Endocrine-Related Cancer (2012) 19 R255–R279 REVIEW Hormone response in ovarian cancer: time to reconsider as a clinical target?

Francesmary Modugno1,2,3, Robin Laskey3,4, Ashlee L Smith4, Courtney L Andersen3,5, Paul Haluska6 and Steffi Oesterreich3,7

1Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 2Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA 3University of Pittsburgh Cancer Institute and Magee Womens Research Institute, Women’s Cancer Research Center, 204 Craft Avenue, Pittsburgh, Pennsylvania 15213, USA 4Division of Gynecologic Oncology, Magee Womens Hospital, UPMC, Pittsburgh, Pennsylvania, USA 5Graduate Program in Molecular Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA 6Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA 7Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA (Correspondence should be addressed to S Oesterreich at University of Pittsburgh Cancer Institute and Magee Womens Research Institute, Women’s Cancer Research Center; Email: [email protected])

Abstract Ovarian cancer is the sixth most common cancer worldwide among women in developed countries and the most lethal of all gynecologic malignancies. There is a critical need for the introduction of targeted therapies to improve outcome. Epidemiological evidence suggests a critical role for steroid hormones in ovarian tumorigenesis. There is also increasing evidence from in vitro studies that estrogen, progestin, and androgen regulate proliferation and invasion of epithelial ovarian cancer cells. Limited clinical trials have shown modest response rates; however, they have consistently identified a small subset of patients that respond very well to endocrine therapy with few side effects. We propose that it is timely to perform additional well-designed trials that should include biomarkers of response. Endocrine-Related Cancer (2012) 19 R255–R279

Introduction distal fallopian tube (Bell 2005, Crum et al. 2007), whereas endometrioid and clear cell carcinomas are Ovarian cancer is the sixth most common cancer believed to arise from endometriotic lesions (Nezhat worldwide among women in developed countries and et al. 2008). In contrast, most mucinous tumors are the most lethal of all gynecologic malignancies (Jemal believed to be metastases to the ovary from the et al. 2011). About 90% of primary malignant ovarian gastrointestinal tract, including the colon, appendix, tumors are epithelial carcinomas and are further and stomach (Lee & Young 2003, Kelemen & Kobel classified as serous, endometrioid, clear cell, muci- 2011, Zaino et al. 2011). nous, transitional, mixed cell, or undifferentiated based Despite the differences in the putative tissues of on cell morphology (Cho & Shih 2009). Recent origin of epithelial ovarian cancers (EOC), the technological advances have shed light on both the presence of sex steroid hormone receptors in many of cellular and the molecular biology of ovarian cancer these tissues of origin for ovarian cancer (Catalano such that it is now widely believed that ‘ovarian et al. 2000, Akahira et al. 2002, Wada-Hiraike et al. cancer’ is a general term for a group of molecularly and 2006, Horne et al. 2009, Shao et al. 2011), as well as in etiologically distinct diseases that share an anatomical many malignant epithelial ovarian tumors (Rao & location (Vaughan et al. 2011). In particular, the Slotman 1991), suggests a potential role for hormones diverse histological types of epithelial tumors are in the origin and promotion of these diseases. believed to be derived from different tissues. For However, at this point in time, detailed mechanistic example, high-grade serous carcinomas are believed to studies are lacking, and models to study hormone arise from the ovarian surface epithelium and/or the response in vitro and in vivo are very limited. Few and

Endocrine-Related Cancer (2012) 19 R255–R279 Downloaded from Bioscientifica.comDOI: 10.1530/ERC-12-0175 at 10/02/2021 04:42:32AM 1351–0088/12/019–R255 q 2012 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.orgvia free access F Modugno et al.: Hormone response in ovarian cancer often small clinical trials have not resulted in any Table 1 Hormonally related epidemiological factors associated advances in the use of endocrine treatment for ovarian with EOC risk cancer. In this review, we will summarize and discuss Strength of epidemiological evidence and laboratory data that relationship collectively strongly support a critical role for hormones in ovarian cancer development and pro- Factors associated with increased EOC gression, focusing on the steroids estrogen, pro- Reproductive factors Nulliparity CCC gesterone, and androgen. We will also provide an Exogenous hormone use overview of clinical trials targeting the receptors of Combined HRT C these steroids. Due to space limitations, we will not Estrogen-only HRT CC discuss the role of gonadotropins in this review and ask Androgens C the readers to refer to previous reviews on this topic Reproductive disorders Endometriosis CCa (Zheng et al. 2007, So et al. 2008, King & Wong PCOS C/0 2011). We will end the review with our suggestions for Infertility CC future directions for the field, such as the need for Other further mechanistic studies and well-designed clinical Age CCC trials, which should include the use of biomarkers. Factors associated with decreased EOC risk Reproductive factors Pregnancy KKK Breast-feeding K The epidemiology of EOC Twinning and other non-singleton births K (note 3) Reproductive and hormonally related risk factors Tubal ligation KKK KK The most consistently reported reproductive and Hysterectomy Exogenous hormone use hormonally related factors found to protect against Oral contraceptive use KKK EOC are use of oral contraceptives (OCs), increasing High vs low progestin OCs K parity, and having a tubal ligation. In contrast, increasing High vs low estrogen OCs 0 age and nulliparity have been consistently shown to Factors not associated with EOC risk increase EOC risk. Other hormonally linked factors, Reproductive factors Early menarche 0 such as hormone replacement therapy (HRT) use, Late menopause 0 infertility, endometriosis, breast-feeding, hysterectomy, Exogenous hormone use and central adiposity, have shown some association Fertility drug use 0 with EOC, but the data are neither as strong nor as aEndometrioid and clear cell subtype only. C, positively consistent as OC use, parity, and tubal ligation. Table 1 associated with EOC; K, negatively associated with EOC; summarizes the relationship between reproductive and 0, no association with EOC. hormonally related risk factors and EOC. whereas some higher progestin dose formulations may OCs, HRT, and exogenous hormones confer greater protection, although that association Both prospective and case–control studies report has not been consistent (Ness et al.2000, Schildkraut about a 30% decrease in ovarian cancer risk with ever et al.2002, Pike et al.2004, Lurie et al.2007). use of OCs (Collaborative Group on Epidemiological While the data on OC use and EOC have been Studies of Ovarian Cancer 2008), and even short-term consistent, the data for HRT have not. However, more use (6 months or less) appears protective (Greer et al. recent studies, including the prospective Women’s 2005). Longer duration of use imparts increased Health Initiative (WHI) (Anderson et al. 2003) and the protection, with a 20% decrease in risk for each 5 years Million Women Study (Beral et al. 2007), report an of use. More recent OC use is associated with greater increase in risk for both estrogen-only (ET) and protection, but even after stopping its use for 30 or more estrogen–progestin (EPT) formulations, although the years, risk is still reduced by about 15% (Collaborative risk associated with EPT was lower than that of ET. Group on Epidemiological Studies of Ovarian Cancer A recent meta-analysis of 14 published studies found 2008). Risk reduction appears consistent for all risk increases 22% per 5 years of ET use compared histological subtypes of EOC, except for possibly with only 10% per 5 years of EPT use, suggesting that mucinous tumors. Estrogen dose does not appear to risk differs by regimen (Pearce et al. 2009). affect the OC–EOC association (Collaborative Group Exogenous androgens may be associated with EOC. on Epidemiological Studies of Ovarian Cancer 2008) One case–control study found that use of Danazol,

Downloaded from Bioscientifica.com at 10/02/2021 04:42:32AM via free access R256 www.endocrinology-journals.org Endocrine-Related Cancer (2012) 19 R255–R279 a synthetic androgen commonly used in the treatment obesity, the metabolic syndrome, hyperandrogenism, of endometriosis, significantly increased EOC risk and insulin resistance. However, the finding was based (Cottreau et al. 2003), although this finding has not on a small number of cases (nZ7) and the association been replicated (Olsen et al. 2008). Ever use of was limited to nonusers of OCs and thin women. testosterone (tablets, patches, troches, or cream) has Further case–control and prospective studies have been associated with a threefold increase in EOC failed to confirm this relationship (Pierpoint et al. (Olsen et al. 2008). 1998, Olsen et al. 2008, Brinton et al. 2010). Tubal ligation has been consistently shown to be Childbearing and breast-feeding associated with reduction in EOC risk (Cibula et al. Like OC use, childbearing has been consistently shown 2011). This protection appears similar in magnitude to to be associated with a reduced risk of EOC in both OC use and child bearing (about 30%) and is protective prospective and case–control studies, with an observed in high-risk women (i.e. BRCA1/2 carriers) as well. protective effect similar to or greater than that observed Hysterectomy has also been shown to reduce EOC risk, for OC use (about 30% for the first full-term although the magnitude of the association is not as pregnancy). Moreover, increasing parity is associated great nor as consistent as that reported for tubal ligation with increasing protection, with each additional full- (Riman et al. 2004). Finally, reproductive factors term pregnancy conferring about a 10% decrease in associated with other hormonally linked cancers, such risk (Braem et al. 2010, Tsilidis et al. 2011). Even an as age at first menarche, age at menopause, and length incomplete pregnancy appears to provide some of reproductive years, have not been consistently protection against EOC, although the magnitude of associated with EOC (Riman et al. 2004). the protective effect is less than that of a full-term pregnancy (Riman et al. 1998). Finally, multiple births Weighing the hormone: EOC epidemiological in a single pregnancy (giving birth to twins, triplets, evidence etc.) may be associated with a greater risk reduction The epidemiological relationships between reproduc- than singleton births (Whiteman et al. 2000). In tive and hormonally related risk factors and EOC contrast to childbearing, the evidence for a relationship suggest that hormones play a role in the etiology of the between breast-feeding and EOC is inconsistent, disease. Indeed, an early, small (31 cases and 62 although most studies show a small negative associ- controls), prospective study reported that circulating ation (Riman et al. 2004, Danforth et al. 2007). levels of androstenedione and DHEA were signi- ficantly associated with increased risk of EOC in a Reproductive disorders and other reproductive dose-dependent fashion, whereas levels of DHEAS, factors estradiol, estrone, and progesterone were not Factors affecting childbearing have also been shown to (Helzlsouer et al. 1995). However, three subsequent be associated with EOC. In most studies, infertility has prospective studies, with a total of over 580 ovarian been associated with an increased risk, which may be cancer cases, have failed to replicate these early greatest among women who fail to conceive (Vlahos positive hormone–EOC associations (Lukanova et al. et al. 2010). In general, infertility treatment does not 2003, Rinaldi et al. 2007, Tworoger et al. 2008). Thus, appear to increase EOC risk, although the subset of the evidence to date suggests that circulating hormone treated women who remain nulliparous may be at an levels are not associated with EOC. Based on the increased risk (Vlahos et al. 2010). existing data, however, the exact nature of the Endometriosis, defined as the presence and growth hormone–EOC link remains unclear, with some factors of endometrial tissue outside the uterine cavity, has supporting and others refuting a direct association. also been associated with EOC. A recent pooled Below we will describe and discuss current under- analysis of 13 case–control studies showed a threefold standing of roles of hormones in EOC. increase in the incidence of clear cell EOC and a twofold increase in endometrioid EOC among Estrogens women with a self-reported history of endometriosis The evidence linking estrogens to EOC are mixed. (Pearce et al. 2012). Although pregnancy raises circulating estrogen levels, An increased risk of EOC was reported by one case– intraovarian levels are reduced. OCs reduce endogen- control study (Schildkraut et al. 1996) among women ous estrogen levels (Killick et al. 1987). In contrast, with polycystic ovary syndrome (PCOS), a condition risk-conferring HRT raises circulating estrogen associated with menstrual dysfunction, infertility, levels. Breast-feeding reduces both circulating and

Downloaded from Bioscientifica.com at 10/02/2021 04:42:32AM via free access www.endocrinology-journals.org R257 F Modugno et al.: Hormone response in ovarian cancer intraovarian estrogen levels (Rosenblatt & Thomas low-dose OCs (Rosenberg et al. 1994). Pregnancy, a 1993). Endometriosis is associated with an increased consistently strong protective factor, raises pro- local production of estradiol as well as increased gesterone levels, too. Third trimester circulating expression of estrogen receptor a (ERa). Moreover, progesterone levels are more than ten times higher compared with levels in the early reproductive years, than luteal phase levels during the menstrual cycle. circulating peri-menopausal estradiol levels are Moreover, progesterone levels in non-singleton births, higher, reflecting the period when EOC risk begins to which are more protective against EOC than singleton sharply rise (Prior 2005). Together, these data suggest births, are higher than in singleton births (Batra et al. that estrogens may be associated with an increase in 1978, Haning et al. 1985). Although the risk of EOC EOC risk. appears increased with HRT use, regimens containing Further evidence for an estrogen–EOC link comes a progestin confer a lower relative risk compared with from genetic susceptibility studies. Specifically, a ET regimens, suggesting that the progestin component large, international, pooled analysis of ten case–control may mitigate the deleterious effect of estrogens. studies comprising 4946 women with primary invasive Ovulatory infertility, which is associated with reduced EOC and 6582 controls found that women with the progesterone production, may increase EOC risk rs1271572 TT genotype were at a significantly (Brinton et al. 1989, Rossing et al. 1994). Finally, increased risk of EOC compared with women with endometriosis is associated with resistance to pro- the G allele (Lurie et al. 2011). The association was gesterone, which has been suggested to be due to the even stronger among women %50 years. rs1271572 is presence of inhibitory PR-A isoform and absence of located in the promoter of the ERb gene (ESR2), where transcription activating PR-B isoform (Attia et al.2000). it maps to a binding region for MyoD and AP-4, Although the epidemiological data linking pro- previously shown to be important for expression of gesterone with reduced EOC risk are substantial, they ERb (Li et al. 2000). ERb is believed to inhibit are not definitive. For example, the data on OC proliferation and motility of ovarian cancer cells as progestin dose and EOC are not consistent. Additional well as facilitate apoptosis (Bardin et al. 2004a, Cheng compelling data come from a large consortium of 12 et al. 2004b, Treeck et al. 2007). Hence, there is a ovarian cancer case–control studies: a functional SNP, potential causal association of rs1271572 with EOC, C331/CT, in the progesterone receptor (PR) alters the especially among pre- and perimenopausal women, relative transcription of the two PR isoforms, PR-A and who have higher circulating estrogen concentrations PR-B. Variants associated with increased PR-B, which compared with their postmenopausal counterparts, acts as a classical steroid receptor, in theory should be further supporting an association between estrogens associated with decreased EOC risk. Conversely, and EOC. variants associated with increased PR-A, which However, other factors do not support an estrogen– inhibits in part PR-B, should be associated with EOC link. No prospective study has found an increased risk. However, in this large study involving association between circulating estrogen levels and 4788 cases and 7614 controls, PR variants were not EOCOC use reduces endogenous estrogen levels; found to alter EOC risk, except for possibly the however, OC estrogen dose does not alter the endometrioid subtype (Pearce et al. 2008). magnitude of the observed EOC protective effect (Collaborative Group on Epidemiological Studies of Androgens Ovarian Cancer 2008). Finally, reproductive factors, Several pieces of epidemiological data support a role such as early menarche and late menopause, which for androgens in EOC development. OCs, one of the are associated with greater estrogen exposure and are strongest protective factors, reduce circulating andro- linked to estrogen-associated breast and endometrial gen levels (Gaspard et al. 1983, Murphy et al. 1990, cancers, have not been consistently associated with EOC. Coenen et al. 1996). Tubal ligation and hysterectomy are also associated with decreased circulating androgen Progesterone and progestins levels (Laughlin et al. 2000, Davison et al. 2005, Epidemiological data suggest that progestins and Danforth et al.2010). The potential association progesterone may have a protective role against between PCOS, a hyperandrogenic condition, and EOC. Progestin-containing OCs raise circulating EOC provides further support for the androgen–EOC progesterone levels about threefold. Progestin-only link. Finally, the possible increased risk associated OCs may be as protective as EPT regimens and high- with use of exogenous androgenic agents further dose progestin OCs may be more protective than supports the relationship.

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Despite these epidemiological associations, the data considered EOCs as a single disease, which may are not conclusive. Circulating androgen levels have partially explain inconsistencies among studies as well not been associated with increased risk in three large as some negative finding. Indeed, a very recent study prospective studies. Notably, androgen levels decline suggests that association between circulating levels of with age, with the decline being greater in the earlier sex steroid hormones and EOC differ by tumor reproductive years than in later decades (Davison et al. histology and invasiveness. These data suggest that 2005). This is in contrast to the age–EOC relationship the previously reported negative findings (Lukanova wherein incidence and risk rise slowly in the early et al. 2003, Rinaldi et al. 2007, Tworoger et al. 2008, reproductive years, then sharply increase beginning at Modugno & Edwards 2012) may be due to treating around age 40, and continue to increase through late EOCs as a single entity. In the future, it will be age (Howlader et al.2011). In addition, factors important to determine potential associations with associated with androgen levels as well as those histological and molecular subtypes of EOC. altering androgen levels have not been consistently associated with EOC. For example, PCOS has not been consistently associated with the disease and the data In vitro and in vivo studies of hormone linking exogenous androgen use with EOC have not action in ovarian cancer been confirmed. Furthermore, OC formulations that Role of ER signaling action in ovarian cancer contain androgenic agents do not differ in the cells magnitude of their protective effect compared with non-androgenic formulations (Greer et al.2005). Estrogen exerts its effect through two receptors, ERa Finally, a trinucleotide repeat polymorphism in exon and ERb. A number of studies have addressed the one of the androgen receptor (AR) gene, the length of expression of both isoforms in clinical samples and which is inversely associated with the ability of the their functions in cell line models. ERb is highly AR–ligand complex to transactivate AR-responsive expressed throughout the normal ovary, including in granulosa cells, theca cells, corpora lutea, oocytes, as genes, has been inconsistently associated with EOC in well as cultures of primary ovarian surface epithelial both magnitude and direction (Spurdle et al. 2000, (OSE) cells (Kuiper et al. 1996, Byers et al.1997, Menin et al. 2001, Santarosa et al. 2002, Lee et al. Brandenberger et al. 1998, Hillier et al. 1998); 2005a, Schildkraut et al. 2007, Ludwig et al. 2009). however, its expression is progressively lost during ovarian cancer development and progression (Lau et al. Summary of epidemiological data and the hormone– 1999, Bardin et al. 2004b, Lazennec 2006, Chan et al. EOC associations 2008). While this loss has been associated with loss at The epidemiological evidence suggests a role for the genetic level, there is increasing evidence that lower androgens and estrogens in the etiology of EOC. Data expression of ERb can also result from epigenetic further support a protective role for progesterone and changes, namely hypermethylation of its promoter progestins against EOC. However, while supportive, (Geisler et al. 2008, Suzuki et al. 2008, Yap et al. 2009). the data are inconclusive and in some cases contra- Of interest, a recent study showed nuclear localization dictory. One possible explanation may be that the of ERb in normal ovarian tissue, but cytoplasmic relationship between hormones and EOC risk depends localization in the tumor tissue, which was associated more on the intraovarian environment than on with worse outcome (De Stefano et al. 2011). In circulating hormone levels (Lukanova & Kaaks contrast, ERa expression is maintained, or even 2005). It is also possible that the timing of exposures, increased, in a subset of ovarian tumors (Rao & for example, in the pre- vs the postmenopause years, Slotman 1991, Chan et al. 2008). As a result, there is may be critical. Moreover, the interaction of lifestyle an increase in the ERa/ERb ratio with malignant and hormonal factors may alter the hormone–EOC progression of the ovary. There is limited knowledge link. However, due to study design issues such as about the expression of ERa/ERb in different histo- sample size and recall of specific details when logical subtypes of ovarian cancer, and even less about assessing exposures that precede diagnosis by many their expression in different molecular subtypes, such as years, such interactions are challenging to assess. the proliferative, immunoreactive, differentiated, and Finally, the heterogeneity of EOC may contribute to mesenchymal subtypes in high-grade serous cancers, as the inconsistent findings linking hormonally associated defined by the TCGA analysis (Bell et al. 2011). reproductive, lifestyle, and host factors with the Although details are little understood, a number of diseases. To date, most epidemiological studies have studies clearly show that estrogen treatment exerts

Downloaded from Bioscientifica.com at 10/02/2021 04:42:32AM via free access www.endocrinology-journals.org R259 F Modugno et al.: Hormone response in ovarian cancer pro-proliferative action, which can be blocked with given the 24-hour treatment, additional experiments the antiestrogens tamoxifen and ICI 182 780 (Galtier- are necessary to show that the identified genes are truly Dereure et al. 1992, Langdon et al. 1994). There is also direct ER targets. Of note, there is one study detailing increasing evidence for estrogen mediating increased mechanism of estrogen-mediated repression of target motility and invasion of ovarian cancer cells (Hua et al. genes, focusing on the folate receptor, in ovarian 2008, Zhu et al. 2012). In a recent in vivo study, using a cancer cells (Kelley et al. 2003). The authors show a mouse model in which overexpression of SV40Tag in role for ERa and the corepressor SMRT, and a lack of OSE results in poorly differentiated ovarian tumors, involvement of coactivators, including those of the estrogen treatment caused an earlier onset of tumors, p160 family in the repression. decreased overall survival (OS) time, and a distinctive In contrast to breast cancer for which ligand- papillary histology (Laviolette et al. 2010). independent activation of ER activity has been well To confirm that estrogen-mediated growth stimu- described, there is limited literature on such activity in latory effects in ovarian cancer cell lines were indeed ovarian cancer. One study has described ERK2- mediated by ERa, O’Donnell et al. (2005) treated mediated phosphorylation of ERa in response to ERa/ERb-expressing ovarian cancer cells with ERa DC44 interaction with hyaluron and subsequent and ERb-specific ligands. Treatment with PPT (the IQGAP1 recruitment (Bourguignon et al. 2005). ERa ligand) but not with DPN (the ERb ligand) There is some preliminary evidence that the observed resulted in growth stimulation, confirming a role for interaction between hormone response and obesity in ERa in the estrogen-mediated growth stimulation. ovarian cancer could result from cross talk between Given the tumor suppressive-like activity of ERb,itis ERa and leptin signaling. Using BG-1 cells as a model not surprising that overexpression of ERb can result in system, Choi et al. (2011) showed that treatment inhibition of ovarian cancer cell motility and invasion with ICI 182 780, a pure ER antagonist, blocked (Zhu et al. 2011). One might expect some growth leptin-induced cell proliferation. The effect was inhibition with ERb ligands, but such studies have yet mediated by ERa interaction between phosphorylated to be performed in ovarian cancer cells. Stat3, which was at least in part mediated by ERK A number of studies have identified ERa target and PI3K pathways. Given the recent finding of BG-1 genes in ovarian cancer cells, revealing some overlap cells being identical to MCF-7 breast cancer cells, with the estrogen response in breast cancer cells but these data should be interpreted with caution, unless also unique targets. Early studies have shown DNA fingerprinting was performed to confirm regulation of genes involved in proliferation, invasion authenticity of the BG-1 cells as ovarian cancer cells and cell cycle regulation such as cathepsin (Rochefort (Korch et al. 2012). et al. 2001), c-fos, pS2, cyclins (Albanito et al. 2007), TGFa (Simpson et al. 1998), fibulin (Clinton et al. Lack of response to estrogen and antiestrogen can 1996, Roger et al. 1998, Moll et al. 2002), c-myc result from primary resistance (e.g. due to lack of ER (Chien et al. 1994), and SDF-1 (Hall & Korach 2003), expression or activity) or can develop as secondary (i.e. PR (Langdon et al. 1998), and more recently members acquired) resistance, for example, resulting from of the semaphorin family (Joseph et al. 2010). In activation of alternative pathways. However, there addition, a number of IGFBPs have been described to has been a paucity of studies on endocrine resistance in be regulated by estrogen (O’Donnell et al. 2005), and ovarian cancer, with few exceptions. The SKOV3 levels of IGFBP3, IGFBP4, and IGFBP5 were cells, for example, have been described to be resistant predictive in a letrozole trial in ovarian cancer patients to estrogen and antiestrogen treatment, associated with (Walker et al. 2007a). loss of PR, and overexpression of Her2 and cathepsin D A gene expression array study has been reported, in (Hua et al. 1995). Subsequently, Lau et al. (1999) which ER-positive PEO1 cells were treated with described a 32 bp deletion in exon 1 of ERa in SKOV3 estradiol for 24 h, and target genes were identified cells, which is potentially very exciting; however, no using a 1.2K array. Using a threefold change as cutoff, follow-up studies have been reported. Further studies the authors identified five induced and 23 down- of ER target genes in vitro but also in vivo, such as in regulated genes. The induced genes were TNFDF7, established estrogen-sensitive xenografts from PE04, TRAP1, FOSL1, TFAP4, and cathepsin D, and among OVA-5, and OVCAR-3 cells (Ritchie & Langdon the repressed genes were cyr61, vimentin, fibronectin, 2001) and in resistance models, and mechanistic IGFBP3, and several keratins (Hall & Korach 2003). analysis of ER and coregulator recruitment, for The finding of repression was more dominant example, using chromatin immunoprecipitation compared with induction, is of interest; however, studies, are warranted to move this field forward.

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Progesterone action in normal ovary and ovarian candidates could be related to progesterone-induced cancer cells antitumor effects. There is evidence that loss of PR expression is Importantly, there is some evidence that pro- gesterone might synergize with chemotherapeutic associated with increasing grade of ovarian cancer drugs to induce apoptosis. For example, high doses (Langdon et al. 1998, Lau et al.1999, Akahira et al. of progesterone were shown to enhance cisplatin- 2002). Also, in contrast to ER, where little is known induced apoptosis (Murdoch et al. 2008). However, about subtype-specific expression, PR levels seem to this is not straightforward, as other studies have be higher in endometrioid tumors compared with other reported opposite effects. Peluso et al. (2008, 2009) ovarian cancers (Langdon et al. 1998). The same study for example, showed that progesterone treatment can reported an association between PR, stage, and result in decreased cisplatin-induced apoptosis. This outcome – PR expression was higher in low-grade apparent controversy might be, at least in part, due to tumors, and high PR expression was associated with progesterone’s action on two receptors, PRA and PRB, improved survival. and their relative expression in the target cells. In A number of studies showed that progesterone addition, progesterone can also bind to a protein treatment of OSE and ovarian cancer cells results in complex containing the progesterone membrane decreased proliferation and increased apoptosis. receptor component 1 (PGMRC1/mPR). Indeed, the Rodriguez et al. (1998) performed in vivo studies, Pelusso laboratory has published a few studies showing using primates, which showed that progesterone an involvement of PGRMC1 in sensitivity of ovarian treatment resulted in a four- to six-fold increase in cancer cells to cisplatin (Peluso et al. 2008, 2009). the number of apoptotic ovarian epithelial cells Interestingly, PGRMC1 shares homology with cyto- compared with control and estrogen treated monkey. chrome b5-related proteins rather than with hormone The same group subsequently showed that this effect receptors and can bind heme (Peluso 2011). Different can be enhanced by treatment with NSAIDs, a concept cellular responses to progesterone could also result of potential interest for the prevention of ovarian from altered expression of the more recently identified cancer (Rodriguez et al. 2012). The induction of membrane PRs mPRa, b, and g. The mPRs belong to apoptosis was associated with decreased expression the larger progestin and adipoQ receptor gene family of TGFb1 and increased expression of TGFb2 and (mPRa – PAQR7; mPRb – PARQ8; and mPRg – TGFb3, suggesting that differential regulation of TGFb PARQ5), and while they are not members of the family members could play a role in progestin- classical G-protein family, they can activate G-proteins mediated induction of apoptosis (Rodriguez et al. and affect cAMP levels. They bind progesterone with 2002). While details of underlying mechanisms are high affinity, but do not interact with synthetic sparse, some studies have addressed this question and progestin R5020, or the PR antagonist RU486. They have shown enhanced TRAIL-mediated cell death are abundantly expressed in ovarian cancer cells (Syed et al. 2007), induction of p53 (Bu et al. 1997), including those that lack expression of classical PR, and increased expression FasL (Syed & Ho 2003). and in clinical specimens representing all major Interestingly, in addition to the induction of apoptosis, histological subtypes (Romero-Sa´nchez et al. 2008, activation of PR was also shown to induce cell cycle Charles et al. 2010). Charles et al. (2010) showed that arrest and senescence (Takahashi et al. 2009). progesterone alone did not affect cAMP levels in ES-2 As for ER, there is limited knowledge of PR and SKOV3 cells; however, it enhanced isoproterenol- downstream target genes in ovarian cancer. Syed induced and b1,2-adrenergic receptor-mediated et al. (2005) treated human OSE cells (HOSE 642, increases in cAMP levels. This resulted in activation HOSE 6-8, and HOSE 12-12) and ovarian cancer cell of JNK1/2 and p38 MAPK activity and subsequently lines (OVCA429, OVCA420, and OVCA432), pre- induction of pro-apoptotic genes like Bax. viously described to be PR positive (Lau et al. 1999), Thus, the effects of progesterone in ovarian cancer with high-dose progesterone. Using a small gene cells are mediated by the classical PR, by PGRMCs, expression array (nZ2000 genes), the authors ident- and finally by mPRs, through both genomic and non- ified 171 progesterone-regulated genes in HOSE genomic actions (for review, see Peluso (2007)). This cells and 135 in ovarian cancer cells. They focused signaling is undoubtedly very complex, and while on ATF3, caveolin-1, DLC1, and nm23-H2, showing potentially attractive as a clinical target, significantly that these genes were indeed direct PR target more research needs to be done before we can begin to genes, and given their antitumor and anti-invasive understand intricate details of progesterone action in properties, the authors speculate that induction of these ovarian cancer.

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Limited understanding of AR action in ovarian G-protein signaling. The G-proteins that were signi- cancer cell lines ficantly induced by androgen treatment in OVCA3 The AR is expressed in both normal ovary and ovarian cells included GNAI3, ELKS, GSTPI, RERG, Rab25, Rab45, and Rab35. The induction of Rab25 is of cancer. Edmondson et al. (2002) have shown that special interest as this small GTPase has previously OSE cells express AR and respond to androgen with been shown to proliferation, survival, and invasion of increased proliferation and attenuated apoptosis. ovarian cancer cells (Fan et al. 2006) and to be Epithelial cells, especially those within inclusion overexpressed in aggressive ovarian cancers (Cheng cysts arising after ovulation, appear to be exposed to et al. 2004a). high levels of androgen (Risch 1998). Ovarian cancer cells also express 17b-hydroxysteroid dehydrogenase (17b-HSD) converting androstenedione (which is a Coregulator proteins in ovarian cancer weak androgen) to testosterone (Blomquist et al. 2002, Although not a major focus of this review, there is little Chura et al. 2009). Importantly, there are also a number doubt that coregulator proteins – activating or repres- of studies showing overexpression of AR in ovarian sing steroid receptors – do play a role in ovarian cancer (Ku¨hnel et al. 1987, Chadha et al. 1993, Ilekis tumorigenesis. SRC3/AIB1 was shown to be amplified et al. 1997, Lau et al. 1999, Lee et al. 2005b). in up to 25% of ovarian cancer (Bautista et al. 1997, Although sparse, there is evidence from in vitro Tanner et al. 2000). The coregulator p44/Mep50/ studies suggesting that androgens affect gene WDR77 increases activities of ER and AR and expression, growth, invasion, and survival in ovarian stimulates proliferation and invasion of ovarian cancer cancer cell lines. Shi et al. (2011) have shown that cells in the presence of estrogen or androgen (Ligr androgen’s effect on survival of ovarian cancer cells et al. 2011). It shows strong cytoplasmic localization in was associated with increased expression, activity, and normal ovarian surface, and fallopian tube epithelia, phosphorylation of telomerase. They also showed an while it is mainly in the nucleus in invasive ovarian androgen-mediated degradation of the cell cycle carcinoma. The coactivator ARA70 was highly inhibitor p27 (Shi et al. 2011). Androgen was reported expressed in invasive ovarian tumors but not in the to stimulate DNA synthesis/S-phase fraction in low- normal ovary (Shaw et al.2001). And finally, passage OSE culture (Syed et al. 2001, Edmondson corepressor proteins have also been described to be et al. 2002), and in ovarian cancer cells (Sheach et al. highly expressed in ovarian cancer – Havrilesky showed 2009); however, other studies failed to observe an that 35% of tumors expressed NCoR, and 71% effect of androgens on growth (Karlan et al. 1995). expressed NCoR2/SMRT (Havrilesky et al. 2001). Finally, activation of AR has been shown to stimulate Given the known critical role of coregulator proteins in ovarian cancer cell invasion (Gogoi et al. 2008, Ligr sensitivity and resistance to hormones, future studies on et al. 2011). their expression and function in ovarian cancer There is evidence for cross talk between androgen development and progression are warranted. signaling and other signaling pathways. For example, Evangelou et al. (2000) showed that dihydrotestoster- Summary: basic science of hormone response in one (DHT) treatment of Hey and SKOV-3 ovarian ovarian cancer cancer cells, and of ascites-derived OVCAS-16 cells, Steroid hormone signaling in ovarian cancer is prevented growth inhibitory effect of TGF-b, while complex yet little understood. It is imperative that we DHT alone had no effect on growth. This effect of DHT develop and use in vitro as well as in vivo models was associated with downregulation of TGF-b1 and representing the different histological and molecular TGF-b2 receptors. Interestingly, the same group went ovarian cancer subtypes to decipher signaling on to show similar effects of DHT on blocking TGF-b- pathways and downstream target genes of the steroid mediated growth inhibition in cells isolated from receptors before we can improve efficacy of endocrine ovarian surface epithelium of women undergoing treatment in ovarian cancer. oophorectomy for non-ovarian indications or with a germline BRCA mutation (Evangelou et al. 2003). To the best of our knowledge, there is only one study Clinical trials involving hormonal therapy reporting a genome-wide analysis of androgen target genes. Sheach et al. (2009) identified more than 100 Introduction AR target genes in OVCAR3 cells with the majority Targeting hormone receptors has been a successful being related to transcription, proliferation, and therapeutic strategy in endocrine-sensitive tumors such

Downloaded from Bioscientifica.com at 10/02/2021 04:42:32AM via free access R262 www.endocrinology-journals.org Endocrine-Related Cancer (2012) 19 R255–R279 as breast, prostate, and endometrial cancers (Moreau endocrine-responsive receptors, hormonal therapy has et al. 2006, Decruze & Green 2007, Poole & Paridaens only a minor role in the treatment of EOC. Therapy 2007). There is clear evidence that EOC is a hormone- targeting the ER, for example, has been employed responsive cancer, at least in a subset of tumors. since the 1960s, but variable clinical responses have Nuclear receptors are widely expressed in EOC: ER is limited their usefulness in ovarian cancer (Langdon & expressed in 61–79% of EOC, with highest expression Smyth 2008). Given that hormonal therapy is a relative in serous and endometrioid subtypes (Glavind & Grove nontoxic anticancer therapy, which is easy to admin- 1990, Rao & Slotman 1991, Lindgren et al. 2001, Lee ister and that it is well tolerated, the question is why et al. 2005b). PR is expressed in w25–50% of all EOC, hormonal therapy is not used more widely in ovarian but is as high as 91% in endometrioid subtypes cancer? Can it be made more effective? Below we (Fujimura et al. 2001, Lindgren et al. 2001, Lee summarize and discuss endocrine therapies in ovarian et al. 2005b), and expression of AR is as high as 90% cancer, again focusing on ER, PR, and AR (also (Ku¨hnel et al. 1987). Despite the high expression of depicted and summarized in Fig. 1).

Progestins: • Medroxyprogesterone acetate (MPA) Selective estrogen receptor • Levonorgestrel modulators (SERMs) • Tamoxifen Ovarian cancer PR antagonist: • Endoxifen • Mifepristone 25–50% PR Selective estrogen receptor 60–80% ERα degraders (SERDs): Up to 90% AR • Fulvestrant (ICI 182 780)

Aromatase inhibitors: • Letrozole • Anastrozole • Exemestane

AR antagonists: • Flutamide • Bicalutamide

Figure 1 Steroid receptors as clinical targets in ovarian cancer. Estimates of % tumors expressing PR, ERa, or AR (without considering subtypes of ovarian cancer due to lack of information). Also listed are approved drugs or drugs used in previous or currently ongoing ovarian cancer trials.

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Targeting the ER in ovarian cancer 95% CIZ1.16–2.68) compared with tamoxifen. Also, Tamoxifen, a selective ER modulator (SERM), that there was significantly less toxicity associated with produces antiestrogen effects through competitive tamoxifen treatment, and more patients in this treatment arm received R3 cycles. As this trial did inhibition of ER has been used with variable results not contain a third arm (no treatment or another active for the treatment of ovarian cancer. The majority of agent), the possible interpretations of the tamoxifen clinical trials involving tamoxifen were small phase II results are limited. However, they are very encoura- trials of patients with heavily pretreated recurrent ging and indicate that additional study of tamoxifen disease. A prospective Gynecologic Oncology Group (and other endocrine treatments) in this patient (GOG) study by Hatch et al. (1991), evaluated the population, i.e. asymptomatic patients with bio- response to tamoxifen in patients with recurrent or chemical evidence of recurrent ovarian cancer, is persistent disease following primary treatment. One warranted. Markman et al.(2004a) examined the hundred and five patients were treated with tamoxifen evidence behind this management strategy with a 20 mg twice a day after frontline chemotherapy. Study retrospective review of 56 women with asymptomatic participants had an 18% objective response rate (RR), recurrent ovarian or primary peritoneal cancer treated with 10% having a complete response (CR). Reana- with 20–40 mg Tamoxifen daily before initiation of lysis of this study, focusing on patients with platinum- cytotoxic chemotherapy. The median duration of refractory disease, showed an objective RR of 13% treatment was 3 months, but 42% of patients were on et al (Markman . 1996). Of note, the objective RRs to Tamoxifen for R6 months and 19% for R12 months. ! second-line platinum-based therapy range from 10 The most common reasons for stopping single-agent O to 40% (Markman & Bookman 2000). A similar tamoxifen were a continued rise of serum CA125, objective RR of 17% (5/29) was seen in patients with progression of disease on CT scan or physical exam, or unknown ER/PR status treated with tamoxifen after the development of cancer-related symptoms. No failure of cytotoxic therapy in three phase II clinical standard of care exists for the management of trials published by the Mid-Atlantic Oncology Pro- asymptomatic recurrent disease, and therefore, trials gram in 1993 (Ahlgren et al.1993). Therefore, testing hormonal therapy in this setting seem warranted. hormonal therapy is well within the response range While investigations continue to examine the utility of chemotherapeutic agents but considerably easier to of hormonal therapy, contemporary studies publishing administer and with fewer side effects. Unfortunately, randomized and nonrandomized trials evaluating the few of these trials report ER status of the ovarian use of tamoxifen in EOC are lacking. A Cochrane C tumors. One study reported that patients with ER review published in 2010 attempted to identify tumors had higher RRs to tamoxifen treatment than randomized and nonrandomized studies of more than ER- tumors, although this difference was not statisti- ten patients with recurrent ovarian cancer treated with cally significant (Hatch et al. 1991). In another small tamoxifen (Williams et al. 2010). Surprisingly, the study, all patients with stable disease (SD) were ER search of articles published between 2002 and 2009 positive (Schwartz et al. 1982). ER status did not yielded no trials that satisfied the inclusion criteria. correlate with response in two other trials; however, Publications during that period consisted only of ER status was known in only one-fourth to one-third observational data from single-arm studies of women of patients enrolled (Shirey et al. 1985, Weiner treated with tamoxifen. Additionally, no data on et al. 1987). tamoxifen’s effect on symptom control, quality of In 2010, the GOG published the results of a phase II life, or prolongation of life were available from the trial of tamoxifen vs thalidomide in women with uncontrolled, non-comparative trials that were biochemical recurrence of EOC, fallopian tube, or screened as part of this Cochrane review. A Cochrane primary peritoneal carcinoma based on rising CA125 review using the same inclusion criteria as the more after CR to frontline platinum/taxane therapy (Hurteau recent publication did identify 11 nonrandomized et al. 2010). The interim analysis did not show any series, one nonrandomized phase II study, and two difference in the benefit of thalidomide relative to randomized trials from 1997 to 2002 (Williams 2001; tamoxifen, and the study was stopped early. At a see Table 2). In total, 60 of the 623 (9.6%) women median follow-up of 31 months, the progression-free treated with tamoxifen had an objective response and survival (PFS) was 3.2 and 4.5 months while median SD of 4 weeks or more was seen in 131/411 (31.9%) survival was 24.0 and 33.2 months for thalidomide women from eight studies. Due to lack of data, and tamoxifen arms respectively. Thalidomide was duration of response, survival, symptoms palliation, associated with an increased risk (HRZ1.76, and quality of life were not assessed.

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Table 2 Response rates of tamoxifen (TAM) in persistent or recurrent EOC

Number of patients responding (%)

References Trial n Drug dosage CR PR SD PD Other

Marth et al. (1997) Nonrandomized 65 TAM 30–40 mg 2 (3) 2 (3) 50 (77) 11 (17) Recurrent disease, phase II PO daily refractory R1 che- motherapy regime Gennatas et al. Nonrandomized 50 TAM 40 mg PO 2 (4) 26 (52) NA NA 50% previously (1996) series daily untreated, 50% refractory or pro- gressive disease Jager et al. (1995) Unblinded 33 TAM 30 mg PO 0 0 2 (6) NA Progressive disease randomized daily controlled trial Van Der Velden Nonrandomized 30 TAM 40 mg PO 2 (7) NA 10 (33) NA Refractory or et al. (1995) series daily recurrent disease Ahlgren et al. Nonrandomized 29 TAM 80 mg 2 (7) 7 (24) 18 (62) 6 (21) Prior cytotoxic (1993) series PO!30 d, chemotherapy then 20 mg PO daily Losa et al. (1993) Randomized trial NA TAM 40 mg PO 0 1 22 32 Prior multi-agent comparing daily cytotoxic hormonal chemotherapy therapy (168 patients in three arms) Hatch et al. (1991) Nonrandomized 105 TAM 40 mg PO 10 (10) 8 (8) 40 (38) 47 (45) Recurrent or phase II daily persistent disease Osborne et al. Nonrandomized 51 TAM 100 mg/m2 0 1 (2) 0 50 (98) Disease refractory to (1988) series PO over 24 h R1 chemotherapy then 40 mg regime PO daily Weiner et al. Nonrandomized 31 TAM 160 mg/m2 1 (3) 2 (6) 6 (19) 22 (71) Prior cytotoxic (1987) series PO!7d, then chemotherapy 20 mg PO daily Slevin et al. (1986) Nonrandomized 22 TAM 20 mg PO 0 0 1 (5) 21 (95) Disease refractory to series daily R1 chemotherapy regime Hamerlynck et al. Nonrandomized 36 TAM 40 mg PO 0 2 (6) 7 (19) NA Prior cytotoxic (1985b) series daily chemotherapy Landoni et al. Nonrandomized 19 TAM 40 mg PO 0 0 7 (37) NA Prior cytotoxic (1985) series daily chemotherapy Shirey et al. Nonrandomized 23 TAM 20–40 mg 0 0 19 (83) NA Disease refractory to (1985) series PO daily R1 chemotherapy regime Schwartz et al. Nonrandomized 13 TAM 20 mg PO 0 1 (8) 4 (31) 8 (62) Rapidly advancing (1982) series daily, increase recurrent disease to 40 mg PO daily if disease progression

PO, oral; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NA, not available.

The majority of women who develop ovarian cancer been shown in malignant ovarian epithelial cells are postmenopausal at the time of diagnosis. In resulting in intratumoral production of estrogen postmenopausal women, the major source of circulat- (Cunat et al. 2005). The use of aromatase inhibitors ing estrogen is from the peripheral conversion (in skin (AI), such as letrozole and anastrozole, for the and adipose tissue) of androstenedione by the enzyme treatment of ERC breast cancer has been a great aromatase. Additionally, aromatase expression has success, and several studies have investigated the use

Downloaded from Bioscientifica.com at 10/02/2021 04:42:32AM via free access www.endocrinology-journals.org R265 F Modugno et al.: Hormone response in ovarian cancer of these agents in the treatment of recurrent or selected patients suggests that a subset of patients may persistent ovarian cancer (see Table 3). Similar to exist that may prove to benefit substantially from this other hormonal therapies, the results of AI treatment approach. It is most critical to be able to identify this are variable. In seven phase II trials, with known ER group of patients that is most likely to respond. There status, the complete and partial RRs were 0–4 and are a few studies that have attempted to identify 0–11% respectively (Bowman et al. 2002, del Carmen biomarkers for endocrine treatment response in ovarian et al. 2003, Papadimitriou et al. 2004, Gourley et al. cancer (Bowman et al. 2002, Smyth et al. 2007, 2006, Verma et al. 2006, Smyth et al. 2007, Ramirez Walker et al. 2007a) but such studies are clearly in et al. 2008). However, benefit from AI therapy can be their infancy and will need to be expanded. measured by prevention of tumor progression in addition to tumor regression. In a phase II trial evaluating the utility of letrozole in a selected group PR ligand in EOC of ERC patients with recurrent ovarian cancer, a 17% Several large clinicopathological studies have shown RR was seen by CA125 criteria and 26% of patients that PR expression is associated with an increased OS had SD at 6 months of treatment (Smyth et al. 2007). in EOC (Mu¨nstedt et al. 2000, Lee et al. 2005b, Response to AI therapy correlated with ERa Tangjitgamol et al. 2009). One study showed that PR expression with those patients having the highest expression was also associated with improved response expression of ERa having the greatest RR, 33%, to chemotherapy (Tangjitgamol et al. 2009). These compared with 0% RR in those with low expression. In findings, together with in vitro studies suggesting that another study, response to letrozole was associated PR induces apoptosis (and potentially senescence) in with increased tumor production of aromatase (Walker ovarian cancer cells, strongly suggest modulation of et al. 2007b). The ideal use of AIs may be following PR levels and/or activity as a form of endocrine initial cytoreductive surgery and adjuvant chemother- treatment of EOC. Niwa et al. (2008) reported their apy for stabilization of any residual disease, potentially findings of the effect of combination medroxyproges- serving to prolong PFS; however, a trial comparing terone acetate (MPA) with primary adjuvant chemo- DFS in ERC patients treated with AIs vs placebo is therapy in advanced EOC in 2008. Both PFS and OS still warranted before such therapy can be justified. were significantly longer in the patients treated with More recently, the pure antiestrogen fulvestrant (ICI combination MPA and platinum-based chemotherapy 182 870) was tested in a phase II study. Multi-recurrent compared with the control group. These effects ERC EOC were treated with single-agent fulvestrant were more pronounced in the group with higher until intolerance or disease progression (Argenta et al. PR expression. 2009). Of the 26 patients in the study, there was one CR Zheng et al. (2007) recently reviewed the utility of (4%), one PR (4%), and nine patients had SD (35%). PR ligands in ovarian cancer treatment by examining While the median time to progression was 2 months, 13 clinical trials that included 432 patients with two patients remained on treatment for O250 days. recurrent or refractory ovarian cancer treated with The drug was well tolerated and there were no grade 3 megestrol acetate or MPA. Ten patients (2.3%) had or 4 toxicities. Similar to the AI trials, the authors of CR, 21 (4.9%) had a partial response, and 47 (10.9%) this study suggest that the clinical utility of this agent had SD. The authors concluded that the efficacy of may be optimized by its use early in the adjuvant progestational agents in recurrent EOC has not been treatment setting or as long-term consolation therapy established based on the currently available literature after primary disease remission. Sustained benefit in (trials are summarized in Table 3).

Table 3 Response rates of aromatase inhibitors in persistent or recurrent EOC (all are phase II trials)

Number of patients responding (%)

References n Drug CR PR SD PD ER status

Bowman et al. (2002) 54 Letrozole 0 5 (9) 14 (26) 30 (56) Mixed ERK/ERC tumors Papadimitriou et al. (2004) 27 Letrozole 1 (4) 3 (11) 5 (19) 18 (67) Mixed ERK/ERC tumors Gourley et al. (2006) 33 Letrozole 0 3 (9) 14 (42) 16 (49) NA Smyth et al. (2007) 42 Letrozole 0 7 (17) 11 (26) NA ERC Ramirez et al. (2008) 33 Letrozole 0 1 (3) 7 (21) 23 (70) ERC Del Carmen et al. (2003) 53 Anastrozole 0 1 (2) 22 (42) 30 (57) Mixed ERK/ERC tumors Verma et al. (2006) 22 Exemestane 0 0 8 (36) NA NA

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The antiprogestin, mifepristone, has also been used AR is not only a great target in prostate cancer but in in the treatment of platinum-resistant ovarian cancer. other hormone-driven tumors, such as breast cancer In 2000, Rocereto et al. (2000) reported an overall RR (Nahleh 2008). However, the use of antiandrogens in of 26.5%, with 8.8% (3/34) having a CR, including one the management of ovarian cancer has been limited to patient that remained without evidence of disease for several small clinical trials in the recurrent setting. over 3 years. These promising results could not be Two trials from the late 1990s evaluated the use of this reproduced in a recent phase II trial in patients with flutamide, a nonsteroidal drug with antiandrogen recurrent or persistent ovarian, peritoneal, and fallo- properties, in recurrent ovarian cancer; Vassilomano- pian tube cancers, in which only one response was lakis et al. (1997) reported a RR and disease seen among the 22 patients (Rocereto et al. 2010). stabilization of 4.3 and 8.7% respectively, while Efforts are also ongoing testing mifepristone speci- Tumolo et al. (1994) had slightly higher RRs and SD fically in endometrioid adenocarcinomas (Ramondetta at 6.3 and 28%. These phase II trials were small, et al. 2009). including only 24 and 32 patients respectively. A more The in vitro data, and the promising evidence of recent trial, published in 2007, examined the use of treatment response in subset of patients, strongly bicalutamide, an antiandrogen, with goserelin, a suggest that further investigation of progestins, either GNRH agonist, in women with EOC who were in alone or in combination with chemotherapy, is their second or higher disease remission (Levine et al. warranted. Given recent preclinical data, and basic 2007). The use of these agents did not appear to science findings, one can expect to see drugs that target prolong PFS in this group of patients, and there was no different PR isoforms (PR-A vs PR-B) and that might association between AR repeat number, genotype, or target other progesterone binding receptors (i.e. mPRs haplotype and PFS. Like for ER and PR-targeting and PGRMCs). trials, the identification of biomarkers of response will be critical. Given recent study by Elattar et al. (2012), nuclear expression of AR might be a viable biomarker Role for targeting AR in ovarian cancer? for androgen sensitivity. DHT treatment of primary In vitro studies have shown that androgen increases ovarian cancer cultures established from ascitic fluid proliferation of normal human OSE cells and human resulted in increased in S-phase, and this was strongly ovarian cancer cells (Syed et al. 2001, Edmondson associated with nuclear AR levels. Thus, in summary, et al. 2002), making targeting AR a promising AR modulation as a viable treatment option has not treatment strategy. There is increasing evidence that been validated at this time; however, additional studies

Table 4 Response rates to progestins (MA and MPA) and antiprogestins in persistent or recurrent EOC (all are phase II trials)

Responders (%)

References n (patients) Drug CR PR SD

Mangioni et al. (1981) 33 MPA 0 5 (15) 2 (6) 30 MPA 0 0 2 (7) Slayton et al. (1981) 19 MPA 0 0 1 (5) Aabo et al. (1982) 27 MPA 0 1 (4) 0 Trope´ et al. (1982) 25 MPA 0 1 (4) 9 (36) Geisler (1985) 23 MA 7 (30) 4 (17) 0 Hamerlynck et al. (1985a) 41 MPA 0 1 (2) 7 (17) Sikic et al. (1986) 47 MA 1 (2) 3 (6) 5 (11) Belinson et al. (1987) 33 MA 0 0 12 (39) Ahlgren et al. (1993) 32 MA 0 0 13 (41) Malfetano et al. (1993) 24 MPA 0 1 (4) 9 (38) Veenhof et al. (1994) 54 MA 0 1 (2) 9 (17) Wiernik et al. (1998) 30 MA 0 0 0 Rocereto et al. (2000) 44 Mifepristone 3 (9) 6 (17) NA Wilailak et al. (2001) 36 MA 3 (8) 4 (11) NA Rocereto et al. (2010) 22 Mifepristone 0 1 3

MA, megestrol acetate; MPA, medroxyprogesterone; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NA, not available.

Downloaded from Bioscientifica.com at 10/02/2021 04:42:32AM via free access www.endocrinology-journals.org R267 F Modugno et al.: Hormone response in ovarian cancer potentially including novel drugs such as abiraterone, disease. The development of chemoresistant disease is and including the use of biomarkers, are needed. a big clinical problem, and while still little understood, increased expression of P-glycoprotein, a trans- membrane energy-dependent drug efflux pump, Combination therapies contributes to resistance in some tumor models PR can be induced with estrogen (and with tamoxifen (Johnson et al. 1993, Patel & Rothenberg 1994). in situation where it functions as an agonist), and Although several preclinical models showed the ability several trials have studied the utility of combination of progestins to overcome P-glycoprotein-mediated hormonal therapy targeting this cross talk. Although no multidrug resistance (Yang et al. 1989, Fleming et al. clinical response was seen with combination tamoxifen 1992, Wang et al. 1994, Panasci et al. 1996, Tansan and progesterone (Belinson et al. 1987, Jakobsen et al. et al. 1997), there were no objective responses 1987), a significant clinical response was seen in one observed in 44 patients with paclitaxel-refractory trial of 65 women with refractory ovarian cancer ovarian cancer treated with combination paclitaxel treated with sequential ethinyl estradiol and medroxy- and megestrol acetate (Panasci et al. 1996). Unfortu- progesterone, with a RR of 14% and SD in 20% of nately, response to combination MPA-cytotoxic patients (Freedman et al. 1986). These findings were chemotherapy as first-line therapy also showed later confirmed with a similar although smaller clinical no difference in RR or survival compared with trial (Fromm et al. 1991). chemotherapy alone in 71 patients with advanced Several small phase II trials have looked at the ovarian cancer (Tansan et al. 1997). addition of goserelin to tamoxifen, again in the Finally, a number of biological agents are being recurrent EOC setting. One trial reported one CR studied for the treatment of ovarian cancer, some in (3.8%), two PR (7.7%), and ten patients with SD combination with hormonal therapy. There is recent (38.5%) with a median progression-free interval (PFI) in vitro evidence that tamoxifen resistance may be of 4 months and OS of 13.6 months for the entire related to EGFR overexpression in solid tumors like cohort (Hasan et al. 2005). A similar trial published 6 breast (Shou et al. 2004) and that combination years earlier had similar findings with a PFI of 5 treatment with gefitinib (Iressa), a signal transduction months and OS of 8 months (Hofstra et al. 1999). inhibitor of EGFR tyrosine kinase, and tamoxifen was Few trials have examined the utility of combining more effective than either agent alone (Hiscox et al. hormonal therapy to chemotherapy vs chemotherapy 2004). Additionally, there is evidence that EGFR alone in the adjuvant setting for advanced ovarian overexpression is seen in 30–70% of cases of platinum- cancer. There was no difference in progression-free resistant ovarian tumors (Scambia et al. 1995, Bartlett or OS in 100 women with stage III or IV EOC et al. 1996). Therefore, a phase II trial of combination randomized to receive combination cisplatin/doxoru- tamoxifen and gefitinib was conducted in 56 patients bicin with or without the addition of tamoxifen (Patel with ovarian cancer refractory or resistant to platinum- & Rothenberg 1994). However, tamoxifen was only and taxane-based therapy. Although no tumor administered during chemotherapy (median time: 36 responses were seen, 16 patients had SD (Wagner weeks), and O54% of patients had residual tumor et al. 2007). Gefitinib has also been used in R2 cm. Additionally, hormone receptor status was combination therapy with the AI anastrozole; in only determined in 72% of patients. The same clinical patients with asymptomatic Mu¨llerian cancer, there question was asked in the recurrent disease setting. was a RR of 3% (1/35 patients) (Krasner 2007). In one trial with 50 patients with recurrent disease, Although this number of responders is disappointingly treatment with a platinum agent and tamoxifen showed low, the authors comment that the single responder had a RR of 50% (Benedetti Panici et al. 2001). The high a durable CR and an additional patient had SD for more RRs in platinum-resistant disease lead other investi- than 600 days. gators to conduct similar trials. However, similar results have yet to be replicated, and in one trial of 14 patients with platinum-resistant disease, there were no Ongoing clinical trials objective responses to combination carboplatin/tamox- At the time of writing of this review, we identified one ifen (Johnson et al. 1993, Markman et al. 2004b). clinical trial involving the use of hormonal modulation Randomized trials of combination progestin therapy for the treatment of ovarian cancer, which is actively and chemotherapy vs chemotherapy alone have also enrolling patients. NCT01273168 is a phase I clinical been plagued by small patient sample size, unknown trial sponsored by the National Cancer Institute (NCI) tumor hormone receptor status, and heavily pretreated of endoxifen, a potent and active metabolite of

Downloaded from Bioscientifica.com at 10/02/2021 04:42:32AM via free access R268 www.endocrinology-journals.org Endocrine-Related Cancer (2012) 19 R255–R279 tamoxifen that may have clinical utility as an Declaration of interest antiestrogen (Wu et al.2009). It is administered to The authors declare that there is no conflict of interest that adults with hormone receptor-positive solid tumors could be perceived as prejudicing the impartiality of the including breast, dermoid, and gynecologic tumors that research reported. did not respond to standard treatment. Study partici- pants will take daily oral endoxifen in escalating doses at 28-day intervals to determine safety, tolerability, Funding pharmacokinetics, and determine the maximum toler- ated dose. Additionally, an investigational radiolabeled Ms C L Andersen is supported by a T32 training grant from imaging agent, 16-a-[(18)F]-fluoro-17b estradiol, will the Molecular Pharmacology Training Program at the be used with positron emission tomography (PET) University of Pittsburgh. to determine in situ tumor ER activity before and after treatment with endoxifen. Another NCI trial, NCT00445887, is not examining the role of hormonal References therapy in the treatment of ovarian cancer but instead is Aabo K, Pedersen AG, Haid I & Dombernowsky P 1982 evaluating the effect of oral levonorgestrel on High-dose medroxyprogesterone acetate (MPA) in prevention of ovarian carcinoma in high-risk patients. advanced chemotherapy-resistant ovarian carcinoma: a Several other clinical trials in recurrent ovarian phase II study. Cancer Treatment Reports 66 407–408. cancer patients have completed enrollment; however, Ahlgren JD, Ellison NM, Gottlieb RJ, Laluna F, Lokich JJ, results have not yet been published, including Sinclair PR, Ueno W, Wampler GL, Yeung KY, Alt D NCT00003865, assessing toremifene citrate, a et al. 1993 Hormonal palliation of chemoresistant ovarian SERM, and NCT00181688, a phase II trial of cancer: three consecutive phase II trials of the Mid- Atlantic Oncology Program. Journal of Clinical Oncol- combination of AI anastrozole and gefitinib. ogy 11 1957–1968. Akahira J, Suzuki T, Ito K, Kaneko C, Darnel AD, Moriya T, Okamura K, Yaegashi N & Sasano H 2002 Differential Conclusion: endocrine treatment in ovarian expression of progesterone receptor isoforms A and B in cancer the normal ovary, and in benign, borderline, and Japanese Journal of Cancer In summary, there is strong in vitro and in vivo malignant ovarian tumors. Research 93 807–815. (doi:10.1111/j.1349-7006.2002. evidence, and epidemiological data showing that tb01323.x) estrogens (and potentially other steroids) regulate Albanito L, Madeo A, Lappano R, Vivacqua A, Rago V, ovarian carcinogenesis. In addition, ER is highly Carpino A, Oprea TI, Prossnitz ER, Musti AM, Ando` S expressed in subsets of ovarian tumors. Clinical trials et al. 2007 G protein-coupled receptor 30 (GPR30) testing endocrine therapy in ovarian cancer to date mediates gene expression changes and growth response to have been poorly designed and not properly evaluated 17b-estradiol and selective GPR30 ligand G-1 in ovarian to allow solid conclusions. Many did not select on ER cancer cells. Cancer Research 67 1859–1866. status, and few correlated ER status with response. (doi:10.1158/0008-5472.CAN-06-2909) While the overall RR to hormonal therapy in ovarian Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, Liu J, McNeeley SG, cancer appears to be modest, there are clearly Lopez AM & Women’s Health Initiative Investigators subgroups of patients that respond very well. As 2003 Effects of estrogen plus progestin on gynecologic hormonal agents have the benefit of easy adminis- cancers and associated diagnostic procedures: the tration, low cost, and data on long-term effects of Women’s Health Initiative randomized trial. Journal of prolonged use, we must identify such subgroups of the American Medical Association 290 1739–1748. patients! Thus, the identification of biomarkers (doi:10.1001/jama.290.13.1739) predicting endocrine treatment response and their Argenta PA, Thomas SG, Judson PL, Downs LS Jr, introduction into clinical practice for both selection Geller MA, Carson LF, Jonson AL & Ghebre R 2009 of patients for enrollment in clinical trials and A phase II study offulvestrant in the treatment of multiply- subsequently for personalized endocrine treatment are recurrent epithelial ovarian cancer. Gynecologic Oncology 113 205–209. (doi:10.1016/j.ygyno.2009.01.012) critical. To accomplish such goals, we must continue to Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR & investigate mechanism of action of hormones in Bulun SE 2000 Progesterone receptor isoform A but not B ovarian cancer, we must perform additional well- is expressed in endometriosis. Journal of Clinical designed clinical trials using biomarkers, and we must Endocrinology and Metabolism 85 2897–2902. collect tissue. (doi:10.1210/jc.85.8.2897)

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