Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO)

Endometrial cancer is the most common cancer of the female genital tract in many Western countries, and some of the highest incidence rates have been observed in European populations [1]. Long-term predictions imply that the burden of endometrial cancer will continue to increase in the forthcoming decades owing not only to the aging population but also to the obesity epidemic [2]. The majority of patients are diagnosed at an early stage with favourable prognosis. However, a considerable proportion of patients continue to present with locally advanced or recurrent disease.

There are two distinct endometrial tumour types, type I and type II endometrial cancer. They differ in pathogenesis, histology and prognosis. Type I tumours are often well differentiated and characterized by endometrioid histology. These tumours are hormone dependent but clinical data on the expression of hormone receptors is scarce. A recent cohort study reported estrogen receptor expression in two-third of the tumors [3]. Hormone therapy is a particularly attractive option for the treatment of advanced endometrial cancer because it is well tolerated and lacks the usual toxicities associated with chemotherapy. Accumulated experience with a variety of hormonal regimens suggests that between 15 and 30 percent of women respond to hormone therapy [4], with a correlation between receptor status and response to hormone therapy [5, 6]. However, metastatic or recurrent disease may be different from primary disease as regards tumour biology and receptor status [7], and a recent Cochrane review found no evidence that hormonal treatment in any form improves survival in this patient group [8].

In postmenopausal women or after oophorectomy, the major source of circulating estrogen is conversion of adrenal androstenedione to estron by aromatase activity in adipose tissue with further conversion to estradiol [9]. In the first line treatment of postmenopausal women with hormone receptor-positive breast cancer, aromatase inhibitors (AI’s) have shown superior efficacy as compared with tamoxifen. However, there is very little clinical evidence on the efficacy of AI’s in endometrial cancer. Previous studies of the AI’s letrozole and anastrozole have only shown limited effect [10, 11]. Exemestane is an oral irreversible steroidal AI and has been shown to decrease circulating estrogens in postmenopausal women [12]. Exemestane is given as an oral dose once daily and may therefore be a convenient drug in the treatment of advanced endometrial cancer. We present the final results of an open-label phase II study on the efficacy and safety of the aromatase inhibitor exemestane in the treatment of patients with advanced, persistent or recurrent endometrial carcinoma of endometrioid type. Preliminary results were previously presented at the 2006 Annual Meeting of the American Society of Clinical Oncology [13].

The treatment with exemestane was generally well toletated. The response rate in the ER positive group was 10%. In the design of the study, a response rate of 10% or less was considered as of no clinical interest. In retrospect, the use of response rate as endpoint for this study can be questioned. Long term stabilization, such as lack of progression at 6 months may be a more relevant endpoint. We observed a lack of progression in 35% of patients at 6 months, which seems of clinical interest. Tumors are heterogeneous, and the definition used for ER positivity in this study was 2+ or more in staining intensity for at least 10% of tumor cells. This means that a substantial proportion of the tumor cells may have stained negative for ER in a number of tumors included in the ER positive group. The tumor cells that stained negative for ER in the ER positive patient group may not have responded to the treatment, and the progressions in this group may be attributable to these tumor cells. Patients with long-term response or stabilization of the disease may show more uniform ER positivity of the tumor cells but unfortunately the degree of staining was not specified in the study. We were therefore not able to validate this hypothesis.

Recruitment in the ER negative subset was stopped prematurely after recruitment of 12 patients because of lack of response and rapid progression in these patients. We cannot conclude too strongly about this subset due to the small number of patients, but do consider the results as disappointing.

There are other weaknesses in this study. Pathological review and histological staining of the tumors were performed on an institutional basis. However, all institutions were university hospitals with well-trained gynecological pathologists. Immunostaining of estrogen receptor is well established, and there is broad consensus about evaluation of staining results. In 24 cases (46.1%), receptor status was evaluated in the primary tumor only. However, expression of hormone receptors may change during progression of the disease and receptor status of metastatic disease may not always correspond to the receptor expression of the primary tumor. The trial was designed as a single-arm phase II study and hence did not include a control arm. Therefore we cannot exclude the lower progression rate observed in the ER positive group being attributable to a difference in tumor biology not related to the ER receptor status.

Two previous studies of the aromatase inhibitors letrozole and anastrozole in endometrial cancer patients have reported disappointing results. Ma et al. reported a response rate of 9% in 32 patients in abstract form [10]. There was no significant correlation with hormone receptor status, but data on receptor status was available in only one third of the patients. Another phase II trial of anastrozole observed only two partial responses in 23 patients. They reported ER and PR positivity in 21.7% of the patients and patients enrolled in the study were older and had mainly non-endometrioid tumors [11]. In a recent abstract report on 42 patients with recurrent endometrial cancer, the effects of concomitant letrozole and the mTOR inhibitor everolimus were studied [16]. The response rate was 20% and the 12 month progression-free rate was 37%. The previously reported low response rates of endocrine therapy in endometrial cancer, especially with AI’s, may reflect the need to identify the subset of women most likely to respond to such therapy. In our study we therefore selected type I endometrial cancers, and 77% of the tumors in our study population were ER positive. In this subgroup, we report a response rate of 10%. The lack of progression within 6 months in 35% of the patients is of clinical interest and may warrant further evaluation in this group of patients. In receptor negative patient, no responses were observed, and patients progressed quickly. In this subgroup, further evaluation of this kind of treatment seems of less interest. In order to evaluate the potential benefit of endocrine treatment, hormone receptor status should always be evaluated, preferably in the metastatic sites, but at least in the primary tumor.

Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and a lack of progression at 6 months of treatment in 35% of patients with ER positive tumors. The treatment was well tolerated.