Rational Management of Endocrine Resistance in Breast Cancer a Comprehensive Review of Estrogen Receptor Biology, Treatment Options, and Future Directions

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Rational Management of Endocrine Resistance in Breast Cancer A Comprehensive Review of Estrogen Receptor Biology, Treatment Options, and Future Directions

Sara A. Hurvitz, MD Endocrine therapy for breast cancer was introduced more than 100 years ago. In Richard J. Pietras, PhD, MD the last 30 years, it has been demonstrated that tamoxifen significantly improves outcomes for patients with hormone-responsive breast tumors. Aromatase inhibi- Department of Medicine, Division of Hematology- tors, which suppress the production of estrogen, are recognized today as an Oncology, University of California-Los Angeles effective alternative for estrogen-receptor-positive breast cancer in postmeno- School of Medicine, Los Angeles, California. pausal women. However, despite an initial response to treatment, many tumors eventually recur or progress. When selecting subsequent endocrine therapy, it is helpful to understand the mechanisms of hormone resistance, consider the goals of treatment, and evaluate the clinical potential of each available drug. The objective of this article was to review the underlying mechanisms of action and resistance for each type of hormone therapy, evaluate the most recent data regarding the use of endocrine agents after disease progression or recurrence, and explore potential combinations of hormone therapies with novel molecules that target key growth factor signaling pathways. Cancer 2008;113:2385–97. 2008 American Cancer Society.

KEYWORDS: endocrine therapy, metastatic breast cancer, fulvestrant, endocrine resistance, tamoxifen, aromatase inhibitors.

he influence of ovarian hormones on breast cancer was appre- T ciated first more than 100 years ago, when Beatson demonstrated that inoperable breast tumors regress after oophorectomy.1 Since then, pharmacologic antiestrogen measures have been developed and have been shown to significantly improve clinical outcomes for patients with both early- and late-stage hormone Supported by funds from AstraZeneca, the Cali- receptor-positive (HR1) breast cancer. Because approximately 75% fornia Breast Cancer Research Program, and the Stiles Program in Oncology. of postmenopausal women with breast cancer have tumors that are positive for estrogen receptor (ER) expression, antiestrogen therapy We thank Monica Nicosia and Tara Ruest of plays a role in disease management for the majority of patients with Health Learning Systems for providing editorial breast cancer.2 Today, 2 classes of antihormone endocrine agents support in the preparation of this review. are considered the standard of care for primary treatment of early- 1 Address for reprints: Sara A. Hurvitz, MD, Depart- or late-stage HR breast cancer: tamoxifen, which blocks ER activity ment of Medicine, Division of Hematology-Oncol- within tumor cells, and aromatase inhibitors (AIs), such as anastro- ogy, UCLA School of Medicine, Box 957077, zole, letrozole, or exemestane, which inhibit the production of estro- 10945 Le Conte Avenue, PVUB Suite 3360, Los gen through the aromatase enzyme pathway. Whereas tamoxifen is Angeles, CA 90095-7077; Fax: (310) 829-6192; effective in both premenopausal and postmenopausal women, AIs E-mail: [email protected] are indicated only in women who are postmenopausal. In the adju- Received April 29, 2008; revision received June vant setting, several studies have demonstrated that AIs are toler- 19, 2008; accepted June 20, 2008. ated well and offer improved disease-free survival compared with

ª 2008 American Cancer Society DOI 10.1002/cncr.23875 Published online 25 September 2008 in Wiley InterScience (www.interscience.wiley.com). 2386 CANCER November 1, 2008 / Volume 113 / Number 9 tamoxifen3-5 or placebo.6 The benefits of AIs also which estrogen binds to the ER and the resulting have been demonstrated in the metastatic7-10 and estrogen-ER unit then interacts directly with DNA to neoadjuvant settings.11-14 regulate gene transcription; and ligand-independent Despite an initial response to hormone therapy activation, in which an ER is activated, in part, after (whether in the adjuvant or metastatic setting), many phosphorylation by growth factor receptors or other patients will progress during therapy. Although it is molecules with serine or tyrosine kinase domains standard practice in recurrent or progressive HR1 (Fig. 1).18 Both ligand-dependent and ligiand-inde- breast cancer to switch to a different endocrine pendent ER activation can lead to the modulation of agent, many questions remain unanswered regarding downstream intracellular signaling cascades.18,21 In the appropriate choice of a subsequent agent.15,16 In this way, activation of the ER pathway ultimately any event, the goals of treatment for patients with may lead to tumor progression and the proliferation metastatic breast cancer are to provide clinical bene- of tumor-associated vascular endothelial cells.25,26 fit (response, stable disease) with the aim of prolong- ing life, delaying disease progression, maintaining Mechanisms of Resistance to Hormone Therapy quality of life (QOL), and postponing the use of cyto- With increased understanding of the complex, inter- toxic chemotherapy that may further impair QOL. connecting signaling pathways that regulate cellular The objectives of this article are to review the under- responses to estrogen has come a realization that lying mechanisms of action and resistance for each tumor cells may take a multitude of different ave- type of hormone therapy, evaluate recent data nues to become resistant to antiestrogen therapy. regarding the use of subsequent endocrine agents af- Unraveling this complexity is essential for optimiz- ter recurrence or progression on initial treatment, ing the use and sequencing of currently available and explore the future directions of hormone agents. drugs and for developing new and more potent ones. Resistance to therapy may be described either as Mechanisms of Estrogen Receptor Activation intrinsic or de novo (a tumor does not respond to a The classic mechanism of steroid hormone action drug from the onset of therapy) or as acquired (a tu- involves estrogen binding to ERs in the nucleus, mor that initially responded to therapy resumes thereby promoting association with specific estro- growing).27 One potential cause of intrinsic resist- gen-response elements in the promoter region of tar- ance to tamoxifen is a genetic polymorphism in the get genes.17 However, it is well documented that enzyme pathway involved in metabolizing tamoxifen significant populations of ERs may be located out- to its more active metabolite, endoxifen. Results side the nucleus18 and that ERs also regulate the from pharmacogenetic studies have revealed that expression of many genes without directly binding to patients treated with tamoxifen who have certain DNA but by interacting with other transcription fac- polymorphisms in the cytochrome P450 2D6 tors, such as activator protein 1, and with extranuc- (CYP2D6) gene (leading to a lower level of endoxifen) lear signaling complexes that modulate downstream may have a higher risk of recurrence.28,29 Although gene expression.19 those results are intriguing, additional studies are When they are not bound by estrogen, ERs often needed to assess possible relations between this interact with coregulator proteins that modulate ER genotype and resistance to tamoxifen therapy. activity20 and/or with chaperone proteins that stabi- Whereas genetic polymorphisms reflect innate differ- lize the receptor or hide its DNA-binding domain. ences in tamoxifen responsiveness, there also are There are 2 major subtypes of ERs—ERa and ERb— many potential mechanisms of acquired resistance, each with different isoforms and splice variants.21 some theoretical and others supported by preclinical ERa is expressed predominantly as a 66-kD transcript or clinical data (Table 1).27,30,31 Antiestrogen-resistant in breast tumors,22 whereas ERb occurs as the prod- tumors may develop through clonal selection of tu- uct of a different gene.18 ERb has structural homology mor cell subsets with altered HR expression, to ERa, particularly in the DNA-binding domain (95% response to tamoxifen, ER structure, or activation of amino acid identity) and in the ligand-binding do- ER pathways. main (55% amino acid identity).23 Ongoing work indicates that ERb can modulate ERa activity, suggesting Altered hormone receptor expression that ERb and its splice variants may affect the respon- Whereas loss of ERa expression has been demon- siveness of breast cancer to estradiol.24 strated in 17% to 28% of patients who have acquired ERs are activated by 2 general mechanisms: resistance to tamoxifen, mutations in the ERa recep- ligand-dependent activation (the classic pathway), in tor rarely are found, suggesting that this is an un- Hormone Resistance in the Clinic/Hurvitz and Pietras 2387

FIGURE 1. Summary of dependent and independent signaling pathways in estrogen receptor (ER)-positive tumor cells.18 ARO indicates aromatase; E2, estradiol; EGF, epidermal growth factor; ARG, amphiregulin; TGFa, transforming growth factor alpha; HRG, heregulin; eNOS, endothelial nitric oxide synthase; AKT, protein kinase C; PI3K, phosphatidylinositol 3-kinase; Src, sarcoma oncogene; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor receptor 1; Shc, Src homology 2 domain-containing transforming protein; Grb2, growth factor receptor bound protein 2; SOS, son of sevenless; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase; MNAR, modu- lator of nongenomic actions of the estrogen receptor; G, G protein; MAPK, mitogen-activated protein kinase; IKK, IjB kinase; mTOR, mammalian target of rapa- mycin; PLC, phospholipase C, cAMP, cyclic adenosine monophosphate; P, protein, Co Reg, coregulator proteins; ERE, estrogen-response element. Reprinted with permission granted by the American Association for Cancer Research and the authors R. J. Pietras and D. C. Marquez-Garban from Pietras RJ, Marquez-Garban DC. Membrane-associated estrogen receptor signaling pathways in human cancers. Clin Cancer Res. 2007;13(16):4672-4676. likely mechanism of tamoxifen resistance.30 The find- pathways that suppress expression of the PR gene, ing that ER expression is maintained in the majority appears to be another mechanism leading to tamoxi- of tamoxifen-resistant tumors suggests that the unre- fen resistance, but not to AI resistance.30,32 Preclini- sponsive phenotype is caused by a complex, multi- cal and clinical data also indicate that increased factorial change in the expression of a network of expression of ER coregulator molecules may increase genes rather than a simple, single-gene effect. This the agonistic effect of tamoxifen, contributing to re- also may explain why approximately 66% of patients sistance.30 Evidence exists that estrogen-independent who develop recurrent disease on tamoxifen will growth may be associated with a high level of ERa,33 respond to AIs or to fulvestrant.31 Loss of progester- and others have reported changes in expression one receptor (PR) expression, possibly related to sus- levels of ERa but little change in ERb expression in tained stimulation of growth factor-signaling tamoxifen- and fulvestrant-resistant tumors.34 2388 CANCER November 1, 2008 / Volume 113 / Number 9

TABLE 1 Potential Mechanisms of Acquired Resistance to Endocrine Therapy*

ER/PR Status Affected at Relapse Mechanism of Resistance Agents Clinical Relevance

ER1 Metabolic tolerance (by drug exclusion or sequestration) in TAM Theoretically, tumor could respond to increased TAM doses; hormone-sensitive cells little supporting evidence ER1 ER1 cell stimulation by agonist component of TAM or its TAM Novel antiestrogens (eg, newer SERMs) may remain active metabolites ER1 Constitutively active or inactive ER mutants or variants TAM Little clinical evidence that ER mutants play a major role in resistance ER1 Tumor remodeling with ER1 cell clones that have altered TAM May remain sensitive to other endocrine therapies (eg, AIs) sensitivity/response to TAM ER1 Activation of ER-regulated growth pathways independent of TAM, AIs Tumor likely to be completely endocrine resistant; may be steroid control (also called adaptive estrogen caused by long-term AI use hypersensitivity) ER2/PR1 Clonal selection of ER2 cells from an original ER1 tumor TAM More likely in metastatic recurrences after adjuvant TAM ER2 or ER low+/PR+ Overexpression of growth factors or their receptors TAM Likely that these tumors develop complete resistance to (eg, EGFR, HER-2/neu, Akt) endocrine therapy; associated with ligand-independent signaling ER2/PR2 Clonal selection of PR2 cells from an original ER1 tumor TAM, AIs Data from clinical trials suggest that TAM and AIs are similarly ineffective in these patients

ER indicates estrogen receptor; PR, progesterone receptor; TAM, tamoxifen; 1, positive; SERMs, selective estrogen-receptor modulators; AIs, aromatase inhibitors; 2, negative; EGFR, epidermal growth factor receptor; HER-2/neu, human epidermal growth factor receptor 2. * Reprinted with permission by Lippincott Williams & Wilkins Wolters Kluwer Health for this use only from Johnston SR. Acquired tamoxifen resistance in human breast cancer—potential mechanisms and clinical implications. Anticancer Drugs. 1997;8(10):911-930.27

Altered crosstalk between estrogen receptors and ways suggest that concurrent or sequential inhibition growth factors of multiple pathways may be a better strategy to Altered expression of growth factors and signaling improve response to endocrine therapy and reduce proteins also may contribute to the antiestrogen- the development of resistance.18,45,46 resistant phenotype. Candidate molecules include epidermal growth factor (EGF) receptor (EGFR), Effects of long-term estrogen deprivation human epidermal growth factor receptor 2 (HER-2/ Human breast cancer cells that are deprived of estra- neu), tumor necrosis factor alpha, protein kinase C diol adapt by developing estrogen hypersensitivity alpha (PKCa), mitogen-activated protein kinase (Fig. 2).47,48 This may explain the clinical observation (MAPK) phosphatase 3, and p21-activated kinase in which hormone-dependent breast cancer that 1.35-39 Evidence suggests that receptor tyrosine kinase initially regressed after oophorectomy-induced estra- signaling has an impact on resistance to endocrine diol deprivation in premenopausal women regrew in therapy by modulating the subcellular localization of response to low-dose estradiol and regressed further ER coregulators.40 Preclinical data suggest that ERa after exposure to AIs. Additional studies in breast function is maintained in the tamoxifen-resistant cancer cell lines subjected to long-term estrogen- MCF-7 breast cancer cell line through EGFR/MAPK- deprivation (LTED) demonstrated that these cells first mediated signaling.41 became hypersensitive to low-dose estrogen and Data from preclinical studies and from retro- then became estrogen independent.49 The acquired spective analyses of clinical trials indicate that HER- hypersensitivity appeared to be linked to increased 2/neu overexpression is a negative predictor of res- expression of ERa and ERb and was accompanied by ponse to tamoxifen and, to a lesser extent, AIs.42-44 a ligand-independent increase in ERa phosphoryla- Changes in the insulin-like growth factor 1 receptor tion.49 Results from several in vitro and in vivo stu- (IGF-1R)/IGF-1 pathway also may be responsible for dies suggest that tumors undergo 3 stages that lead resistance to antiestrogen therapy.42 Understanding to tamoxifen resistance: In stage 1, tamoxifen acts as the precise mechanisms and outcomes of crosstalk an estrogen antagonist; in stage 2, the tumor increas- between ERs and these molecules remains incom- ingly becomes sensitive to the agonistic (proestro- plete; however, ligand-independent activation of ER genic) effects of tamoxifen; and, in stage 3, the may play an important role. The complexity and re- tumor has increased sensitivity (hypersensitivity) to dundancy observed in these interconnected path- estradiol (as shown in Fig. 3).50,51 Long-term expo- Hormone Resistance in the Clinic/Hurvitz and Pietras 2389

FIGURE 2. Dose-response effects of estradiol on wild-type (WT) (solid line) and long-term estrogen-deprived (LTED) (hatched line) MCF-7 cells. The leftward shift in the response to estradiol in the LTED cell line demonstrates the concept of estrogen hypersensitivity.47 Reprinted with permission granted by the Endocrine Society to reproduce this figure from Masamura S, Santner SJ, Heitjan DF, Santen RJ. Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab. 1995;80:2918- 2925. sure of breast cancer to tamoxifen, thus, may lead to estrogen hypersensitivity, which, in turn, creates an environment that selects for the growth of tumors with tamoxifen resistance.52 The possibility that LTED with tamoxifen leads to estrogen hypersensitivity bolsters the rationale for using agents that do not have proestrogenic activity (eg, AIs, fulvestrant) for breast cancer that has progressed or recurred on tamoxifen.52 Therefore, the concept of adaptive hypersensitivity to estradiol and the biologic mechanisms underlying this phenomenon have important clinical implications. FIGURE 3. Effects of estradiol (E2) on MCF-7 human breast cancer tumor xenograft (A) and uterine (B) weight in mice after long-term (5-month) treat- Biologic Basis of Sequential Endocrine Therapy ment with tamoxifen (black bars) or vehicle (gray bars).51 Reprinted from After resistance to initial endocrine therapy for breast Berstein LM, Wang JP, Zheng H, Yue W, Conaway M, Santen RJ. Long-term cancer develops, no clear treatment guidelines exist exposure to tamoxifen induces hypersensitivity to estradiol. Clin Cancer Res. regarding subsequent hormone treatment for 2004;10(4):1530-1534. Reprinted with permission granted by the American patients with recurrent or systemic disease. Although Association for Cancer Research and the authors. National Comprehensive Cancer Network guidelines recommend second-line hormone therapy (nonsteroidal or steroidal AIs; fulvestrant or other selective second-line therapy. A primary consideration is the estrogen-receptor modulators [SERMs]; estrogen nature of the response to initial hormone therapy, antagonists; and estrogens, progestins, or androgens) because it is an excellent predictor of subsequent in patients with systemic disease, the guidelines do response, even when a patient’s tumor becomes re- not recommend a preferred treatment or the appro- fractory to current hormone therapy. An estimated priate sequencing of agents in this setting.15 40% to 50% of patients with breast cancer who had a The remaining critical issues faced by clinicians response to initial hormone therapy will respond to and their patients are the timing and choice of subsequent treatment with other hormone agents.53 2390 CANCER November 1, 2008 / Volume 113 / Number 9

Other important considerations include the effi- considered a pure estrogen antagonist with no ago- cacy and safety profiles of available options and nist activity. Unlike tamoxifen or the AIs, fulvestrant issues related to patient compliance with treatment. completely inhibits ER signaling.61 In addition, ful- Because of possible cross-resistance, it is also impor- vestrant, as an ER down-regulator, has a unique bio- tant to select a drug for subsequent treatment that logic mechanism of action compared with other has a different mechanism of action from the initial available hormone agents, including AIs and tamoxi- therapy.53 Minimally toxic endocrine therapies usu- fen. There are several pathways involved in ER acti- ally are preferred over cytotoxic chemotherapy given vation, as detailed above. The finding that fulvestrant its greater potential for serious adverse events (AEs) directly targets the ER and leads to both cessation of and effects on QOL.15 ER signaling and ER degradation may prevent or postpone resistant disease.62-64 Treatment options after initial therapy with an aromatase Studies in MCF-7 breast cancer cells in vitro and inhibitor and/or tamoxifen in vivo have demonstrated that, although LTED cells The optimal sequence of hormone therapy remains are refractory to treatment with tamoxifen, they are to be established in randomized, controlled clinical sensitive to treatment with fulvestrant (Fig. 4).49,60 trials. However, depending on the initial therapy, we These cells reportedly had enhanced ERa and IGF- describe current options after treatment failure. IR/insulin receptor substrate-2 expression and sig- Whereas tamoxifen historically has been the first- naling, supporting a role for these molecules in the choice therapy for postmenopausal women with stimulation of tumor growth by tamoxifen and sug- ER1 early breast cancer; now, it is surpassed increas- gesting a mechanism for their susceptibility to ful- ingly by the AIs administered either alone or in vestrant.60 These experiments provided the rationale sequence with tamoxifen, because AIs produce a sig- for the clinical development of fulvestrant as a treat- nificant benefit in the primary adjuvant setting.54 In ment for HR1 breast cancer that is refractory to anti- patients who were treated previously with tamoxifen, estrogen therapy. an AI can be used as subsequent therapy. Several Further evidence of the lack of agonistic effects trials demonstrated that AIs significantly prolong sur- of fulvestrant comes from clinical trials results in vival55,56 and time to disease progression55-57 versus healthy volunteers and women with breast cancer. megestrol acetate when used as second-line therapy Results from a phase 1 trial in healthy postmeno- in advanced ER1 breast cancer after failure on first- pausal volunteers demonstrated that, compared with line tamoxifen. However, the converse (tamoxifen as placebo, fulvestrant administered as a single intra- second-line therapy after an AI) may not be viable in muscular injection did not have estrogenic effects on some patients because of the potential for tamoxifen the endometrium and significantly inhibited estro- resistance in LTED cells. Although some evidence gen-stimulated thickening of the endometrium.65 suggests that the AIs may differ in terms of their When administered as a monthly intramuscular pharmacokinetics58 and potencies,59 the biologic injection in women with advanced breast cancer, ful- meaning and clinical utility of these findings remain vestrant had minor effects on serum hormones and unresolved. It is noteworthy that there is some evi- lipid levels and did not induce or aggravate hot dence in favor of fulvestrant as a viable option in flushes, sweats, or vaginal dryness, all of which are this situation, because it induces antitumor effects in AEs frequently associated with tamoxifen treat- LTED cells.60 ments.66

Fulvestrant as an option after failure on aromatase Efficacy and safety of fulvestrant. Overall, phase 3 inhibitors or tamoxifen trials have demonstrated comparable efficacy and tolerability between fulvestrant and anastrozole (after Antagonist versus Agonist Properties. Like tamoxifen, tamoxifen failure) or exemestane (after nonsteroidal fulvestrant completely inhibits binding of estradiol to AI failure). the ER, although fulvestrant has a higher affinity than tamoxifen for the ER.61 Unlike tamoxifen, ful- Phase 3 comparison of fulvestrant versus anastrozole. The vestrant induces a conformational change in the ER efficacy of fulvestrant versus anastrozole was estab- and inhibits receptor dimerization, rendering the lished in 2 randomized, controlled clinical trials (1 complex transcriptionally inactive. Fulvestrant bind- conducted in North America and 1 conducted in Eur- ing also reduces nuclear uptake of the drug-receptor ope, Australia, and South Africa) in postmenopausal complex, inhibits coactivator recruitment and ER women with locally advanced or metastatic breast binding to estrogen-responsive genes, and enhances cancer.67-69 In a prospectively planned, combined rapid degradation of the receptor. Thus, fulvestrant is analysis of those trials, a total of 851 postmenopausal Hormone Resistance in the Clinic/Hurvitz and Pietras 2391

vestrant (CRs and partial responses) was 16.7 months versus 13.7 months for those who responded to anastrozole. In addition, a retrospective analysis indicated that 43 of 82 patients (52%) who responded to fulvestrant maintained their response for >12 months versus 30 of 70 patients (43%) for anastrozole (P 5.16).70 With an extended median follow-up of 27 months, the median overall survival (OS) was 27.4 months for the fulvestrant treatment arm and 27.7 months for the anastrozole group (hazard ratio, 0.98; P 5.809).68 Fulvestrant and anastrozole were tolerated similarly well. The only AE category that differed between the 2 groups was joint disorders, which were more frequent in the anastrozole arm (P 5 .0036).67 Phase 3 comparison of fulvestrant versus exemestane. The Evaluation of Faslodex versus Exemestane Clini- cal Trial (EFECT), a randomized, double-blind, multicenter, phase 3 trial, demonstrated similar benefits with fulvestrant loading dose (500 mg on Day 0, followed by 250 mg on Days 14 and 28, with 250 mg monthly thereafter) versus exemestane 25 mg daily in postmenopausal women with HR-positive advanced breast cancer that progressed or recurred after nonsteroidal AI therapy.71 In the EFECT trial, the median TTP was 3.7 FIGURE 4. Dose-response curves for fulvestrant (A) and tamoxifen (B) in months for both treatment groups (hazard ratio, wild-type and long-term estrogen-deprived (LTED) high (LTED-H) and interme- 0.963; 95% confidence interval, 0.819-1.133; P 5 diate (LTED-I) cells.49,60 (A) Reprinted with permission by the Society for .6531).71 The ORR (7.4% for fulvestrant vs 6.7% for Endocrinology as it appeared in Martin LA, Pancholi S, Chan CM, et al. The exemestane; P 5 .736) and the clinical benefit rate anti-oestrogen ICI 182,780, but not tamoxifen, inhibits the growth of MCF-7 (CBR), which was defined as the ORR and stable dis- breast cancer cells refractory to long-term oestrogen deprivation through ease that lasted 24 weeks, also were similar down-regulation of oestrogen receptor and IGF signaling. Endocr Relat Can- between the 2 groups (32.2% for fulvestrant vs 31.5% cer. 2005;12(4):1017-1036. Copyright Society for Endocrinology 2005. Repro- for exemestane; P 5 .853).71 The median response duced by permission. (B) Reprinted from the Journal of Steroid Biochemistry duration from the time of randomization was 13.5 and Molecular Biology with permission from Elsevier Ltd. as it appeared in months for fulvestrant and 9.8 months for exemes- Chan CM, Martin LA, Johnston SR, Ali S, Dowsett M. Molecular changes tane.71 More recently, at a median follow-up of 20.9 associated with the acquisition of oestrogen hypersensitivity in MCF-7 breast months, OS did not differ significantly between the cancer cells on long-term oestrogen deprivation. J Steroid Biochem Mol Biol. fulvestrant and exemestane treatment arms (P 5 2002;81(4-5):333-341. Copyright 2002 Elsevier. .9072; median OS, 24.3 months vs 23.1 months, respectively).71 The 2 treatment arms had similar AE profiles, with only 2% and 2.6% of fulvestrant- and exemestane-treated patients withdrawing because of women who had recurrent or progressive disease on an AE, respectively.71 These data support the efficacy endocrine therapy (>95% had received prior tamoxi- and safety of fulvestrant (loading dose) and exemes- fen) were randomized to receive fulvestrant or anastro- tane as hormone therapy after AI failure. zole until disease progression or early study In addition to the approved dose, alternate dos- withdrawal.67,69 After a median follow-up of 15.1 ing strategies, including the loading dose and high months, the median time to progression (TTP) was 5.5 dose, were used in several recently completed trials months for fulvestrant and 4.1 months for anastrozole (eg, EFECT; Neoadjuvant Endocrine Therapy for (P 5 .48).67 The overall response rates (ORRs) in Women With Estrogen-Sensitive Tumors [NEWEST]) patients with visceral metastases were 18.8% for ful- and currently are under investigation in ongoing fulvestrant (complete response [CR] rate, 10.1%) and 14% vestrant trials (eg, the COmparisoN of Faslodex In for anastrozole (CR rate, 1.2%; P 5 .43).69 The median Recurrent or Metastatic breast cancer [CONFIRM] duration of response in patients who responded to ful- trial and the FINDER clinical fulvestrant trials) to 2392 CANCER November 1, 2008 / Volume 113 / Number 9 further elucidate the optimal fulvestrant dosing strat- During 1 of these stages, after stopping tamoxi- egy.72 Pharmacokinetic evidence suggests that using fen treatment, the administration of physiologic the loading dose substantially shortens the time to doses of estradiol was tumoricidal, leading to a more steady-state levels of fulvestrant (shortened to effective reduction in tumor size than that observed approximately 1 month vs 3 to 6 months with the with stopping tamoxifen alone. Later, some of the approved dose).71,73 Despite this, it remains unclear breast cancer cells reverted to an estrogen-dependent whether use of the loading dose confers additional phenotype that, once again, was sensitive to tamoxi- clinical benefits. However, recent data from the NEW- fen inhibition. The authors proposed a cyclic model EST study were the first to demonstrate superior effi- of breast cancer hormone dependency and postu- cacy of high-dose fulvestrant (500-mg loading dose lated that it may be possible to maintain patients followed by 500 mg per month) compared with the on tamoxifen therapy with intermittent estrogen approved dose (250 mg per month).74 That study treatment.79 reported significant reductions in the Ki67 cell prolif- Further preclinical investigations by the same eration marker (P < .0001) and in ER expression (P < laboratory led to the proposal of a cyclic clinical .0003) in patients who received high-dose fulvestrant therapeutic strategy of alternating treatment with ta- compared with patients who received the approved moxifen, AIs, or fulvestrant with brief periods of low- dose (P < .0001).75 In addition, the overall tumor dose estrogen to prevent the development of resist- response rate at Week 4 of treatment was 17.4% in the ance and, thus, forestall the use of cytotoxic chemo- high-dose group and 11.8% in the low-dose group.76 therapy.80,81 Those authors identified 2 phases of resistance: the first phase, in which the tumor has Use of steroidal aromatase inhibitors after progression become resistant to tamoxifen but is susceptible to on nonsteroidal aromatase inhibitors AIs or fulvestrant; and, after long-term tamoxifen A single-arm, phase 2 study demonstrated that exe- treatment, the second phase, in which the tumor mestane had activity in patients with metastatic growth is stimulated by tamoxifen but inhibited by breast cancer after failure of prior nonsteroidal AIs.77 estrogen.82 Clinical development of this strategy is Patients in that study received exemestane 25 mg per intriguing and would be served best by identification day orally; at the time of disease progression, they and validation of biologic markers to distinguish were offered dose escalation to exemestane 100 mg between first- and second-phase resistance. Limited per day. Among the 242 enrolled patients, the ORR trials of estrogen treatment for advanced, resistant was 6.6%, 17.4% of patients had stable disease that breast malignancies currently are ongoing in the lasted 24 weeks, and there was an overall CBR of clinic.83,84 24.3% for third-line or fourth-line exemestane.77 It is noteworthy that updated analyses of an These data suggest, perhaps surprisingly, that exe- early randomized trial of diethylstilbestrol (DES) (a mestane has incomplete cross-resistance with non- potent synthetic estrogen) versus tamoxifen in post- steroidal AIs. The efficacy of exemestane after failure menopausal women with metastatic breast cancer of a nonsteroidal AI also was supported in a retro- revealed that long-term survival was significantly spective study of 114 patients with metastatic breast better for women who received DES than for women cancer.78 In that analysis, the CBR of exemestane who received tamoxifen (35% for the DES arm vs was 46% (33% in patients with visceral disease), and 16% for the tamoxifen arm).85 The basis of this sur- the median progression-free survival and OS were vival advantage is not known. Although tamoxifen 18 weeks and 61 weeks, respectively. remains a preferred agent in the treatment of metastatic breast cancer, that trial highlighted the finding Low-dose and high-dose estradiol that high doses of estrogenic agents may have signif- Results of in vivo studies have demonstrated the in- icant activity and may play a role in the treatment of triguing antitumor potential of low-dose estradiol in selected patients with metastatic breast cancer. tamoxifen-stimulated tumors. Investigators led by V. Craig Jordan developed an ovariectomized, athymic Progestins and androgens nude mouse model with serial xenotransplants to Early studies demonstrated the comparable efficacy study exposure of breast cancer cells to 5 years of ta- of the progestin megestrol acetate and tamoxifen in moxifen adjuvant therapy. By using this model, Jor- women with metastatic breast cancer.86 Subsequent dan and collaborators observed that breast tumors studies have focused on optimizing the dosing of appear to cycle through different stages of hormone this agent in advanced breast cancer. Megestrol ace- dependency during the course of long-term tamoxi- tate still is used by many oncologists in this setting, fen exposure.79 because it has demonstrated antitumor efficacy; and, Hormone Resistance in the Clinic/Hurvitz and Pietras 2393

TABLE 2 Ongoing Trials of Combinations of Hormone Therapies in Postmenopausal Women With Estrogen Receptor-Positive, Advanced Breast Cancer*

Primary Trial Phase Treatment Eligibility No. Endpoint Study Start

NCT00256698 (FACT) 3 Anastrozole fulvestrant Local recurrence or metastases; no prior 512 TTP Jan 2004 ET for advanced or recurrent disease NCT00253422 (SOFEA) 3 Fulvestrant anastrozole vs Prior single-agent NSAI 750 PFS Mar 2004 exemestane NCT00075764 (SWOG-S0226) 3 Anastrozole fulvestrant No prior HT for recurrent or metastatic 690 TTP Apr 2004 disease; prior adjuvant HT allowed

NCT indicates National Clinical Trials; FACT, FulvestrAnt Combination Therapy; , with or without; ET, endocrine therapy; TTP, time to progression; SOFEA, Study Of Faslodex with or without concomitant Arimidex vs Exemestane following progression on nonsteroidal aromatase inhibitors; NSAI, nonsteroidal aromatase inhibitor; PFS, progression-free survival; SWOG, Southwest Oncology Group; HT, hormone therapy. *See National Institutes of Health 2008.72 as a side effect, it stimulates appetite and causes symptom relief in approximately 20% of patients. weight gain.87 Because of this history, additional pro- However, androgens are associated with a high rate gestin-based therapies are being evaluated. The 2 of adverse effects, including masculinization, hair pathways for estrogen formation in breast tumors are loss, increased libido, and edema.91 the aromatase pathway, which is targeted by AIs, and the sulfatase pathway, which converts estrogen sul- Future Directions fate into estrone.88 Interest in new clinical applica- Combinations of endocrine therapies currently are tions of progestins may resurface because of under investigation in an effort to improve treatment experimental evidence indicating high activity of sul- strategies for postmenopausal patients with ad- fatase in breast cancer tumors (especially from hor- vanced or metastatic breast cancer (Table 2).72 The mone-dependent cell lines) and the possibility of Faslodex and Arimidex in Combination Trial and inhibiting this pathway with progestins. Results of Southwest Oncology Group Study S0226 are multi- preclinical studies have indicated that certain proges- center, phase 3 studies comparing single-agent tins are strong inhibitors of sulfatase activity in hor- anastrozole with anastrozole plus fulvestrant in post- mone-dependent breast cancer cells. It also has been menopausal women with ER1/PR1 breast cancer that noted that progestins inhibit 17b-hydroxysteroid de- recurs after the primary treatment of localized tumor. hydrogenase conversion of estrone to estradiol and The Study of Faslodex, Exemestane, and Arimidex Trial stimulate sulfotransferase synthesis of estrogen sul- is comparing fulvestrant monotherapy versus fulves- fate.88 Data from studies in humans are very limited. trant plus anastrozole versus exemestane monotherapy Perhaps future clinical trials will determine whether in patients with advanced or metastatic breast cancer progestins, possibly in association with AIs, may that progressed on a non-steroidal AI. have a role in the treatment of hormone-sensitive Data from preclinical studies and from a few breast cancer. Additional studies suggest that proges- clinical studies indicate that, as discussed above, tins also may stimulate tumor progression by pro- crosstalk between the ER and growth factor path- moting the expression of vascular endothelial growth ways, such as EGF, HER-2/neu, IGF-1, and phospha- factor (VEGF), which, in turn, acts to facilitate tu- tidylinositol 3-kinase/Akt, is critical in developing mor-associated angiogenesis, underscoring the need resistance to endocrine therapy.18,92 Studies also have for more research in this area.89 demonstrated that, in breast tumors, estrogens and Although some previous reports suggested a role ERs can stimulate the enhanced expression or activa- for androgen therapy in reducing breast cancer pro- tion of key molecules involved in the regulation of gression after failure on antiestrogen therapy, more these pathways, which, in turn, can phosphorylate recent clinical trials have not demonstrated superior- and thus activate ERs in the absence of an estradiol ity of tamoxifen plus fluoxymesterone over tamoxifen ligand, resulting in loss of estrogen dependence.37,43 alone as adjuvant therapy for postmenopausal The evidence that enhanced growth factor signal women with resected, early breast cancer with transduction is a major factor in the development of known ER1 status.90 Androgens (ie, testosterone, endocrine resistance suggests that combining signal fluoxymesterone, testolactone, and calusterone) cur- transduction inhibitors with endocrine therapy may rently are used in some patients with advanced ER1 delay or supplant the emergence of this acquired cancer and have been associated with responses and resistance. 2394 CANCER November 1, 2008 / Volume 113 / Number 9

TABLE 3 Recently Completed and Ongoing Trials of Signal Transduction Inhibitors and Monoclonal Antibodies Combined With Aromatase Inhibitors or Fulvestrant in Postmenopausal Women With Estrogen Receptor-Positive Advanced Breast Cancer That Recurs of Is Refractory to Prior Endocrine Therapy*

Primary Trial Phase Treatment Eligibility No. Endpoint Study Start

TAnDEM Trial 2 Anastrozole and trastuzumab Prior TAM; HER21 208 PFS Data presented at ESMO 2006y NCT00179296 2 Letrozole and erlotinib No more than 1 prior chemotherapy and 150 CBR Nov 2003 1 prior HT NCT00118157 2 Lapatinib and TAM Primary or secondary resistance to prior TAM 41 ORR May 2005 NCT00238290 2 Trastuzumab and letrozole Prior NSAI 40 ORR May 2005 NCT00217399 1/2 Sorafenib and anastrozole MBC, 1 prior AI 50 CBR Jun 2005 NCT00240071 2 Bevacizumab and prior HR Response and then resistance to prior HT 30 Safety and Oct 2005 efficacy NCT00390455 3 Fulvestrant lapatinib Prior HT (1 or 2) 324 PFS Sept 2006 (CALGB 40302) NCT00424164 1 Lapatinib and TAM Prior AI, prior TAM 20 PK Nov 2006 NCT00423917 2 Fulvestrant and bevacizumab Prior AI 51 6-Mo PFS Aug 2007 NCT00451555 2 Fulvestrant enzastaurin Resistance to AI 132 CBR Mar 2007 NCT00454805 2 Fulvestrant and AZD2171 Prior HT, no fulvestrant; no more than 64 PFS Apr 2007 1 prior chemotherapy NCT00066378 2 Anastrozole gefitinib Failure on prior TAM; no prior AI for MBC 108 PFS at 1 y NA (EORTC 10021)

TAnDEM indicates the Trastuzumab in Dual HER2/Estrogen Receptor-Positive Metastatic Breast Cancer trial; TAM, tamoxifen; HER2, human epidermal growth factor receptor-2; 1, positive; PFS, progression- free survival; ESMO, European Society for Medical Oncology; NCT, National Clinical Trials; HT, hormone therapy; CBR, clinical benefit rate; ORR, overall response rate; NSAI, nonsteroidal aromatase inhibitor; MBC, metastatic breast cancer; AI, aromatase inhibitor; HR, hazard ratio; CALGB, Cancer and Leukemia Group B; , with or without; PFS, progression-free survival; PK, pharmacokinetics; EORTC, European Organization for Research and Treatment of Cancer; NA, not available. *See National Institutes of Health 2008.72 ySee Kaufman 2006.95

Many studies are examining the effectiveness ERa activity, and ERb and its splice variants, such as and safety of combinations of hormone therapies ERb2/ERbcx, may have an impact on the responsive- with signal transduction inhibitors to overcome en- ness of breast tumors to hormone agents. Results of docrine resistance by targeting possible crosstalk recent retrospective studies suggest that tumor between the ER and growth factor signaling path- expression of specific isoforms of ERb is associated ways (Table 3).72,93-95 Some of these combinations with clinical outcome of adjuvant endocrine treat- involve tyrosine kinase inhibitors that inhibit EGFR ment for primary breast cancer.24 Such work may (gefitinib and erlotinib), VEGF receptor (VEGFR) lead to new approaches in the management of HR- (cediranib), and PKCb mediated Akt signaling (enzas- positive breast malignancies in the near future. taurin) as well as multitargeted tyrosine kinase inhi- Although the optimal sequence of hormone bitors, such as sorafenib (inhibits c-Raf, b-Raf, KIT, therapies remains to be determined in randomized, fms-related tyrosine kinase 2, VEGFR, and platelet- controlled clinical trials, effective agents currently derived growth factor receptor-b) and lapatinib (inhi- exist that prolong life, reduce or postpone the need bits EGFR and HER-2/neu). Other combinations for cytotoxic chemotherapy, and maintain QOL in involve monoclonal antibodies, such as bevacizu- patients who have progressed on or become resistant mab, which targets VEGF, and trastuzumab, which to initial hormone therapy. Experimental evidence targets HER-2/neu. Potential trials of c-src kinase suggests the potential utility of sequencing or alter- inhibitors in combination with hormone therapy also nating various agents with different mechanisms of are under consideration.96 Ongoing clinical investiga- action and proven efficacy and tolerability profiles to tions will determine which of these hypothetical extend the viability of hormone therapy in women combinations will translate to clinical benefits. with metastatic breast cancer. However, clinical trials Clinical investigation of the potential role of ERb need to be designed to test these strategies. 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