Forty-one articles were identified, with 5 relevant for the purpose of this review. Thirty-six were excluded: 13 reviews, 15 on endometrial stromal sarcomas, and 8 on other gynecologic or breast diseases. Studies were done to evaluate the role of AIs in the treatment of women with advanced and/or recurrent EC.
Bellone et al.7 presented a case report of a 58 year old female who presented with recurrent endometrioid type EC with a lung nodule and new pelvic mass following surgical and radiation therapy. Initially treated with 6 rounds of carboplatin and paclitaxel chemotherapy with a partial response showing resolution of the lung nodule and reduction in size of the pelvic mass, she was treated with anastrozole, 1 mg daily. By 9 months, she showed continued resolution of the lung nodule and reduction in the pelvic mass. They concluded that there was potential for use of AIs in tumors with high estrogen receptor (ER) positivity.
Data show that the response to single agent AI therapy in larger studies is limited. For example, in one phase 2 trial, Rose et al.8 evaluated the efficacy of anastrozole in patients with poorly differentiated tumors with unknown ER status. There was a 9% response rate, with 2 partial responses and 2 patients with stable disease. Overall progression-free survival (PFS) was 1 month; overall survival (OS) was 6 months. The patients’ ER/PR status was analyzed if available—of the 5 ER/PR+ patients, only 1 responded, though the therapy was well-tolerated. Limitations included the inclusion of an older population with poorly differentiated carcinomas of any histologic type, including serous, mixed cell, etc., which carry a worse prognosis. The authors concluded that anastrozole had minimal activity in these tumors.
Ma et al.9 authored a study evaluating the use of letrozole in a phase 2 trial following 32 patients, including those with histories of the use of first-line progestins or adjuvant chemotherapy in the metastatic setting. In this population, 86% were ER/progesterone receptor (PR) positive and 82% had a known PTEN mutation. Similarly, the response rate was 9.4% with 1 complete response, 2 partial responses, and 11 cases of stable disease. Overall PFS was 3.9 months and OS was 8.8 months. The authors concluded that compared to historical results using single agent tamoxifen or other GnRH agonists, the OS and PFS were not inferior.
Lindemann et al.10 designed a prospective phase 2 trial following patients treated with exemestane with good result. Enrolling 51 patients with advanced or relapsed EC, the authors had a response rate of 10%. Unlike the other studies analyzed, the patients with ER positivity showed variable response, with 2 complete responses, 2 partial responses, 10 cases of stable disease, and 26 cases of progressive disease, but none with ER negative disease derived a benefit from treatment. PFS was 3.1 months (3.8 months for ER+ /2.6 months for ER-) and OS was 10.9 months (13.3 months for ER+/6.1 months for ER-). ER positivity was defined by having more than 10% cells with 2+ staining, a factor in the lack of correlation to response.
One trial combined the use of an AI with a targeted therapy. Slomovitz et al.11 enrolled 35 patients in a phase 2 study with letrozole with everolimus, an mTOR inhibitor. The response rate to the combination therapy was 32%, with 9 complete responses, of which 7 were taken off therapy, along with 2 partial responses. PFS was 3 months, while OS was 14 months. The clinical benefit rate was noted to be 40% after 16 weeks of therapy. Of the patients, those with endometrioid histology and CTNNB1 mutations responded best to the therapy, while serous histology was the strongest predictor of nonresponse. ER/PR hormonal status was not a predictor of response. This combination was well-tolerated by patients.
Women presenting with recurrent or advanced endometrial cancer have a poor prognosis with limited options for treatment. As many ECs are estrogen-positive, AIs have been proposed as a treatment option. Yet whether ER-positivity predicts response to AI therapy has not been established.
Our review shows that data on the efficacy of AIs in advanced or recurrent EC are limited. Published studies show, however, that single agent AI results in a low response rate. One study of letrozole with everolimus suggests that the combination may be effective, but the data cannot be used to support the use of this combination outside of a randomized trial. Future research may elucidate the relationship between hormonal effects and the PI3K/AKT pathway.
In sum, the data available suggest that the use of AIs in women with recurrent endometrial cancer offers little improvement in PFS or OS and is not a first-line option for treatment. Nevertheless, further study of their use in combination with other therapies may prove their benefit in treatment. Decisions to treat advanced or recurrent EC with AIs currently may be made on an individualized basis. Larger studies are needed to better evaluate which patients will respond well to therapy and the optimal combination therapy for treatment.
- Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271-89.
- Bogliolo S, Gardella B, Dominoni M, et al. Effectiveness of aromatase inhibitors in the treatment of advanced endometrial adenocarcinoma. Arch Gynecol Obstet. 2016;293:701-8.
- Gao C, Wang Y, Tian W, Zhu Y, Xue F. The therapeutic significance of aromatase inhibitors in endometrial carcinoma. Gynecol Oncol. 2014;134(1):190-5.
- Watanabe K, Sasano H, Harada N, et al. Aromatase in human endometrial carcinoma and hyperplasia: Immunohistochemical, in situ hybridization, and biochemical studies. Am J Pathol. 1995;146(2):491-500.
- Ryan PD, Goss PE. Adjuvant hormonal therapy in peri- and postmenopausal breast cancer. Oncologist. 2006;11(7):718-31.
- Del Carmen MG, Boruta DM 2nd, Schorge JO. Recurrent Endometrial Cancer. Clin Obstet Gynecol. 2011 Jun;54(2):266-77.
- Bellone S, Shah HR, McKenney JK, Stone PJ, Santin AD. Recurrent endometrial carcinoma regression with the use of the aromatase inhibitor anastrozole. Am J Obstet Gynecol. 2008;199(3):e7-e10.
- Rose PG, Brunetto VL, VanLe L, Bell J, Walker JL, Lee RB. A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2000;78(2):212-6.
- Ma BB, Oza A, Eisenhauer E, et al. The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers—a study of the National Cancer Institute in Canada Clinical Trials Group. Int J Gynecol Cancer. 2004;14(4):650-8.
- Lindemann K, Malander S, Christensen RD, et al. Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO). BMC Cancer. 2014;14:68.
- Slomovitz BM, Jiang Y, Yates MS, et al. Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol. 2015;33(8):930-6