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Aromatase inhibitors in gynecologic cancers
Journal of Steroid Biochemistry & Molecular Biology 106 (2007) 76–80
Review
Aromatase inhibitors in gynecologic cancers夽 Carolyn Krasner Gillette Center for Women’s Oncology, Massachusetts General Hospital, United States
Abstract The female genital tract is hormonally responsive, and consequently some tumors, which arise within in it, may be treated at least in part, with hormonal manipulation. The range of responses in clinical trials and case reports will be reviewed. Many of these diseases are too rare for clinical trial testing, and in some cases evidence is anecdotal at best. Recurrences of ovarian cancer have been treated with tamoxifen and megesterol acetate with variable response rates from 0 to 56%. The favorable toxicity profile of aromatase inhibitors led to trials of these agents for the treatment of relapsed epithelial ovarian cancer. These agents have proved tolerable with minor response rates but a significant disease stabilization rate, which may be prolonged in a minority of cases. It is unclear if these responses may be predicted by estrogen receptor expression or aromatase expression. Anastrazole has also been tried in combination with an EGFR receptor-inhibitor, again showing minor responses but possibly an increase in TTT in some patients. Granulosa cell tumors of the ovary are rare, hormonally sensitive tumors, with reported responses to a variety of hormonal manipulations, including aromatase inhibition. In addition, combined endocrine blockade, including aromatase inhibition, has been tried with reports of success. Endometrial cancers, particularly type I lesions, are often treated with hormonal manipulation, most commonly with progestins, but also with antiestrogens such as tamoxifen. A trial of aromatase inhibition in the treatment of recurrent endometrial cancer showed minimal responses. Endometrial stromal sarcoma, an uncommon uterine malignancy, has shown response to hormonal treatments, with multiple case reports of efficacy of aromatase inhibition. Despite the rarity of some of these tumor types, rare tumor study groups, such as within the Gynecologic Oncology Group, should make an effort to prospectively define the utility of these treatments. © 2007 Published by Elsevier Ltd. Keywords: Aromatase inhibitors; Gynecologic cancer
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aromatase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of hormonal treatment in gynecologic cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Many gynecologic cancers express hormone receptors, including ovarian epithelial cancer, endometrial carcinomas and sarcomas and ovarian stromal tumors. This fact has
76 76 77 78 79 79 79
spurred an attempt to treat a range of gynecologic malignancies with various hormonal manipulations, including aromatase inhibition. This review will present an overview of the hormonal therapies of these cancers. 2. Ovarian cancer
夽 Presented at the VIII International Aromatase Conference: ‘Aromatase 2006’ (Baltimore, MD, USA, 18–20 September 2006).
0960-0760/$ – see front matter © 2007 Published by Elsevier Ltd. doi:10.1016/j.jsbmb.2007.05.026
Ovarian cancer is the second most common gynecologic malignancy, but the most common cause of death among
C. Krasner / Journal of Steroid Biochemistry & Molecular Biology 106 (2007) 76–80
women who develop gynecologic cancer, and the fifth most common cause of cancer-related death in females in the United States. The majority (90%) of primary ovarian tumors derive from epithelial cells, the remainder arise from other cell types (germ cell tumors, sex cord-stromal tumors, and mixed cell tumors). Initial therapy for ovarian cancer is debulking surgery. Surgery is then followed by chemotherapy, which is typically a platinum and a taxane. Despite objective response rates of 60–80% to combination platinum-based chemotherapy, the majority of women with advanced epithelial ovarian cancer ultimately develop progressive disease and die of complications of their malignancy. Relapsed disease is not curable; therefore, salvage chemotherapy is primarily palliative in nature. Thus, in addition to the critical need to develop new drugs with activity in the upfront treatment of ovarian cancer, it is important to develop rational therapeutic strategies in the relapsed/refractory setting which focus on optimizing quality of life and prolonging time to development of symptomatic disease, as well as extending overall survival in this malignancy. While there are numerous cytotoxic salvage regimens available, less toxic hormonal regimens are particularly appealing in this setting. Another setting in which hormonal therapy is being investigated is in the consolidation or maintenance treatment of women who have achieved a complete response to chemotherapy. Treatment decisions for relapsed disease is based on multiple factors: patient’s age and performance status, length of time from completion of initial therapy, i.e. platinum sensitivity, appearance of radiographic changes, and presence or absence of symptoms. As therapy for relapsed disease is palliative and not curative, there has been a desire not to instigate toxic chemotherapies immediately, in the absence of a survival benefit. Therefore, this is really the perfect scenario for the investigation of new agents on clinical trials. However, these patients with early, marker only relapses are often not eligible for clinical trials without measurable disease (although Ca125 kinetics are increasingly being accepted for assessment of response). All these factors combine to make endocrine therapy appealing in non-bulky, asymptomatic ovarian cancer. Ovarian cancer has been shown to stain for steroid hormone receptors, including estrogen, progesterone and androgen. Epidemiologic studies indicate that hormones may play a role in the genesis of ovarian cancer, and there are data to show that pregnancy, breast-feeding and oral contraceptive use can decrease the risk of developing ovarian cancer [1]. These endocrine associations have lead to the investigation of hormonal therapy in patients with ovarian cancer; however, no hormonal therapies have been approved by the FDA for the treatment of ovarian malignancies. Hormonal treatment of ovarian cancer date back at least to the 1960s. Three consecutive Phase II trials of MidAtlantic Oncology Program in heavily pretreated patients studied megestrol acetate, aminoglutethemide and tamox-
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ifen [2]. With assessment by radiographic response criteria, tamoxifen showed a response rate of 17% with stable disease lasting >60 days in 62% of patients. The other two agents showed no responses. A similar GOG study of tamoxifen in the second line setting again demonstrated a RR of 17% with time to progression of 4.4 months [3]. A Cochrane database metanalysis from 2001 looked at 14 studies comprising 623 patients, and found overall response rates ranged from 0 to 56%, with the rate of stable disease for 4 weeks or greater 31.9% reported in eight studies [4]. Important to note however, is the absence of data for response from randomized trials. Some studies showed correlation with ER receptors, others did not, though none designed specifically to assess that. Some had heavily pretreated patients though studies do not agree that this is significantly correlated with response [5–8]. Clearly, the predictors of response to hormonal agents in this population is not known.
3. Aromatase inhibitors Bowman tried letrazole and found an overall response by UICC criteria was 0%, but response by Ca125 criteria was 8%. Importantly, they reported a positive correlation of ER, PR and EGF with response p = 0.0087 [9]. This is a nonrandomized study, so it is possible that the tumors with the highest ER and PR levels may have an intrinsically more favorable course because of intrinsic differences in the tumor, rather than any response or stabilizing effect of letrozole. By contrast, Papadimitriou also studied letrozole in relapsed ovarian cancer showing an ORR of 15% with 19% of patients achieving stable disease but no correlation between response and ER/PR expression [10]. Del Carmen et al. studied anastrazole in this population, finding one partial response; median TTP = 85 days (one patient stable for 500 days), stable disease at 3 month 42%. There was no correlation between ER/PR and TTP [11]. Bowman showed a correlation between TTP and ER/PR positive tumors [9], while Del Carmen showed a trend (but not statistical significance) to longer TTP with ER/PR negative tumors. Possible explanations for this discrepancy include differences in IHC staining and histoscore reading, as well as heterogeneity in receptor status in ovarian cancer between primary (Bowman) and metastatic lesions (Del Carmen). These divergent results underscore the need for randomized trials of endocrine therapy versus placebo in patients with potentially endocrine sensitive tumors. Krasner et al. studied the combination of anastrazole with gefitinib (Iressa) in patients with all ER/PR positive tumors [12]. Preclinical studies had suggested that simulatenous interruption in ER/PR and EGFR pathways might be synergistic ER interacts with multiple kinases. Preclinical models in breast cancer suggest that tumors resistant to tamoxifen have up-regulated EGFR expression, and that tumor cells adapt to estrogen receptor deprivation during treatment with aromatase inhibitors by the activation of alternate signing
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C. Krasner / Journal of Steroid Biochemistry & Molecular Biology 106 (2007) 76–80
pathways. Abrogation of alternative growth factor signing may restore sensitivity to endocrine therapy. The formal response rate was only 3% (1/35 cases) although, this the sole responsive patient had a durable complete response. In addition, one additional patient had stable disease in excess of 600 days and came off trial for patient’s questioning of continued therapeutic benefit at 538 days. In NSCLC, most clinical responses to gefitinib are associated with the presence of specific, activating somatic mutations in EGFR. In contrast, neither the responsive ovarian cancer case (exons 1–24) nor the case with prolonged stable disease had a somatic mutation of EGFR (exon 18–21). Since EGFR functions by forming heterodimers with other ERBB family members, we hypothesized that mutations affecting partner proteins, such as ERBB2, ERBB3, or ERBB4, might influence EGFR signaling and consequently gefitinib response. However, no mutations in exons 18–21 of ERBB2, ERBB3, or ERBB4 were identified in the responsive ovarian cancer case. Recently, several studies indicated that increased EGFR copy number might also be predictive of clinical responses to gefitinb [13,14]. However, both responsive cases seen by Krasner showed no evidence of increased EGFR gene copy number by FISH. Interestingly, a recent report of single-agent gefitinib from the Gynecologic Oncology Group demonstrated one partial response in among 27 women with platinum resistant ovarian cancer (RR-4%) [15]. Notably, a tumor-associated EGFR mutation, of the kind associated with TI-sensitivity in NSCLC, was identified in the responsive case. The absence of EGFR mutations or increased gene copy number in tumors from the two responsive cases reported by Krasner et al. suggests that, as for NSCLC, there may be other molecular determinants of TKI response in ovarian cancer, alternatively, the observed responses may be attributable to anastrozole rather than gefitinib.
4. Endometrial cancer Endometrial carcinoma is the most common gynecologic malignancy in the United States; it accounts for 6% of all cancers in women. Fortunately, most cases are diagnosed at an early stage when surgery alone may be adequate for cure. Endometrial cancer is a heterogenous disease. Differences in epidemiology and presentation suggest that two forms of endometrial cancer exist: those related to and those unrelated to estrogen stimulation. Type I endometrial carcinoma is estrogen-related, usually presents histologically as a lowgrade endometrioid tumor, and tends to be associated with atypical endometrial hyperplasia. These patients tend to have risk factors such as obesity, nulliparity, endogenous or exogenous estrogen excess, diabetes mellitus, and hypertension. Type II endometrial carcinoma appears unrelated to estrogen or endometrial hyperplasia, and tends to present with higher grade tumors or poor prognostic cell types, such as papillary serous or clear cell tumors. These patients are often multiparous, and do not have an increased prevalence of obesity,
diabetes, or hypertension. They also tend to be older than women with endometrioid tumors. Our current understanding of risk factors only helps to identify patients at risk for type I disease, which is the more common type (80% of cases are type I, 20% of cases are type II). The etiology of this type of endometrial cancer stems from the effects of excess estrogen, either from exogenous or endogenous sources. Exogenous exposure to estrogenic influences may be due to estrogen replacement therapy or tamoxifen, while endogenous exposure may result from obesity, anovulatory cycles, or estrogen-secreting tumors. Presence of steroid receptors correlates with better histologic differentiation, lesser degree of myometrial invasion and lower FIGO stage, all well-known indicators of good prognosis. Most studies have shown that steroid receptor content is an independent prognostic variable. Needed are large studies to focus on determining the relative contribution of the possible independent effects of receptor status on prognosis. The use of different arbitrary cut-off values to define steroid receptor positivity between individual studies makes it difficult to formulate definitive statements about the predictive value of PR and ER. A response rate to progestins for PR positive endometrial cancers of 72% compared with 12% for PR negative tumors has been reported [16,17]. Using several different progestins (e.g., megestrol acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate) response rates as high as 56% are reported, although more recent experience using more rigorous response criteria and multi-institutional participation suggests that objective response rates are lower, in the range of 15–20%. Unfortunately, the duration of benefit is limited; average response duration is only 4 months, and mean survival is approximately 8–11 months following the institution of therapy. Three features predict a favorable response to progestin therapy: hormone receptor expression, low-grade histology, and a long treatment-free interval between initial diagnosis and the development of advanced disease. Women with well-differentiated tumors that express estrogen and/or progesterone receptors are more likely to experience a response to progestin therapy than are those with hormone receptor-negative tumors [18]. As an example, in one GOG study, the response rates for women with and without tumoral PR expression were 37 and 8%, respectively, while response rates for grade 1 as compared to grade 3 tumors were 37% versus 8% [19]. It is unclear why some tumors that express hormone receptors fail to respond to progestin therapy, while a minority of PR-negative tumors respond. However, welldifferentiated tumors are also associated with a significantly longer survival than grade 3 tumors (median survival 18.8 months versus 6.9 months), which complicates the interpretation of the impact of hormone therapy on survival in published reports [20]. Tamoxifen appears to have some efficacy in women with advanced endometrial cancer as a single agent, with response rates of 10–22%. Tamoxifen is inactive in women who are resistant to progestins or chemotherapy [21]. As with pro-
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gestin therapy, low-grade endometrial cancers are far more likely to respond to tamoxifen than are high-grade tumors. The antitumor efficacy of two available SERMs, toremifene and raloxifene, is unknown. A high percentage of endometrial cancers possess receptors for gonadotropin-releasing hormone, including high-grade cancers. Unfortunately, while one trial observed a 28% response rate using a gonadotropin-releasing hormone agonist, outcomes were disappointing in other reports. Response rates are low in the setting of prior progestin treatment. In post-menopausal or oophorectomized patients the principle source of estrogen is conversion of adrenal androstenedione by aromatase in peripheral adipose tissue. In addition to peripheral aromatization, aromatase is elevated in endometrial cancer stroma and locally produced estrogen may act in a paracrine fashion to stimulate cancer growth [20]. Endometrial cancer seems to have increased in situ aromatase activity when compared with normal endometrium by one report of Sasano [1]. However, aromatase inhibitors appear to have limited activity in advanced endometrial cancer. In one report of 32 patients treated with letrozole (31% previously treated with progestins) there were one compete and two partial responses (overall response rate 10%) [21]. Responses were not correlated with PgR expression. Similar results were noted in a GOG study of anastrozole conducted in 23 patients with advanced disease (four of whom had received prior hormonal therapy); there were only two partial responses (9%) [22]. This suggests the need to evaluate aromatase inhibitors in the correct population, i.e, well-differentiated, hormone-receptor positive tumors.
5. Endometrial sarcoma In addition to endometrial cancer, an epithelial tumor, the uterus, can give rise to a variety of sarcomas. These sarcomas include leiomyosarcoma, carcinosarcoma, adenosarcoma and endometrial stromal sarcomas. Pure endometrial stromal tumors are either benign (endometrial stromal nodules) or malignant (endometrial stromal sarcomas, ESS). ESS are composed of cells that are identical to those found in the stromal component of the endometrium. They arise within the endometrium and infiltrate the myometrium as they grow. These slow-growing tumors may metastasize or recur after resection and recurrences are often treated with repeat surgical excision. If surgery is not possible, systemic therapy may be tried, with chemotherapy or hormonal therapy. Because these are uncommon diseases, there is a paucity of data supporting some of these interventions and most published accounts are clinical anecdotes. There are no prospective trials of hormonal treatment in ESS. Given that these tumors are derived from endometrial stroma, it follows that they should be responsive to hormonal manipulation. Patients, who undergo oophorectomy at time
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of initial surgery or reoperation, appear to have a better prognosis. One series showed a relapse rate of 43% compared with 100% for patients who had undergone oophorectomy [19]. Despite the lack of prospective trials, hormone therapy has become a standard approach to the treatment of advanced ESS. There are multiple reports documenting the presence of steroid receptors, though it is not clear if this correlates with response. A large proportion of ESS expresses estrogen and progesterone receptors, albeit at lower concentrations than in breast or endometrial carcinomas. Despite this finding, expression of hormone receptors does not predict hormone responsiveness, as was shown in a report in by Wade in which 48% of 60 uterine sarcomas were ER-positive and 30% were PR-positive [24]. In this uncontrolled review, only 1 of 28 patients with residual or recurrent disease after surgery had an objective response to hormone therapy with progestins. Expression of estrogen and progesterone receptors in lowgrade endometrial stromal sarcomas. In another study by Reich et al. found ER were seen in 15 (71%) and PR in 20 (95%) of tumors, respectively [25]. Hormonal therapy with progestins is occasionally associated with dramatic and durable responses in patients with advanced ESS, as illustrated in anecdotal reports and small case series. Medroxyprogesterone has induced major responses in lung metastases [24]. A reasonable, though unstudied approach might be to use an LHRH to reduce estrogen levels in patients unable to undergo surgical oophorectomy. Pink et al. reviewed 11 cases and found that 9 of 10 patients responded to hormonal manipulation, including withdrawal of ERT or tamoxifen [26]. In total, letrozole was used in 10 patients with eight responses [27]. Another reports from MSKCC documents response to letrozole after progression on tamoxifen and then on megace [28]. 6. Summary of hormonal treatment in gynecologic cancers The level of evidence supporting the effectiveness of hormonal treatment in gynecologic cancers is often low (the notable exception being endometrial cancer) and consists mainly of case reports and small, uncontrolled single institution trials. Clearly we need more research with randomized trials and better understanding of basic mechanisms, to select appropriate target patients. One important and unanswered question is why is the rate of ER positive tumors similar for ovary as compared to breast but the responses so much less frequent and in general less robust? [29]. References [1] H. Sasado, N. Harada, Intratumoral aromatase in human breast, endometrial, and ovarian malignancies, Endocr. Rev. 19 (1998) 593–607.
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[2] J. Ahlgren, N. Ellison, R. Gottlieb, F. Laluna, J.J. Lokich, P.R. Sinclair, W. Ueno, G.L. Wampler, K.Y. Yeung, D. Alt, J.G. Fryer, Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program, J. Clin. Oncol. 11 (1993) 1957–1968. [3] M. Markman, K. Webster, K. Zanotti, J. Rohl, J. Belinson, Use of tamoxifen in asymptomatic patients with recurrent small-volume ovarian cancer, Gynecol. Oncol. 93 (2004) 390–393. [4] K. Hatch, J. Beecham, J. Blessing, W. Creasman, Responsiveness of patients with advanced ovarian carcinoma to tamoxifen. A Gynecologic Oncology Group study of second-line therapy in 105 patients, Cancer 68 (1991) 269–271. [5] J.L. Perez-Gracia, E.M. Carrasco, Tamoxifen therapy for ovarian cancer in the adjuvant and advanced settings: systematic review of the literature and implications for future research, Gynecol. Oncol. 84 (2002) 201–209. [6] E.P. Gelmann, Tamoxifen for the treatment of malignancies other than breast and endometrial carcinoma, Semin. Oncol. 24 (1997) S1-65–S170. [7] J.H. Edmonson, Whither tamoxifen, Gynecol. Oncol. 62 (1996) 1–3. [8] C.J. Williams, Tamoxifen for relapse of ovarian cancer, Cochrane Database Syst. Rev. (2001) CD001034. [9] A. Bowman, H. Gabra, S.P. Langdon, A. Lessells, M. Stewart, A. Young, J.F. Smyth, CA125 response is associated with estrogen receptor expression in a phase II trial of letrozole in ovarian cancer: identification of an endocrine-sensitive subgroup, Clin. Cancer Res. 8 (2002) 2233–2239. [10] C.A. Papadimitriou, S. Markaki, J. Siapkaras, G. Vlachos, E. Efstathiou, I. Grimani, G. Hamilos, M. Zorzou, M.A. Dimopoulos, Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long-term results of a phase II study, Oncology 66 (2004) 112–117. [11] M.G. Del Carmen, A.F. Fuller, U. Matulonis, N.K. Horick, A. Goodman, L.R. Duska, R. Penson, S. Campos, M. Roche, M.V. Seiden, Phase II trial of anastrozole in women with asymptomatic mullerian cancer, Gynecol. Oncol. 91 (2003) 596–602. [12] C. Krasner, R. Debernardo, M. Findley, et al., Phase II trial of anastrazole in combination with gefitinib in women with asymptomatic mullerian cancer, in: ASCO Annual Meeting Proceedings, J. Clin. Oncol. 23 (2005) 5063. [13] T.J. Lynch, D.W. Bell, Sordella RActivating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib, N. Engl. J. Med. 350 (2004) 2129–2139. [14] J.G. Paez, P.A. Janne, J.C. Lee, S. Tracy, H. Greulich, S. Gabriel, P. Herman, F.J. Kaye, N. Lindeman, T.J. Boggon, K. Naoki, H. Sasaki, Y. Fujii, M.J. Eck, W.R. Sellers, B.E. Johnson, M. Meyerson, EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy, Science 304 (2004) 1497–1500. [15] R. Schilder, M. Sill, X. Chen, K.M. Darcy, S.L. Decesare, G. Lewandowski, R.B. Lee, C.A. Arciero, H. Wu, A.K. Godwin, Phase II
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Review
Aromatase inhibitors in gynecologic cancers夽 Carolyn Krasner Gillette Center for Women’s Oncology, Massachusetts General Hospital, United States
Abstract The female genital tract is hormonally responsive, and consequently some tumors, which arise within in it, may be treated at least in part, with hormonal manipulation. The range of responses in clinical trials and case reports will be reviewed. Many of these diseases are too rare for clinical trial testing, and in some cases evidence is anecdotal at best. Recurrences of ovarian cancer have been treated with tamoxifen and megesterol acetate with variable response rates from 0 to 56%. The favorable toxicity profile of aromatase inhibitors led to trials of these agents for the treatment of relapsed epithelial ovarian cancer. These agents have proved tolerable with minor response rates but a significant disease stabilization rate, which may be prolonged in a minority of cases. It is unclear if these responses may be predicted by estrogen receptor expression or aromatase expression. Anastrazole has also been tried in combination with an EGFR receptor-inhibitor, again showing minor responses but possibly an increase in TTT in some patients. Granulosa cell tumors of the ovary are rare, hormonally sensitive tumors, with reported responses to a variety of hormonal manipulations, including aromatase inhibition. In addition, combined endocrine blockade, including aromatase inhibition, has been tried with reports of success. Endometrial cancers, particularly type I lesions, are often treated with hormonal manipulation, most commonly with progestins, but also with antiestrogens such as tamoxifen. A trial of aromatase inhibition in the treatment of recurrent endometrial cancer showed minimal responses. Endometrial stromal sarcoma, an uncommon uterine malignancy, has shown response to hormonal treatments, with multiple case reports of efficacy of aromatase inhibition. Despite the rarity of some of these tumor types, rare tumor study groups, such as within the Gynecologic Oncology Group, should make an effort to prospectively define the utility of these treatments. © 2007 Published by Elsevier Ltd. Keywords: Aromatase inhibitors; Gynecologic cancer
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aromatase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of hormonal treatment in gynecologic cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Many gynecologic cancers express hormone receptors, including ovarian epithelial cancer, endometrial carcinomas and sarcomas and ovarian stromal tumors. This fact has
76 76 77 78 79 79 79
spurred an attempt to treat a range of gynecologic malignancies with various hormonal manipulations, including aromatase inhibition. This review will present an overview of the hormonal therapies of these cancers. 2. Ovarian cancer
夽 Presented at the VIII International Aromatase Conference: ‘Aromatase 2006’ (Baltimore, MD, USA, 18–20 September 2006).
0960-0760/$ – see front matter © 2007 Published by Elsevier Ltd. doi:10.1016/j.jsbmb.2007.05.026
Ovarian cancer is the second most common gynecologic malignancy, but the most common cause of death among
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women who develop gynecologic cancer, and the fifth most common cause of cancer-related death in females in the United States. The majority (90%) of primary ovarian tumors derive from epithelial cells, the remainder arise from other cell types (germ cell tumors, sex cord-stromal tumors, and mixed cell tumors). Initial therapy for ovarian cancer is debulking surgery. Surgery is then followed by chemotherapy, which is typically a platinum and a taxane. Despite objective response rates of 60–80% to combination platinum-based chemotherapy, the majority of women with advanced epithelial ovarian cancer ultimately develop progressive disease and die of complications of their malignancy. Relapsed disease is not curable; therefore, salvage chemotherapy is primarily palliative in nature. Thus, in addition to the critical need to develop new drugs with activity in the upfront treatment of ovarian cancer, it is important to develop rational therapeutic strategies in the relapsed/refractory setting which focus on optimizing quality of life and prolonging time to development of symptomatic disease, as well as extending overall survival in this malignancy. While there are numerous cytotoxic salvage regimens available, less toxic hormonal regimens are particularly appealing in this setting. Another setting in which hormonal therapy is being investigated is in the consolidation or maintenance treatment of women who have achieved a complete response to chemotherapy. Treatment decisions for relapsed disease is based on multiple factors: patient’s age and performance status, length of time from completion of initial therapy, i.e. platinum sensitivity, appearance of radiographic changes, and presence or absence of symptoms. As therapy for relapsed disease is palliative and not curative, there has been a desire not to instigate toxic chemotherapies immediately, in the absence of a survival benefit. Therefore, this is really the perfect scenario for the investigation of new agents on clinical trials. However, these patients with early, marker only relapses are often not eligible for clinical trials without measurable disease (although Ca125 kinetics are increasingly being accepted for assessment of response). All these factors combine to make endocrine therapy appealing in non-bulky, asymptomatic ovarian cancer. Ovarian cancer has been shown to stain for steroid hormone receptors, including estrogen, progesterone and androgen. Epidemiologic studies indicate that hormones may play a role in the genesis of ovarian cancer, and there are data to show that pregnancy, breast-feeding and oral contraceptive use can decrease the risk of developing ovarian cancer [1]. These endocrine associations have lead to the investigation of hormonal therapy in patients with ovarian cancer; however, no hormonal therapies have been approved by the FDA for the treatment of ovarian malignancies. Hormonal treatment of ovarian cancer date back at least to the 1960s. Three consecutive Phase II trials of MidAtlantic Oncology Program in heavily pretreated patients studied megestrol acetate, aminoglutethemide and tamox-
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ifen [2]. With assessment by radiographic response criteria, tamoxifen showed a response rate of 17% with stable disease lasting >60 days in 62% of patients. The other two agents showed no responses. A similar GOG study of tamoxifen in the second line setting again demonstrated a RR of 17% with time to progression of 4.4 months [3]. A Cochrane database metanalysis from 2001 looked at 14 studies comprising 623 patients, and found overall response rates ranged from 0 to 56%, with the rate of stable disease for 4 weeks or greater 31.9% reported in eight studies [4]. Important to note however, is the absence of data for response from randomized trials. Some studies showed correlation with ER receptors, others did not, though none designed specifically to assess that. Some had heavily pretreated patients though studies do not agree that this is significantly correlated with response [5–8]. Clearly, the predictors of response to hormonal agents in this population is not known.
3. Aromatase inhibitors Bowman tried letrazole and found an overall response by UICC criteria was 0%, but response by Ca125 criteria was 8%. Importantly, they reported a positive correlation of ER, PR and EGF with response p = 0.0087 [9]. This is a nonrandomized study, so it is possible that the tumors with the highest ER and PR levels may have an intrinsically more favorable course because of intrinsic differences in the tumor, rather than any response or stabilizing effect of letrozole. By contrast, Papadimitriou also studied letrozole in relapsed ovarian cancer showing an ORR of 15% with 19% of patients achieving stable disease but no correlation between response and ER/PR expression [10]. Del Carmen et al. studied anastrazole in this population, finding one partial response; median TTP = 85 days (one patient stable for 500 days), stable disease at 3 month 42%. There was no correlation between ER/PR and TTP [11]. Bowman showed a correlation between TTP and ER/PR positive tumors [9], while Del Carmen showed a trend (but not statistical significance) to longer TTP with ER/PR negative tumors. Possible explanations for this discrepancy include differences in IHC staining and histoscore reading, as well as heterogeneity in receptor status in ovarian cancer between primary (Bowman) and metastatic lesions (Del Carmen). These divergent results underscore the need for randomized trials of endocrine therapy versus placebo in patients with potentially endocrine sensitive tumors. Krasner et al. studied the combination of anastrazole with gefitinib (Iressa) in patients with all ER/PR positive tumors [12]. Preclinical studies had suggested that simulatenous interruption in ER/PR and EGFR pathways might be synergistic ER interacts with multiple kinases. Preclinical models in breast cancer suggest that tumors resistant to tamoxifen have up-regulated EGFR expression, and that tumor cells adapt to estrogen receptor deprivation during treatment with aromatase inhibitors by the activation of alternate signing
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pathways. Abrogation of alternative growth factor signing may restore sensitivity to endocrine therapy. The formal response rate was only 3% (1/35 cases) although, this the sole responsive patient had a durable complete response. In addition, one additional patient had stable disease in excess of 600 days and came off trial for patient’s questioning of continued therapeutic benefit at 538 days. In NSCLC, most clinical responses to gefitinib are associated with the presence of specific, activating somatic mutations in EGFR. In contrast, neither the responsive ovarian cancer case (exons 1–24) nor the case with prolonged stable disease had a somatic mutation of EGFR (exon 18–21). Since EGFR functions by forming heterodimers with other ERBB family members, we hypothesized that mutations affecting partner proteins, such as ERBB2, ERBB3, or ERBB4, might influence EGFR signaling and consequently gefitinib response. However, no mutations in exons 18–21 of ERBB2, ERBB3, or ERBB4 were identified in the responsive ovarian cancer case. Recently, several studies indicated that increased EGFR copy number might also be predictive of clinical responses to gefitinb [13,14]. However, both responsive cases seen by Krasner showed no evidence of increased EGFR gene copy number by FISH. Interestingly, a recent report of single-agent gefitinib from the Gynecologic Oncology Group demonstrated one partial response in among 27 women with platinum resistant ovarian cancer (RR-4%) [15]. Notably, a tumor-associated EGFR mutation, of the kind associated with TI-sensitivity in NSCLC, was identified in the responsive case. The absence of EGFR mutations or increased gene copy number in tumors from the two responsive cases reported by Krasner et al. suggests that, as for NSCLC, there may be other molecular determinants of TKI response in ovarian cancer, alternatively, the observed responses may be attributable to anastrozole rather than gefitinib.
4. Endometrial cancer Endometrial carcinoma is the most common gynecologic malignancy in the United States; it accounts for 6% of all cancers in women. Fortunately, most cases are diagnosed at an early stage when surgery alone may be adequate for cure. Endometrial cancer is a heterogenous disease. Differences in epidemiology and presentation suggest that two forms of endometrial cancer exist: those related to and those unrelated to estrogen stimulation. Type I endometrial carcinoma is estrogen-related, usually presents histologically as a lowgrade endometrioid tumor, and tends to be associated with atypical endometrial hyperplasia. These patients tend to have risk factors such as obesity, nulliparity, endogenous or exogenous estrogen excess, diabetes mellitus, and hypertension. Type II endometrial carcinoma appears unrelated to estrogen or endometrial hyperplasia, and tends to present with higher grade tumors or poor prognostic cell types, such as papillary serous or clear cell tumors. These patients are often multiparous, and do not have an increased prevalence of obesity,
diabetes, or hypertension. They also tend to be older than women with endometrioid tumors. Our current understanding of risk factors only helps to identify patients at risk for type I disease, which is the more common type (80% of cases are type I, 20% of cases are type II). The etiology of this type of endometrial cancer stems from the effects of excess estrogen, either from exogenous or endogenous sources. Exogenous exposure to estrogenic influences may be due to estrogen replacement therapy or tamoxifen, while endogenous exposure may result from obesity, anovulatory cycles, or estrogen-secreting tumors. Presence of steroid receptors correlates with better histologic differentiation, lesser degree of myometrial invasion and lower FIGO stage, all well-known indicators of good prognosis. Most studies have shown that steroid receptor content is an independent prognostic variable. Needed are large studies to focus on determining the relative contribution of the possible independent effects of receptor status on prognosis. The use of different arbitrary cut-off values to define steroid receptor positivity between individual studies makes it difficult to formulate definitive statements about the predictive value of PR and ER. A response rate to progestins for PR positive endometrial cancers of 72% compared with 12% for PR negative tumors has been reported [16,17]. Using several different progestins (e.g., megestrol acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate) response rates as high as 56% are reported, although more recent experience using more rigorous response criteria and multi-institutional participation suggests that objective response rates are lower, in the range of 15–20%. Unfortunately, the duration of benefit is limited; average response duration is only 4 months, and mean survival is approximately 8–11 months following the institution of therapy. Three features predict a favorable response to progestin therapy: hormone receptor expression, low-grade histology, and a long treatment-free interval between initial diagnosis and the development of advanced disease. Women with well-differentiated tumors that express estrogen and/or progesterone receptors are more likely to experience a response to progestin therapy than are those with hormone receptor-negative tumors [18]. As an example, in one GOG study, the response rates for women with and without tumoral PR expression were 37 and 8%, respectively, while response rates for grade 1 as compared to grade 3 tumors were 37% versus 8% [19]. It is unclear why some tumors that express hormone receptors fail to respond to progestin therapy, while a minority of PR-negative tumors respond. However, welldifferentiated tumors are also associated with a significantly longer survival than grade 3 tumors (median survival 18.8 months versus 6.9 months), which complicates the interpretation of the impact of hormone therapy on survival in published reports [20]. Tamoxifen appears to have some efficacy in women with advanced endometrial cancer as a single agent, with response rates of 10–22%. Tamoxifen is inactive in women who are resistant to progestins or chemotherapy [21]. As with pro-
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gestin therapy, low-grade endometrial cancers are far more likely to respond to tamoxifen than are high-grade tumors. The antitumor efficacy of two available SERMs, toremifene and raloxifene, is unknown. A high percentage of endometrial cancers possess receptors for gonadotropin-releasing hormone, including high-grade cancers. Unfortunately, while one trial observed a 28% response rate using a gonadotropin-releasing hormone agonist, outcomes were disappointing in other reports. Response rates are low in the setting of prior progestin treatment. In post-menopausal or oophorectomized patients the principle source of estrogen is conversion of adrenal androstenedione by aromatase in peripheral adipose tissue. In addition to peripheral aromatization, aromatase is elevated in endometrial cancer stroma and locally produced estrogen may act in a paracrine fashion to stimulate cancer growth [20]. Endometrial cancer seems to have increased in situ aromatase activity when compared with normal endometrium by one report of Sasano [1]. However, aromatase inhibitors appear to have limited activity in advanced endometrial cancer. In one report of 32 patients treated with letrozole (31% previously treated with progestins) there were one compete and two partial responses (overall response rate 10%) [21]. Responses were not correlated with PgR expression. Similar results were noted in a GOG study of anastrozole conducted in 23 patients with advanced disease (four of whom had received prior hormonal therapy); there were only two partial responses (9%) [22]. This suggests the need to evaluate aromatase inhibitors in the correct population, i.e, well-differentiated, hormone-receptor positive tumors.
5. Endometrial sarcoma In addition to endometrial cancer, an epithelial tumor, the uterus, can give rise to a variety of sarcomas. These sarcomas include leiomyosarcoma, carcinosarcoma, adenosarcoma and endometrial stromal sarcomas. Pure endometrial stromal tumors are either benign (endometrial stromal nodules) or malignant (endometrial stromal sarcomas, ESS). ESS are composed of cells that are identical to those found in the stromal component of the endometrium. They arise within the endometrium and infiltrate the myometrium as they grow. These slow-growing tumors may metastasize or recur after resection and recurrences are often treated with repeat surgical excision. If surgery is not possible, systemic therapy may be tried, with chemotherapy or hormonal therapy. Because these are uncommon diseases, there is a paucity of data supporting some of these interventions and most published accounts are clinical anecdotes. There are no prospective trials of hormonal treatment in ESS. Given that these tumors are derived from endometrial stroma, it follows that they should be responsive to hormonal manipulation. Patients, who undergo oophorectomy at time
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of initial surgery or reoperation, appear to have a better prognosis. One series showed a relapse rate of 43% compared with 100% for patients who had undergone oophorectomy [19]. Despite the lack of prospective trials, hormone therapy has become a standard approach to the treatment of advanced ESS. There are multiple reports documenting the presence of steroid receptors, though it is not clear if this correlates with response. A large proportion of ESS expresses estrogen and progesterone receptors, albeit at lower concentrations than in breast or endometrial carcinomas. Despite this finding, expression of hormone receptors does not predict hormone responsiveness, as was shown in a report in by Wade in which 48% of 60 uterine sarcomas were ER-positive and 30% were PR-positive [24]. In this uncontrolled review, only 1 of 28 patients with residual or recurrent disease after surgery had an objective response to hormone therapy with progestins. Expression of estrogen and progesterone receptors in lowgrade endometrial stromal sarcomas. In another study by Reich et al. found ER were seen in 15 (71%) and PR in 20 (95%) of tumors, respectively [25]. Hormonal therapy with progestins is occasionally associated with dramatic and durable responses in patients with advanced ESS, as illustrated in anecdotal reports and small case series. Medroxyprogesterone has induced major responses in lung metastases [24]. A reasonable, though unstudied approach might be to use an LHRH to reduce estrogen levels in patients unable to undergo surgical oophorectomy. Pink et al. reviewed 11 cases and found that 9 of 10 patients responded to hormonal manipulation, including withdrawal of ERT or tamoxifen [26]. In total, letrozole was used in 10 patients with eight responses [27]. Another reports from MSKCC documents response to letrozole after progression on tamoxifen and then on megace [28]. 6. Summary of hormonal treatment in gynecologic cancers The level of evidence supporting the effectiveness of hormonal treatment in gynecologic cancers is often low (the notable exception being endometrial cancer) and consists mainly of case reports and small, uncontrolled single institution trials. Clearly we need more research with randomized trials and better understanding of basic mechanisms, to select appropriate target patients. One important and unanswered question is why is the rate of ER positive tumors similar for ovary as compared to breast but the responses so much less frequent and in general less robust? [29]. References [1] H. Sasado, N. Harada, Intratumoral aromatase in human breast, endometrial, and ovarian malignancies, Endocr. Rev. 19 (1998) 593–607.
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