USC cell lines in culture challenged with peripheral blood lymphocytes in the presence of Herceptin in a stan- dard 5-hour-chromium-release cytotoxicity assay endured signiﬁcant killing, up to 75%, compared to control. This was mainly attributed to Herceptin-induced antibodydependent cell-mediated cytotoxicity reaction. Herceptin also had an anti-proliferative eﬀect on those cell cultures [14, 29]. 6. Trastuzumab in Breast Cancer 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 chem- otherapy alone. The addition of trastuzumab to either an- thracyclines plus cyclophosphamide or a taxane was also as- sociated with a longer time to disease progression, a high rate of objective response, and a longer duration of response 3 [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 over- all 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 Adju- vant 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 chem- otherapy in this setting was associated with a 33% reduction in the risk of death (P = 0.015) [33]. The sentinel indication for Herceptin therapy, namely, erbB2 positivity, was determined in various trials by either IHC or ﬂuorescent insitu hybridization (FISH). While IHC shows erbB2 receptor overexpression in cancer specimens, FISH conﬁrms erbB2 gene ampliﬁcation. The concordance of those two techniques was retrospectively analyzed and was generally found to be 82% [34]. Concordance between IHC 3+ and FISH-positive tumors was even greater (89%). However, concordance between IHC 2+ tumors and FISH positivity was 24%, begging the question if conﬁrmation of IHC 2+ by FISH would ensure better results. 7. Trastuzumab in Endometrial Cancer A phase II study of single-agent trastuzumab in advanced/re- current 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