On the basis of historical controls for inactive cytotoxic and targeted agents investigated in previous GOG phase II trials, bevacizumab is worthy of further investigation based on PFS, with 21 patients (40.4%) surviving progression free for at least 6 months. In addition, seven patients (13.5%) experienced an objective response. This trial, as is the case for most previously completed trials of targeted therapy in recurrent/persistent endometrial cancer, entered all patients without regard to histologic or genomic type.
Endometrial cancers are heterogeneous and can be classified into at least two major types. Type I endometrial cancers, those with endometrioid histology, are the most common and are associated with unopposed estrogen exposure. Type II endometrial cancers have nonendometrioid histology (usually papillary serous or clear cell). Inactivation of the PTEN
tumor-suppressor gene is the most common genetic defect in endometrial cancers and is seen in up to 83% of endometrioid tumors.33–36 PIK3CA
mutation, seen in 36% of endometrial carcinomas, is most frequent in tumors that also have PTEN
GOG endometrial cancer trials are subject to central pathology review and categorization of histologic type. It is of great interest as to whether histologic type can be used as a biomarker of response to targeted therapies as a result of the previously mentioned known genetic alterations. In the current study, responses were seen across histologic type (although interestingly, the one patient with a complete response and three of six patients with a partial response had serous histology), and the percentage of patients alive and progression free at 6 months was similar for serous and endometrioid histologies. Patient numbers are too small to formally evaluate the role of histologic subtype and response to bevacizumab in this study, but it is worthy of further study.
Three mammalian target of rapamycin inhibitors, temsirolimus, everolimus, and ridaforolimus, are in clinical trials in endometrial cancer. Preliminary results of a phase II trial of temsirolimus in recurrent or metastatic endometrial cancer (chemotherapy naive) demonstrated encouraging results, with five confirmed partial responses (26%) in 19 evaluable patients.8
Evaluation of a second cohort, women who must have had treatment with one prior regimen of cytotoxic chemotherapy, revealed an ORR of 7% (two of 27 patients).9
A phase II trial of everolimus, in patients with one to two prior chemotherapy regimens, reported no responses.10
Entry was limited to patients with endometrioid histology. A phase II trial of intravenous ridaforolimus in recurrent or metastatic endometrial cancer and carcinosarcoma of the uterus (up to two prior cytotoxic regimens) revealed a response rate of 9% (four of 45 patients).11
Epidermal growth factor receptor as a therapeutic target has also been evaluated in endometrial cancer. Erlotinib was evaluated in chemotherapy-naive patients, showing an ORR of 12.5% (four of 32 patients).13
Gefitinib failed to meet criteria for further evaluation in patients with one to two prior chemotherapy regimens (ORR, 3.8% [one of 26 patients]; 6-month PFS, 8.3% [four of 26 patients]).14
One (5%) of 20 evaluable patients (one to four prior chemotherapy regimens) treated with cetuximab experienced a partial response.15
A phase II trial of trastuzumab did select patients based on human epidermal growth factor receptor 2 positivity (either by overexpression or amplification), although it failed to showed responses.12
Prior attempts to target VEGF have shown modest activity. Treatment of patients with recurrent/persistent endometrial cancer (one to two prior regimens) with thalidomide yielded an ORR of 12.5% (three of 24 patients), but with only 8.3% of patients (two of 24 patients) surviving progression free for at least 6 months.16
On preliminary report, the oral tyrosine kinase inhibitors sunitinib and sorafenib have resulted in minimal activity, with ORRs of 15% (three of 20 patients) and 5% (two of 39 patients), respectively.17
The most striking translational finding was the relationship of high circulating VEGF-A levels with poor outcome in this study. This raises the following important question: What is the source of circulating VEGF-A? VEGF-A is produced by many cells in the body, including the vascular endothelium, and our finding that archival VEGF-A levels from tissues obtained remote from bevacizumab treatment did not correlate with pretreatment circulating levels suggests that sources other than the tumor contribute to plasma VEGF-A levels. Indeed, although high plasma VEGF-A concentrations assessed by ELISA were associated with lack of tumor response and an increased risk of death, high VEGF-A staining intensity in archival tumor was associated with a reduced risk of death. It is possible that VEGF-A staining in remote archival tumor does not reflect the state of the tumor immediately before treatment when the plasma pretreatment VEGF-A levels were assessed. Pretreatment biopsies of recurrent or persistent lesions were not performed in this study. It is also possible that because of the small patient numbers in this study, this result is spurious. Regardless, these data imply that relying on the tumor phenotype when assessed from archival tissues remote from treatment to predict clinical response may have limitations. Despite the limitations in sample size and exploratory nature of the studies, angiogenic markers in tumor and serum may provide prognostic value in recurrent/persistent endometrial cancer and are being prospectively evaluated in the GOG randomized phase II trial of paclitaxel, carboplatin, and bevacizumab; paclitaxel, carboplatin, and temsirolimus; and ixabepilone, carboplatin, and bevacizumab.