2 sampling, and peritoneal cytology obtained upon entry into the abdominal cavity. Adjuvant therapy is usually recom- mended [7]. A Gynecologic Oncology Group trial (GOG 94) reported a 35% 5-year-disease-free survival when 31 women with stages I and II USC received adjuvant postoperative whole abdomen radiation therapy. Some institutional experiences suggest that whole abdomen radiation therapy may be beneﬁcial. Others have not found it to be eﬀective [6, 8, 9]. Martin et al. hypothesized that USC radiation resistance may be attributed to p53 overexpression through the evasion of radiation-induced apoptosis. Indeed, radioresistance of breast cancer has been associated with erbB2 overexpres- sion [9]. The Yale experience suggests that vaginal apex brachytherapy plays an important part in the management of the disease, as no recurrences presented at the vaginal apex among 43 stage I patients with early stage USC treated with this technique [6]. Platinum-based chemotherapy has been routinely em- ployed in the management of both early and advanced stages of USC. Although conﬂicting data exist, a Yale series suggested that carboplatin and paclitaxel in surgical stage I USC should be employed as part of the routine method of management of the disease [6]. Only one of 29 stage IA– IC patients (3.4%) recurred, who received platinum-based chemotherapy, whereas 20 out of 32 (62.5%) who did not receive chemotherapy recurred [6]. Recently, a study of 25 stage I-II USC patients treated at Sloan-Kettering memorial hospital with acombination of carboplatin/paclitaxel and vaginal brachytherapy found comparable results [10]. The overall survival of women with USC, however, remains about 30%. The survival of women with stages I-II USC is 35–50% and for stages III-IV is 0–15% [11]. Overall recurrence rate is about 80%, and new therapeutic modalities are still needed [12]. 3. erbB2 in USC Whereas USC does not share the typical risk factors known to inﬂuence its endometrioid counterpart, several unique prog- nosticators 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. In 2002, Santin et al. reported for the ﬁrst time on erbB2 overexpression in USC specimens in vitro. Eight out of 10 specimens stained heavily (2+, 3+) for erbB2 by immunohis- tochemistry. Furthermore, USC cell lines expressed 10-fold higher erbB2 levels than erbB2-positive ovarian and breast cancer cell lines by ﬂowcytometry. The sensitivity of those cell lines to antibody dependent cytotoxicity in vitro was also demonstrated in this study [14]. The same group then used oligonucleotide microarrays to analyze gene expression proﬁling of USC and normal Obstetrics and Gynecology International endometrial cells in culture. Among 529 diﬀerentially expressed genes, c-erbB2 gene which, encodes for the erbB2 receptor, was found to be highly expressed in USC [15]. In later publications, the same group, as well as others, have shown that erbB2 receptor is expressed in 18–62% of USC. USC overexpression and ampliﬁcation was found to be associated with chemoresistance, higher stage, and worse overall survival [12, 14, 16, 17]. Indeed, erbB2 gene ampli- ﬁcation by FISH was observed more frequently in African American patients compared to Caucasians (P = 0.02), and to be associated with a worse prognosis in this subgroup of patients (P = 0.01). It was associated with a shorter overall survival in all patients tested (P = 0.0008) [18]. The correlation between erbB2 overexpression by im- munohistochemistry (IHC) and erbB2 gene ampliﬁcation by ﬂuorescent in situ hybridization (FISH) was addressed in two further studies. In one study, moderate to strong expression of erbB2 was found in 16 (62%) of 26 USC samples evaluated, with 7 (27%) samples showing moderate staining (2+) and 9 (35%) showing strong staining (3+). Ampliﬁcation of the erbB2 gene by FISH was observed in 11 (42%) of the 26 samples. Protein overexpression and gene ampliﬁcation were found to correlate in 100% (9 of 9) of the 3+ tumors and in 29% (2 of 7) of the 2+ tumors. None of the 10 USC samples that scored 0 or 1+ by IHC tested positive for gene ampliﬁcation by FISH [19]. In another study, strong erbB2 membrane staining (3+) of USC samples was observed in 16.6% (2 of 12) of samples tested. There was perfect correlation with gene ampliﬁcation by FISH, as well as messenger RNA expression by quantitative real time reverse transcription (RT) polymerase chain reaction (PCR) [16]. Interpretation of IHC results follow the breast cancer guidelines, where a 3+ score is deﬁned as heavy staining of the cell membrane in more than 10% of tumor cells, 2+ is deﬁned as moderate staining in more than 10% of cells, and a score of 1+ or 0 is deﬁned as light or no membrane staining, respectively. A score of 1+ or 0 indicates a negative test. We have also adopted the same treatment strategy used in breast cancer, where conﬁrmation of an IHC 2+ score by FISH testing, performed before treatment with trastuzumab, is begun. A Gynecologic Oncology Group (GOG) analysis of 234 samples of advanced and recurrent endometrial cancer found erbB2 overexpression and gene ampliﬁcation in 44% and 12% of cases, respectively. There was a signiﬁcant increased frequency of overexpression in USC versus all oth- ers (61% versus 41%) [20]. Neither protein overexpression nor gene ampliﬁcation predicted overall survival, however, the study included highly advanced cases, and the analysis combined endometrioid and serous cancers (i.e., Type I and Type II endometrial carcinomas). 4. erbB2 erbB2 is a member of the erbB receptor tyrosine kinase. This is a family of 4 transmembrane glycoproteins (EGFR/erbB1, erbB2, erbB3, and erbB4) that are expressed on epithelial, mesenchymal, and neuronal cells. erbB receptors are acti- vated in response to binding with 11 ligands produced in