Therapeutics and Clinical Risk Management
`
`Open Access Full Text Article
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`Dovepress
`open access to scientific and medical research
`
`REvI E W
`
`New and emerging treatments for estrogen
`receptor-positive breast cancer: focus
`on everolimus
`
`Elisavet Paplomata
`Ruth O’Regan
`Department of Hematology and
`Medical Oncology, Winship Institute
`of Emory University, Atlanta, GA, USA
`
`Correspondence: Ruth O’Regan
`Winship Cancer Institute of
`Emory University, 1365 Clifton Road,
`Atlanta, GA 30322, USA
`Tel +1 404 778 1900
`Email roregan@emory.edu
`
`Abstract: Management of patients with metastatic hormone receptor-positive breast cancer
`poses a challenge due to the inevitable development of endocrine resistance. Hormone resistance
`is associated with a complex interaction of the estrogen receptor with growth factors, trans-
`membrane receptors, and intracellular growth cascades. The PI3K/Akt/mTOR pathway plays
`a major role in hormone resistance and proliferation of breast cancer. Preclinical and clinical
`data indicate that inhibitors of human epidermal growth factor receptor-2, epidermal growth
`factor receptor, insulin-like growth factor-1 receptor, and the mammalian target of rapamycin
`pathway may act synergistically with hormone therapy to circumvent endocrine resistance.
`Everolimus is currently approved for combination with exemestane in postmenopausal women
`with advanced hormone receptor-positive breast cancer. However, we still need to unfold the
`full potential of targeted agents in the hormone-refractory setting and to identify the subsets of
`patients who will benefit from combination hormonal therapy using targeted agents.
`Keywords: everolimus, estrogen receptor-positive breast cancer, hormone resistance,
` mammalian target of rapamycin, inhibition
`
`Background
`Breast cancer is the most common malignancy among women in the US, accounting
`for nearly one in three cancers diagnosed.1 It is estimated that 226,870 women will be
`diagnosed and 39,510 women will die of breast cancer in 2012.2 Approximately two-
`thirds of breast cancers are estrogen and/or progesterone receptor-positive. Hormone
`receptor status is determined using immunohistochemistry on paraffin-embedded
` tissues. The presence of at least 1% staining nuclei is required to define hormone-
`positive disease and predict clinical response to hormone-directed therapy.3
`The natural history of hormone receptor-positive breast cancer tends to be differ-
`ent from hormone receptor-negative disease. The presence of hormone sensitivity is
`usually associated with a favorable prognosis. Use of adjuvant endocrine therapy has
`dramatically decreased breast cancer mortality in patients with early-stage disease,
`and hormone therapy is the cornerstone treatment in advanced stages. However,
`a subset of hormone receptor-positive breast cancers do not benefit from endocrine
`therapy (intrinsic resistance), and all hormone receptor-positive metastatic breast
`cancers ultimately develop resistance to hormonal therapies (acquired resistance).
`Most patients who have experienced treatment failure after several hormonal agents
`in the metastatic setting are treated with chemotherapy, which is associated with
`increased toxicity.4,5
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`Therapeutics and Clinical Risk Management 2013:9 27–36
`© 2013 Paplomata and O’Regan, publisher and licensee Dove Medical Press Ltd. This is an Open Access
`article which permits unrestricted noncommercial use, provided the original work is properly cited.
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`This review focuses on new and emerging treatments
`for hormone receptor-positive breast cancer and particularly
`on the role of inhibition of mTOR (mammalian target of
` rapamycin) in reversing resistance to endocrine agents.
`
`Endocrine therapy
`Tamoxifen, a selective estrogen receptor modulator, had
`been the standard of care for all stages of hormone receptor-
` positive breast cancer since its initial approval by the US Food
`and Drug Administration in 1986.6 Aromatase inhibitors,
`which act by blocking the peripheral conversion of andro-
`gens to estrogen and therefore decrease levels of circulating
`estrogens in postmenopausal women, were approved for the
`treatment of metastatic breast cancer, and subsequently for
`early-stage cancer. The currently approved third-generation
`aromatase inhibitors are divided into steroidal (exemestane)
`and nonsteroidal (anastrozole and letrozole) agents.7
`A study comparing anastrozole and tamoxifen in more
`than 1000 patients with advanced breast cancer showed that
`anastrozole was superior to tamoxifen in terms of time to pro-
`gression, although there was no difference in overall survival.8,9
`BIG 1-98 was a Phase III trial of letrozole versus tamoxifen in
`postmenopausal women with advanced breast cancer, which
`demonstrated that time to progression was increased from
`6 to 9.4 months in the letrozole arm. The response rate and
`overall clinical benefit were also increased in the letrozole
`arm when compared with tamoxifen.10–12 Exemestane was also
`shown to be superior to tamoxifen in terms of clinical benefit
`in postmenopausal patients with breast cancer.13 The ATAC
`(Arimidex, Tamoxifen, Alone or in Combination) trial dem-
`onstrated that aromatase inhibitors were superior to tamoxifen
`in the adjuvant setting. Aromatase inhibitors have thus become
`the preferred regimen in postmenopausal women.14,15
`Fulvestrant, an estrogen receptor downregulator with no
`known agonist activity, was initially found to be equivalent
`to anastrozole in patients previously treated with tamoxifen.16
`Fulvestrant was also compared with tamoxifen in the first-
`line setting in women with metastatic disease and was
`found to have similar efficacy in patients with hormone
`receptor-positive tumors.17 Fulvestrant was initially approved
`at a dose of 250 mg as a monthly intramuscular injection.
`Subsequent studies have examined the efficacy of different
`doses and schedules. CONFIRM (COmparisoN of Faslodex
`In Recurrent or Metastatic breast cancer) was a Phase III
`trial examining the difference in progression-free survival
`between the doses of 250 mg and 500 mg, and demonstrated
`that the higher dose improved the median progression-free
`survival, reducing the risk of progression by 20%.18
`
`Combination of hormonal agents
`Fulvestrant has been evaluated in combination with anas-
`trozole in two trials with differing results. Mehta et al
`recently reported the results of a study combining anastro-
`zole and fulvestrant in the metastatic setting.19 The authors
`hypothesized that the combination would be more effective
`than anastrozole alone in patients with hormone receptor-
`positive metastatic breast cancer. The trial randomized
`postmenopausal women with previously untreated metastatic
`disease to anastrozole alone or anastrozole plus fulvestrant.
`Fulvestrant was administered intramuscularly at a dose of
`500 mg on day 1, 250 mg on days 14 and 28, and monthly
`thereafter. The median progression-free survival was
`13.5 months in the anastrozole alone arm and 15.0 months
`in the combination arm (hazards ratio 0.80; P = 0.007).
`The combination therapy was generally more effective
`than anastrozole alone in all subgroups, with no significant
`interactions. Overall survival was also improved in the
`combination arm compared with anastrozole alone (median
`47.7 versus 41.3 months, respectively). In this study, 41%
`of patients in the anastrozole arm crossed over to fulvestrant
`after progression. The study concluded that the combination
`of anastrozole and fulvestrant was more effective and better
`tolerated than anastrozole alone. It is notable that this study
`enrolled hormone-naïve patients who, judging from the out-
`comes seen in the anastrozole alone arm, included a large
`percentage of hormone-sensitive patients. The results of this
`study are in contrast with those of FACT (Fulvestrant and
`Anastrozole in Combination Trial), an open-label, random-
`ized Phase III investigation of fulvestrant plus anastrozole
`versus anastrozole alone as first-line treatment for patients
`with receptor-positive postmenopausal breast cancer.20 This
`trial reported no significant differences in time to progression
`or median overall survival between the two groups. The dif-
`ferent results reported in these two studies may be attributed
`to the size and choice of patient population. Combination of
`hormonal therapies may warrant further investigation, but
`it does not address the issue of hormone resistance, which
`eventually develops in all patients.
`
`Mechanisms of resistance
`to endocrine therapy
`Estrogen receptor activation leads to phosphorylation,
`dimerization, and downstream signaling through estrogen
`response elements which promote cell survival, division, and
`growth of cancer.21,22 Clinical and preclinical data indicate
`that hormone receptors interact with growth factor recep-
`tors, including human epidermal growth factor receptor
`
`28
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`Emerging treatments in hormone receptor-positive breast cancer
`
`(HER2/neu), epidermal growth factor receptor (EGFR), and
`insulin-like growth factor-1 receptor (IGF1R), which likely
`play a role in hormone resistance.23,24 Crosstalk between the
`estrogen receptor and membrane tyrosine kinase receptors
`(EGFR, HER2, and IGF1R) can lead to gene expression and
`cell growth independent of hormonal activation, mainly via
`activation of the mitogen-activated protein kinase (MAPK)
`and phosphoinositide 3-kinase (PI3K) pathways. The
`estrogen receptor can also be regulated by these membrane
`receptors, which act as coactivators and lead to estrogen
`receptor phosphorylation in the absence of estrogen (ligand-
` independent receptor activation, Figure 1). The interaction of
`the estrogen receptor with growth factor receptors is complex.
`It is believed that the estrogen receptor can activate mem-
`brane growth factors via expression of transforming growth
`factor-alpha and IGF1. However at the same time, it down-
`regulates EGFR and HER2 while inducing IGF1R. In turn,
`
`activation of MAPK and PI3K pathways by growth factor
`receptors downregulates estrogen receptor signaling.25
`In summary, it appears that membrane growth factor
`receptors can phosphorylate and activate the estrogen receptor
`independently of estrogen and they can activate downstream
`pathways and induce cell growth independently of estrogen
`receptor activation, but can also downregulate estrogen
`receptor expression, leading to hormone independence.
`
`HER2/EGFR
`Breast cancers with high levels of HER2 expression are
`more likely to be resistant to hormonal therapy. Transfection
`of HER2 in estrogen receptor-positive breast cancer cells
`renders them resistant to tamoxifen.26,27 Further, it has been
`shown that selective estrogen receptor modulator-resistant
`breast cancer cells have increased expression of HER2 com-
`pared with selective estrogen receptor modulator-sensitive
`
`Estrogen
`
`EGFR/HER2neu/IGF1R
`
`Estrogen
`receptor
`
`ER
`
`Src
`
`ER
`
`P
`
`Cell membrane
`
`Ras
`
`Raf
`
`MAPK
`
`NFκB
`
`PI3K
`
`Akt
`
`TSC1/2
`
`Rheb
`
`PTEN
`
`mTORC2
`
`Rictor
`
`mLST8
`
`mTOR
`
`Deptor
`
`GSK3-β
`
`Cyclin D1
`
`Cyclin E
`
`S6K1/4EBP1
`
`Gene expression
`Anti-apoptosis
`Cell proliferation
`Angiogenesis
`
`mTORC1
`
`mTOR
`
`mLST8
`
`Raptor
`
`PRAS40
`
`Deptor
`
`Rapamycin
`
`Figure 1 Crosstalk between the estrogen receptor and EGFR/HER2/IGF1R membrane tyrosine kinase receptors can lead to gene expression and cell growth independent
`of hormonal activation, mainly via activation of the MAPK and PI3K pathways.
`Notes: The estrogen receptor can also be regulated by these membrane receptors, which act as coactivators and lead to phosphorylation of estrogen receptors in the
`absence of estrogen (ligand-independent receptor activation). The PI3K/Akt/mTOR pathway is a major downstream cellular circuit, which leads to cell proliferation via the
`mTORC1 complex. The mTORC2 complex activates Akt, which in turn inhibits the proteolysis of cyclin D1/E.
`Abbreviations: EGFR, epidermal growth factor receptor; IGF1R, insulin-like growth factor-1 receptor; mTOR, mammalian target of rapamycin; HER2, human epidermal
`growth factor receptor-2; ER, estrogen receptor; TSC1/2, tuberous sclerosis complex proteins 1/2; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein
`kinase; Src, steroid receptor coactivator.
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`breast cancer cells.28,29 A meta-analysis by De Laurentiis et al
`reported that HER2-positive patients with metastatic receptor-
`positive breast cancer treated with tamoxifen had a shorter
`time to treatment failure when compared with patients hav-
`ing HER2-negative disease.30 These findings suggest that
`HER2 plays a significant role both in intrinsic and acquired
`hormone resistance. Preclinical evidence supports that
`crosstalk between HER2 and the estrogen receptor leads to
`tamoxifen resistance, and disruption of this crosstalk can
`restore tamoxifen sensitivity.31,32
`A randomized Phase III, double-blind, multicenter study
`by Johnston et al enrolled 1286 postmenopausal patients with
`advanced or metastatic estrogen receptor-positive and/or
`progesterone receptor-positive breast cancer. No prior treat-
`ment was allowed, except for neoadjuvant/adjuvant hormonal
`or anti-HER2 therapy. Patients were randomly assigned to
`receive letrozole and lapatinib or letrozole and placebo.
`Median progression-free survival was significantly improved
`in patients with HER2-positive disease who received lapatinib
`plus letrozole, compared with letrozole alone (3 months in the
`placebo arm and 8.2 months in the combination arm, hazards
`ratio 0.71, P = 0.019). Among the HER2-negative patients,
`there was no significant improvement in progression-free
`survival or clinical benefit. However, a subset of patients
`with HER2-negative disease and estrogen receptor expres-
`sion in the lowest quartile appeared to benefit from adding
`lapatinib to letrozole (progression-free survival 13.6 versus
`6.6 months, hazards ratio 0.65, P , 0.005).33,34
`Similarly, expression of EGFR in vivo and in vitro has
`been shown to be associated with endocrine resistance, and
`in preclinical models EGFR inhibition can restore sensi-
`tivity to hormone treatment.35–38 A Phase II, randomized,
`double-blind, placebo-controlled study by Cristofanilli et al
`evaluated the combination of anastrozole and gefitinib
`(a selective EGFR tyrosine kinase inhibitor) versus anas-
`trozole and placebo in postmenopausal patients with hor-
`mone receptor-positive metastatic breast cancer. The study
`population consisted of patients who had not received prior
`endocrine therapy for this stage or had developed metastatic
`disease during/after adjuvant tamoxifen. Although the study
`was closed early due to slow accrual, the combination arm
`showed improvement in progression-free survival versus
`placebo (median progression-free survival 14.7 versus
`8.4 months, respectively). The treatment was tolerated very
`well.39 Osborne et al reported a randomized Phase II trial of
`tamoxifen with or without gefitinib in patients with meta-
`static disease who had experienced treatment failure while
`on tamoxifen or aromatase inhibitors. The combination arm
`
`showed improved progression-free survival in patients who
`had relapsed after adjuvant tamoxifen. However, no clinical
`benefit was seen in patients who had been previously treated
`with aromatase inhibitors.40
`
`IGF1R
`The IGF1R pathway plays a significant role in tumor growth
`and inhibition of apoptosis. IGF1R can activate the estrogen
`receptor pathway in the absence of estrogen and thus lead
`to tumor growth. It appears that there is crosstalk between
`IGF1R and the estrogen receptor, which possibly contributes
`to hormone resistance. In vivo and in vitro models show
`that IGF1R inhibition can act synergistically with hormone
`therapy.41–44 However, a clinical study of AMG 479 (a human
`anti-IGF1R monoclonal antibody) in combination with
`exemestane or fulvestrant in postmenopausal women failed
`to show a clinical benefit or difference in progression-free
`survival with IGF1R inhibition.45
`
`Steroid receptor coactivator
`The steroid receptor coactivator (Src) is a nonreceptor
`tyrosine kinase, which plays an essential role in the life cycle
`of the cell.46 Breast cancer tissue has higher expression of
`Src than normal breast tissue. In hormone receptor-positive
`breast cancer cells, Src binds and phosphorylates the estro-
`gen receptor and activates downstream signaling pathways
`(Figure 1). Src is thought to play a pivotal yet complex role in
`endocrine resistance. Elevated levels of cytoplasmic Src have
`been linked with an attenuated response to hormone therapy
`in vitro, and high expression of Src has been associated
`with increased metastatic potential and poor survival in the
`clinical setting.47,48 Preclinical studies indicate that treatment
`of resistant cells with Src inhibitors restores sensitivity to
`tamoxifen.49 However, a Phase II study of dasatinib (an oral
`multi-BCR/ABL and Src family tyrosine kinase inhibitor)
`as a single agent showed very limited activity in women
`with advanced HER2-positive or estrogen receptor-positive
`metastatic breast cancer, probably due to the complexity
`of the cellular circuits which ultimately lead to hormone
`resistance.50
`
`PI3K, Akt, and mTOR
`The PI3K/Akt/mTOR pathway is a major intracellular cas-
`cade, which can be regulated by nutrient availability and
`growth factor receptors, including EGFR, HER2, IGF1R, and
`the estrogen receptor. When activated, this pathway induces
`tumor growth, proliferation, and resistance to targeted agents
`and chemotherapy.51,52 The PI3K/Akt pathway can activate
`
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`Emerging treatments in hormone receptor-positive breast cancer
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`both estrogen-dependent and estrogen-independent estrogen
`receptor alpha.53
`In this pathway, a central role is played by PI3K heterodi-
`mer, which consists of a p85 regulatory and p110 catalytic
`subunit. Activation of PI3K will phosphorylate Akt. Akt is a
`serine/threonine kinase, which activates major downstream
`intracellular effectors. Akt can directly activate the estrogen
`receptor by phosphorylation in the absence of estrogen, thus
`promoting estrogen-independent growth and resistance to
`hormone therapy.54–58 The PI3K/Akt pathway is often aber-
`rantly regulated in cancer, and the PIK3CA mutation is the
`most common point mutation seen in breast cancer.59 Akt
`can be also activated by loss of PTEN, a mechanism that has
`been associated with a poor prognosis and increased risk of
`relapse after treatment with tamoxifen.60
`PI3K/Akt mutations, loss of PTEN, and constitutive acti-
`vation of the PI3K/Akt pathway have been associated with
`hormone resistance. Activation of the PI3K pathway has been
`associated with intrinsic and acquired hormone resistance,
`and preclinical data indicate that PI3K inhibitors are active
`when combined with endocrine therapy.56,61 Multiple clinical
`studies are currently evaluating PI3K inhibitors in hormone
`receptor-positive tumors.
`Downstream of PI3K and Akt, mTOR is a serine/
`threonine protein kinase, which is activated by inhibition
`of the tuberous sclerosis complex proteins 1/2.62 mTOR
`exerts its effects via two very different protein complexes.
`The mTORC1 complex includes the regulatory-associated
`protein of mTOR (Raptor), mLST8, and proline-rich Akt
`substrate 40.63 It is irreversibly inhibited by rapamycin and
`exerts its action by activating S6K1 (40S ribosomal protein
`S6 kinase 1) and eukaryotic initiation factor 4E-binding pro-
`tein, thus leading to protein production, cell activation, divi-
`sion, and tumor growth.64,65 mTORC2 has been traditionally
`thought to be insensitive to rapamycin, but there is evidence
`that prolonged exposure to rapamycin can induce sufficient
`inhibition of mTORC2.66 Although its role in the cell cycle
`remains largely unknown, mTORC2 is believed to modulate
`cell lipid metabolism and cell growth via Akt, by inhibition of
`glycogen synthase kinase-3β and cyclin D1/E proteolysis.63
`Studies suggest that targeted inhibition of TORC2 inhibits
`breast cancer cells in vitro and in vivo.67
`Several preclinical studies provide evidence that mTOR
`inhibition can restore hormone sensitivity and induce apop-
`tosis in breast cancer cells. The mTOR inhibitor, rapamycin,
`can reverse resistance to endocrine therapy when combined
`with tamoxifen or fulvestrant.68,69 Interestingly, restoration
`of sensitivity to endocrine therapy can be associated with
`
`increased estrogen receptor-α protein expression levels
`and alteration of the phospho-ser167 estrogen receptor-α
`to total estrogen receptor-α ratio.69 Treatment of letrozole-
`resistant or fulvestrant-resistant breast cancer cells with low
`concentrations of the mTOR inhibitor, everolimus, reverses
`Akt-mediated resistance and restores responsiveness to
`antiestrogen treatment.70 When combined with letrozole,
`everolimus acts synergistically to promote cell cycle arrest
`and induce apoptosis.71 In summary, these preclinical data
`strongly support that mTOR inhibition could play a signifi-
`cant role in the treatment of hormone receptor-positive breast
`cancer, especially in resistant tumors.
`
`Clinical studies with mTOR inhibitors
`Rapamycin (sirolimus) was the first identified mTOR
`inhibitor, and was initially used as an immunosuppressant
`to prevent organ transplant rejection. The novel inhibitors,
`everolimus, temsirolimus, and ridaforolimus, are rapamycin
`analogs with improved pharmacological properties.
`
`Temsirolimus
`In a randomized, Phase II three-arm study of temsirolimus
`in combination with letrozole in postmenopausal women
`with hormone receptor-positive metastatic breast cancer,
`combination treatment with an intermittent schedule of
`temsirolimus was tolerable and showed clinical activity, with
`preliminary results indicating improvement in progression-
`free survival.72,73 A subsequent Phase III study by Chow et al
`who enrolled patients with metastatic breast cancer randomly
`assigned patients to letrozole or combination of letrozole
`with temsirolimus.74 The study had to be closed prematurely
`because there was no clinical benefit from the combination.
`An unplanned subset analysis suggested that patients who
`had been previously treated with chemotherapy might benefit
`from addition of the mTOR inhibitor to hormonal therapy.75
`It is possible that this study failed to reach its endpoint due
`to suboptimal dosing and inappropriate selection of the study
`population.
`
`Everolimus
`BOLERO-2 (Breast Cancer Trials of Oral Everolimus) is a
`randomized Phase III investigation by Baselga et al which
`evaluated a combination of everolimus with the steroidal
`aromatase inhibitor, exemestane, in postmenopausal patients
`with advanced estrogen receptor-positive breast cancer who
`had recurrence or progression while receiving a nonsteroidal
`aromatase inhibitor.76 In total, 724 patients were randomized
`to receive exemestane 25 mg daily plus everolimus 10 mg
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`daily or exemestane 25 mg daily plus placebo. At the interim
`analysis, with a median follow-up of 12.5 months, the patients
`treated with everolimus had a significant improvement in
`progression-free survival compared with the placebo arm
`(by local assessment, 6.9 months versus 2.8 months respec-
`tively, hazards ratio 0.43, P , 0.001; by central assessment
`10.6 versus 4.1 months respectively, hazards ratio 0.36,
`P , 0.001). More serious adverse events were reported in
`the combination group, and a higher percentage of patients
`discontinued everolimus (19% versus 4%). The most com-
`mon grade 3 or 4 adverse events were stomatitis, anemia,
`dyspnea, hyperglycemia, fatigue, and pneumonitis.
`TAMRAD (tamoxifen and RAD001) was an open-label
`Phase II study that randomized patients to tamoxifen alone
`or tamoxifen in combination with everolimus 10 mg daily.77
`The clinical benefit rate, which was the primary endpoint,
`was significantly improved in patients receiving tamoxifen
`plus everolimus versus tamoxifen alone (61% versus 42%,
`respectively, P = 0.045). Time to progression was also
`significantly improved in patients treated with tamoxifen
`and everolimus compared with tamoxifen alone (8.6 versus
`4.5 months, respectively). Preliminary analysis demon-
`strated that the risk of death was also reduced by 55% with
`everolimus. Patients with secondary resistance seemed to
`benefit more from the addition of everolimus to tamoxifen
`than patients with primary resistance. The main toxicities
`seen in the everolimus arm were fatigue, stomatitis, rash,
`anorexia, and diarrhea.
`Baselga et al reported a neoadjuvant study of everoli-
`mus plus letrozole versus placebo plus letrozole in estro-
`gen receptor-positive disease.78 Two hundred and seventy
`postmenopausal women with operable estrogen receptor-
`positive breast cancer were randomly assigned to receive
`4 months of neoadjuvant treatment with letrozole 2.5 mg/day
`and either everolimus 10 mg/day or placebo. The primary
`endpoint was clinical response by palpation. The response
`rate was higher in the everolimus arm (68% versus 59%).
`
`Biopsies were obtained at baseline and after 2 weeks of
`treatment. Progesterone receptor and cyclin D1 expression
`were decreased in both treatment arms, but phospho-S6 was
`downregulated significantly in the everolimus arm. Ki67
`expression also decreased more dramatically in the everoli-
`mus arm compared with placebo. This study showed that
`everolimus significantly increased the efficacy of letrozole
`in the neoadjuvant setting.
`These clinical studies (Table 1) continue to support that
`everolimus has synergistic anticancer activity and improves
`outcomes when combined with hormonal therapy in hormone
`receptor-positive breast cancer.
`
`Sirolimus
`Bhattacharyya et al have reported a Phase I/II trial that evalu-
`ated the combination of tamoxifen and sirolimus 2 mg daily
`in hormone receptor-positive and HER2-negative breast
`cancer.79 The study was divided into two groups and included
`a total of 400 patients. The first group included patients
`who could not afford aromatase inhibitors and thus were
`hormone-naïve. The second group included patients who
`had experienced treatment failure on aromatase inhibitors or
`tamoxifen. Response rates and time to progression were the
`primary endpoints. The Phase II study showed a response
`rate of 4% versus 40% and time to progression of 3 versus
`11 months in the tamoxifen alone versus the tamoxifen plus
`sirolimus arm, respectively. The patients who had progres-
`sion of disease within 6 months had less benefit (2.2 versus
`7.4 months), and both hormone-naïve and hormone-resistant
`patients seemed to benefit from the combination therapy.
`This study concluded that the combination of sirolimus and
`tamoxifen was effective and well tolerated.80
`
`Resistance to mTOR inhibitors
`Drug resistance is a potential challenge that may arise with
`the use of mTOR inhibitors, and can be mediated by dys-
`regulation of p27, feedback activation of PI3K/Akt by S6K,
`
`Table 1 Phase II and III trials of everolimus in patients with hormone receptor-positive, HER2-negative breast cancer
`Trial
`Phase
`Patients (n)
`Study treatment
`Primary endpoint
`Outcomes
`Exemestane 25 mg/day + everolimus
`III
`724
`Progression-free
`Median PFS 10.6 months
`BOLERO-2
`versus 4.1 months, P , 0.001
`survival
`Baselga et al76
`10 mg/day versus exemestane
`25 mg/day + placebo
`Tamoxifen 20 mg/day + everolimus
`10 mg/day versus tamoxifen 20 mg/day
`Everolimus 10 mg/day + letrozole
`2.5 mg/day versus placebo + letrozole
`2.5 mg/day
`Abbreviations: CR, complete response; CBR, clinical benefit rate; BOLERO-2, Breast Cancer Trials of Oral Everolimus; TAMRAD, tamoxifen and RAD001; PFS,
`progression-free survival.
`
`TAMRAD
`Bachelot et al77
`Neoadjuvant
`Baselga et al78
`
`II
`
`II
`
`111
`
`270
`
`Clinical benefit rate
`
`Clinical response
`by palpation
`
`CBR 61% versus 42%,
`P = 0.046
`CR 68.1% versus 59.1%,
`P = 0.062
`
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`Emerging treatments in hormone receptor-positive breast cancer
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`activation of the ERK, PIM, and PDK1 pathways, alterations
`in protein synthesis, and increased bcl-2.81,82 Resistance
`can potentially be overcome by a combination of agents
`that target the mTOR pathway and PI3K/Akt, EGFR, or
`mTORC2 inhibitors. There are ongoing Phase I and II studies
`which are investigating the combination of these agents.83
`BELLE-3 (clinicaltrials.gov, NCT01633060) is an ongoing
`Phase III study evaluating the combination of BKM120 and
`fulvestrant in previously treated, hormone receptor-positive,
`HER2-negative patients who have progressed on or after an
`mTOR inhibitor. BKM120 is an oral pan-class PI3K inhibi-
`tor, which can potentially overcome mTOR resistance by
`targeting upstream PI3K signaling.61
`
`Conclusion and future directions
`The development of resistance to hormonal agents represents
`a significant challenge in the management of advanced hor-
`mone receptor-positive breast cancer. Several cellular path-
`ways have been investigated as potential targets in an effort
`to bypass the estrogen receptor and block tumor growth.
`Preclinical data suggest that there is crosstalk between the
`estrogen receptor and membrane growth factors, which can
`stimulate cell growth independent of hormonal activation.
`HER2, EGFR and mTOR inhibitors appear to have activity
`and act synergistically with hormonal therapy. On the other
`hand, a recent review reports that it may be possible to iden-
`tify a subset of patients who are HER2-positive and estrogen
`receptor-positive who will benefit from the combination
`of HER2 and hormone inhibition, while patients with low
`hormone expression may not benefit from hormonal therapy
`and should be treated with chemotherapy and HER2-directed
`therapy instead.84
`Recent studies have shown that everolimus is active in
`combination with hormonal therapy in the metastatic and
`neoadjuvant setting, with an acceptable side effect profile.
`Based on the progression-free survival data in the control
`arm of the BOLERO-2 trial, as well as the data from the
`TAMRAD trial, it is possible that mTOR inhibitors may
`be more effective in tumors that have developed secondary
`resistance to endocrine agents.
`It is unclear why the temsirolimus trials did not produce
`the clinical benefit that was seen with everolimus, but it may
`be attributed to the selection of hormone-naïve patients.
`Ridaforolimus is another rapamycin analog, which is
` currently being studied in multiple tumors. In hormone recep-
`tor-positive and HER2-negative breast cancer, ridaforolimus
`is currently being evaluated in combination with daloto-
`zumab (an IGF1R inhibitor) in one study that has completed
`
` recruitment (clinicaltrials.gov, NCT01234857). Another
`study, which is comparing the combination of ridaforolimus
`plus dalotozumab plus exemestane versus ridaforolimus plus
`exemestane, is currently recruiting patients (clinicaltrials.
`gov, NCT01605396). Another study which is currently
`recruiting patients is comparing trastuzumab or everolimus
`in combination with endocrine therapy in patients with
`hormone-refractory, HER2-negative metastatic breast cancer
`(clinical trials.gov, NCT00912340).
`The most common side effects of mTOR inhibitors
`include stomatitis, rash, pneumonitis, hyperglycemia, and
`hyperlipidemia. Pneumonitis may warrant interruption of
`treatment and dose reduction if moderate or severe. The
`clinician should be aware that use of mTOR inhibitors is
`associated with an increased cost and side effects, especially
`in elderly patients with multiple comorbidities. In future
`research, we need to define biomarkers to help us identify
`better those patients who will benefit from addition of mTOR
`inhibitors, such as those with known mutations of the PI3K
`pathway. Use of gene expression profiling might also identify
`subsets of patients who will benefit from a combination of
`targeting therapies, such as pat