UPSC is a rare type of endometrial cancer, whose clinical features are different from endometrioid endometrial adenocarcinoma. The median age of UPSC was 64 years in this study, similar to previous report, but older than the median age of women with endometrioid endometrial cancers in China [25
]. Unlike endometrioid endometrial cancers, UPSC was not associated with obesity. The median BWI was 23.8
in this study. And most important of all, compared to patients with endometrioid endometrial adenocarcinomas, patients with UPSC tend to have deep myometrial invasion, high-stage diseases, and worse overall survival, as we had discussed previously in [25
]. In our study, 61% were late stages. More than half of patients (58.3%) had deep myometrial invasion. The 1-year, 3-year, and 5-year overall survival was 73.1%, 51.9%, and 43.9%, respectively.
Although racial differences in the uterine cancer have been previously published, most of these studies have focused on disparities between African Americans and whites. Santin et al. noted that black patients with UPSC tended to be younger, had higher Her-2/neu expression and short survival than white [26
]. Slomovitz [9
] summarized the clinical features of 129 cases with UPSC. In his study, 93% patients were Caucasian, and only 2% were Asian. Therefore, little is known about Asian patients with UPSC till now. Recent study had reported the racial disparities between Asians and whites. Zhang et al. [27
] compared 2,144 Asians and 32,999 whites with corpus cancer in the United States, and found that Asians presented at a younger age, with more advanced stage disease and higher 5-year survival rates than whites. In our study, similar to whites, main presenting symptoms were abnormal vaginal bleeding and with median BWI of 23.8
, patients with UPSC ware not associated with obesity. On the other hand, Asian patients with UPSC had younger age (64 years) and more late stage diseases (61%) than whites compared to the previous report [9
], in which median age was 68 years for whites and 56% patients were in late stages. The 3-year and 5-year overall survival in our study was 51.9% and 43.9%, respectively, which was a little worse than whites, whose 3-year and 5-year overall survival was 62.6% and 45.9%, respectively [9
Recently, Her-2/neu overexpression was found to be a common event in UPSC. Grushko et al. [28
] found that UPSC had more Her-2/neu overexpression than all other types of endometrial cancers (23 of 38, 61% versus 81 of 196, 41%, resp., P
= .03). Santin et al. [20
] reported that 62%~80% of UPSC overexpressed Her-2/neu protein, and others reported overexpression rates varyng from 40% to 48% [29
]. In contrast, Slomovitz et al. [19
] reported overexpression of Her-2/neu in only 18% (12 of 68) of UPSC patients. summmariued the results and methods of the studies on Her-2/neu status in UPSC. In our study, we demonstrated that 36% of patients with UPSC overexpressed Her-2/neu protein. The differences of the rate of Her-2/neu overexpression, might be due to different antibody, inherent intraobserver variability, and most important of all, racial disparity.
Summary of related articles on Her-2/neu status in UPSC.
In our study, patients with Her-2/neu overexpression were significantly more likely to have advanced stage disease when compared to Her-2/neu negative patients (P
= .03). Overexpression of Her-2/neu was seen in 50.0% (11/22) of UPSC patients with advanced disease, compared to 14.3% (2/14) of patients with early disease. Similar findings were reported by Slomovitz, Santin, and Díaz-Montes et al., in which overexpression of Her-2/neu in patients with advanced disease were 24%~81.8%, compared to 8%~28.6% of patients with early disease [19
]. Díaz-Montes et al. also demonstrated that overexpression of Her-2/neu was associated with higher Ki-67 index, larger tumor sizes, and worse survival outcome.
In survival analysis, we found that the overall survival was worse for patients with Her-2/neu protein positive tumors than Her-2/neu negative ones (P
= .0023). The 5-year overall survival for Her-2/neu IHC positive and negative cases was 12.9% and 68.6%, respectively. Slomovitz et al. [19
] also revealed that the 5-year overall survival in UPSC patients was 0% in Her-2/neu IHC positive cases versus 45% in Her-2/neu negative ones (P
= .008). And Santin et al. [26
] demonstrated that short survival was associated significantly with Her-2/neu overexpression compared with IHC expression 0~1+(P
= .002). All of these findings suggested that Her-2/neu overexpression was a useful prognostic factor for this aggressive subtype of endometrial cancer. Besides Her-2/neu IHC overexpression, we also found that deep myometrial invasion (P
= .0138) and late stages (P
= .003) were associtated with a shorter OS.
We used CISH to detect the Her-2/neu gene amplification in our study and found Her-2/neu gene amplification in four cases (11.1%). Santin et al. [32
] revealed that Her-2/neu gene amplification was correlated with a poor survival outcome in patients with UPSC (P
= .0084). Because of the small size of Her-2/neu amplification in our study, we did not find the effect of Her-2/neu amplification on overall survival.
Her-2/neu gene amplification was found in all IHC 3+ cases (100%, 3/3). But in IHC 2+ cases, only one out of ten cases had Her-2/neu gene amplification. As we know, patients who have Her-2/neu gene amplification respond better to trastuzumab. Therefore, like breast cancer, the entry criteria of trastuzumab in UPSC should be confined to IHC 3+ cases, excluding the 2+ cases unless it is proved to have Her-2/neu amplification by CISH or FISH. The Gynecologic Oncology Group conducted a phase II study using trastuzumab as a single agent in patients with advanced stage or recurrent endometrial cancer with Her-2/neu IHC 2+ or 3+ staining, but found no activity of trastuzumab in heavily pretreated patients. 13% of cases demonstrated gene amplification and 37% demonstrated moderate or high immunostaining. Entry criteria were then revised to include only those patients whose tumors were FISH positive, but the study was finally closed due to slow enrollment [33
Santin et al. [21
] studied the effects of trastuzumab in UPSC cell lines and found that UPSC cell lines were highly sensitive to Herceptin mediated antibody-dependent cellular cytotoxicity (ADCC) and cell proliferation was inhibited. Villella et al. [34
] tried to use trastuzumab therapy (4
mg/kg intravenously over 90
min, then maintenance dose of 2
mg/kg intravenously over 30
min weekly until progression of disease) in patients with UPSC who expressed Her-2/neu 3+ by IHC. Two patients with 3+ overexpression received trastuzumab treatment. One patient with IVB disease had complete response and the other with IIIC disease had stable disease for 3 months. Targeting Her-2/neu might be beneficial for a select group of patients with UPSC.
In conclusion, our data revealed that Chinese patients with UPSC had characteristics of deep myometrial invasion, advanced stages and poor overall survival. Her-2/neu overexpression, rather than Her/neu gene amplification, is associated with advanced stage and poor survival outcome. Her-2/neu might be a therapeutic target in refractory UPSC patients, but it should be further evaluated by randomized clinical trials.