Cancer Management and Research
`
`open access Full text article
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`open access to scientific and medical research
`
`C o M Me n taR y
`
`Clinical implications of recent studies
`using mtoR inhibitors to treat advanced
`hormone receptor-positive breast cancer
`
`Francis arena
`Clinical Research alliance, Lake
`Success, new york, ny, USa
`
`Correspondence: Francis arena
`1999 Marcus ave, Suite 120,
`Lake Success, ny 11042, USa
`tel +1 516 466 6611
`Fax +1 516 466 6080
`email francis.arena@nyumc.org
`
`Abstract: Breast cancer is a leading cause of cancer-related death worldwide. Approximately
`75% of breast cancer is hormone receptor-positive (HR+) and is managed with endocrine thera-
`pies. However, relapse or disease progression caused by primary or acquired endocrine resistance
`is frequent. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of
`rapamycin (mTOR)-mediated signaling is one of the molecular mechanisms leading to endo-
`crine resistance. mTOR inhibitors that target the PI3K/Akt/mTOR pathway are the first of the
`targeted therapies to be evaluated in clinical trials to overcome endocrine resistance. Although
`the clinical trial with temsirolimus, an mTOR inhibitor, did not show any benefit when com-
`pared with endocrine therapy alone, a Phase II clinical trial with sirolimus has been promising.
`Recently, everolimus was approved in combination with exemestane by the US Food and Drug
`Administration for treating postmenopausal women with advanced HR+ breast cancer, based
`on the results of a Phase III trial. Therefore, everolimus represents the first and only targeted
`agent approved for combating endocrine resistance.
`Keywords: advanced breast cancer, hormone receptor-positive, endocrine resistance, mTOR
`inhibitors
`
`Introduction
`Breast cancer is one of the most frequently diagnosed cancers and a leading cause of
`death among women worldwide. In 2008, the worldwide incidence of female breast
`cancer was approximately 1.4 million, and the estimated number of deaths as a result
`of breast cancer was more than 450,000.1 Breast cancer is the second most common
`cancer diagnosed in US women.2 Approximately 75% of primary breast cancers
`test positive for a hormone (estrogen or progesterone) receptor protein.3,4 Endocrine
`therapies such as tamoxifen, fulvestrant, and aromatase inhibitors that interfere with
`signaling through the estrogen receptor have revolutionized the treatment of hormone
`receptor-positive (HR+) breast cancer. Despite significant advances in the treatment
`of HR+ breast cancer, primary or acquired resistance to endocrine therapy is a major
`obstacle in this treatment and a frequent cause of disease recurrence.
`Deregulation or aberrant signaling in the phosphatidylinositol-3-kinase (PI3K)/
`protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signal transduction
`pathway through activation of mutations in PI3K or inactivation of mutations in protein
`tyrosine phosphatase is thought to contribute to the development of breast cancer.5–7
`mTOR is a serine/threonine protein kinase located immediately downstream of the
`PI3K/Akt pathway and upstream of several key mediators of cell growth, proliferation,
`survival, metabolism, and angiogenesis (Figure 1).8–10 Activation of the mTOR pathway
`
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`Cancer Management and Research 2014:6 389–395
`© 2014 Arena. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0)
`License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
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`Estrogen
`
`Growth factor
`
`Growth factor receptor
`
`IRS1/2
`
`ER
`
`P
`
`m ic
`
`o
`
`n
`
`e
`
`g
`
`n
`
`o
`
`a r/n
`
`u cle
`
`n
`
`n
`
`o
`
`N
`
`ER
`
`Ras
`
`Raf
`
`Mek
`
`PI3K
`
`AkT
`
`mTOR1
`
`Plasma membrane
`
`Cytoplasm
`
`PTEN
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`mTOR2
`
`4E-BP1
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`elF4E-F-G
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`Erk
`
`S6K1
`
`Nuclear/genomic
`
`PP
`ER
`
`PP
`ER
`
`ER target gene transcription
`
`Nucleus
`
`Figure 1 PI3K/akt/mtoR signaling pathway.
`Note: Villarreal-Garza C, Cortes J, andre F, et al. mtoR inhibitors in the management of hormone receptor-positive breast cancer: the latest evidence and future directions. Ann
`Oncol. 2012;23(10):2526–2535,10 by permission of oxford University Press on behalf of the european Society for Medical oncology. Copyright © 2012, oxford University Press.
`Abbreviations: 4e-BP1, 4 eukaryotic binding protein 1; eIF-4e, eukaryotic translation initiation factor 4e; akt, protein kinase B; eR, estrogen receptor; mtoR, mammalian
`target of rapamycin; PI3k, phosphatidylinositol; Pten, phosphatase and tensin homolog; S6K1, ribosomal protein S6 kinase.
`
`results in the phosphorylation of two downstream targets,
`the ribosomal p70 S6 kinase and the eukaryotic translation
`initiation factor 4E-binding protein, which mediate the
`translation of proteins involved in regulation of cell growth
`and proliferation.8,9 In addition, activation of mTOR may
`result in phosphorylation of several downstream effectors
`and transcription factors that regulate survival, metabolism,
`and angiogenesis.8,9 Therefore, mTOR is the central nexus
`in a series of signaling pathways that integrate intracellular
`nutrient, energy, and redox needs with extracellular amino
`acid, nutrient, growth factor, and cytokine availability.8
`Hormone-independent breast cancer cell growth is associ-
`ated with increased PI3K/mTOR signaling and inhibition of
`PI3K and mTOR-induced apoptosis.11 Additionally, activation
`of the PI3K pathway after endocrine therapy was shown to be
`predictive of poor disease outcome.11 mTOR inhibition restores
`sensitivity to endocrine therapy in resistant breast cancer cells
`expressing aberrant Akt activity.12,13 Altogether, these pre-
`clinical observations suggest that mTOR plays a central role
`in endocrine resistance. As a strategy to overcome endocrine
`resistance, mTOR inhibitors have been studied in several clini-
`cal trials in combination with endocrine therapies, and recent
`evidence from these trials will be discussed here.
`
`Temsirolimus
`A Phase II study (NCT00062751)14 of temsirolimus in
`postmenopausal women with locally advanced or metastatic
`
`breast cancer showed that intermittent dosing of temsiroli-
`mus (30 mg daily for 5 days, every 2 weeks) plus daily letro-
`zole (2.5 mg) improved the clinical benefit rate (80% versus
`69%) and median progression-free survival (13.2 months
`versus 11.6 months), compared with daily letrozole alone.15
`Based on this finding, intermittent dosing of temsirolimus
`was studied in combination with letrozole as first-line
`therapy in the Phase III HORIZON trial (NCT00083993)16
`in postmenopausal women with aromatase inhibitor-naïve,
`HR+, locally advanced or metastatic breast cancer.17 Data
`from an interim analysis showed that the objective response
`rate (27% each) and median progression-free survival
`(hazard ratio [HR] 0.90; 95% confidence interval [CI]
`0.76–1.07; P=0.25) were similar between the temsirolimus
`plus letrozole arm (n=556) and the letrozole alone (n=556)
`arm. No difference in overall survival (HR 0.89; 95% CI
`0.65–1.23) was noted between the two arms.17 Therefore,
`lack of efficacy led to the early termination of this trial.
`The most frequently reported grade 3–4 adverse events in
`the Phase III trial were consistent with those observed in
`the Phase II trial with temsirolimus.17 Despite the lack of
`efficacy observed in the main trial, an exploratory subgroup
`analysis showed that, in patients #65 years of age, but not
`in those .65 years, temsirolimus plus letrozole improved
`median progression-free survival from 5.6 months to
`9.0 months (HR 0.75; 95% CI 0.60–0.93; P=0.009),17 sug-
`gesting that temsirolimus plus letrozole might be beneficial
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`mtoR inhibitors in advanced breast cancer
`
`in younger women; however, larger trials are necessary to
`confirm this finding.
`
`Sirolimus
`A Phase II trial in patients with HR+, human epidermal receptor
`2-negative (HER2−) metastatic breast cancer evaluated the
`efficacy and safety of sirolimus in combination with tamox-
`ifen.18 In patients whose disease progressed while they were
`receiving prior tamoxifen or an aromatase inhibitor, treatment
`with sirolimus plus tamoxifen significantly improved median
`progression-free survival from 3.3 months to 11.7 months
`(HR 0.43; 95% CI 0.25–0.92; P=0.0023).18 Sirolimus plus
`tamoxifen improved median progression-free survival by
`7.0 months in the second part of this Phase II trial, in which
`patients with HR+, HER2− metastatic breast cancer who could
`not afford aromatase inhibitor therapy were randomly assigned
`to receive sirolimus plus tamoxifen and compared with those
`randomly assigned to receive tamoxifen alone (HR 0.48; 95%
`CI 0.25–0.93; P=0.0028).18 Respectively, anemia (21% versus
`18%), hyperglycemia (16% versus 8%), hypercholesterolemia
`(11% versus 1%), hypertriglyceridemia (11% versus 1%),
`stomatitis (8% versus 0%), rash (7% versus 1%), anorexia
`(7% versus 2%), and fatigue (6% versus 8%) were the most
`frequently reported grade 3–4 adverse events with sirolimus
`plus tamoxifen or tamoxifen alone in this trial.18 Although the
`results of this small Phase II trial are promising, larger trials
`are necessary before sirolimus can be used to treat patients
`with advanced breast cancer.
`
`Everolimus
`Phase I studies suggested that treatment with everolimus in
`combination with endocrine therapy was feasible for patients
`
`with HR+ breast cancer.19 TAMRAD (NCT01298713),20
`a randomized, open-label, Phase II study, evaluated the
`efficacy and safety of everolimus 10 mg/day plus tamox-
`ifen 20 mg/day (n=54) versus tamoxifen 20 mg/day alone
`(n=57) in postmenopausal women with HR+, HER2−,
`aromatase inhibitor-resistant metastatic breast cancer.21
`Randomization was stratified by primary (relapsing during
`or within 6 months of stopping adjuvant aromatase inhibi-
`tor treatment or progressing within 6 months of starting
`aromatase inhibitor treatment in the metastatic setting) and
`secondary resistance relapsing .6 months after stopping
`adjuvant aromatase inhibitors or responding for $6 months
`to aromatase inhibitors in the metastatic setting.21 The
`primary end point of clinical benefit rate was 61% (95%
`CI 47–74) among patients in the everolimus/tamoxifen
`arm, compared with 42% (95% CI 29–56) for patients in
`the tamoxifen only arm (exploratory P=0.045, Table 1).21
`Time to progression was significantly longer in the combi-
`nation group (8.6 months versus 4.5 months; exploratory
`P=0.002), and a 55% reduction in risk of death was associ-
`ated with combination therapy (HR 0.45; 95% CI 0.24–0.81;
`exploratory P=0.007).21 The clinical benefit rate and time
`to progression were higher in patients receiving everoli-
`mus who had secondary hormone resistance (Table 1),
`suggesting a potential compensatory adaptive response
`to long-term estrogen depletion and a potential clinical
`benefit from adding everolimus to hormone therapy in this
`subpopulation of patients.21 The safety profile of everolimus
`was consistent with those of previous reports; the severity
`of most adverse events were grade 1 or 2, and the adverse
`events could be managed without treatment interruption.21
`Adverse events more common in the combination group
`
`Table 1 Efficacy of mTOR inhibitors in combination with endocrine therapy in HR+/HER2− patients with advanced breast cancer
`CBR
`TTP
`EVE + TAM, %
`EVE + TAM, months
`P-value
`TAM, %
`taMRaD – Phase II trial comparing everolimus/tamoxifen versus tamoxifen alone
` overall population
`61
`42
`0.045
`8.6
` Primary resistance
`46
`36
`–
`5.4
` Secondary resistance
`74
`48
`–
`14.8
`CBR
`PFS
`EVE + EXE, %
`EVE + EXE, months
`P-value
`EXE, %
`BoLeRo-2 – Phase III trial comparing everolimus/exemestane versus exemestane alone
`Median follow-up
`6.9
`na
`na
`na
` 7.1 months
`7.4
`25.5
`50.5
` 12.5 months
`,0.0001
`7.8
`26.4
`51.3
` 18.0 months
`,0.0001
`Note: Data from Bachelot et al,21 Baselga et al,22 Hortobagyi et al,23 and yardley et al.24
`Abbreviations: CBR, clinical benefit rate; CI, confidence interval; EVE, everolimus; EXE, exemestane; HER2−, human epidermal receptor 2–negative; HR, hazard ratio; HR+, hormone
`receptor-positive; mTOR, mammalian target of rapamycin; NA, not available; NS, not significant; PFS, progression-free survival; TAM, tamoxifen; TTP, time to progression.
`
`TAM, months HR (95% CI)
`
`P-value
`
`4.5
`3.8
`5.5
`
`0.54 (0.36–0.81)
`0.70 (0.40–1.21)
`0.46 (0.26–0.83)
`
`0.0021
`nS
`0.0087
`
`EXE, months
`
`HR (95% CI)
`
`P-value
`
`2.8
`3.2
`3.2
`
`0.43 (0.35–0.54) ,0.0001
`0.44 (0.36–0.53) ,0.0001
`0.45 (0.38–0.54) ,0.0001
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`were stomatitis, rash, diarrhea, anorexia, and infection.21
`The overall incidence of serious adverse events was similar
`in the two treatment groups.21
`BOLERO-2 (NCT00863655),25 a randomized, inter-
`national, double-blind, placebo- controlled Phase III study,
`evaluated the safety and efficacy of everolimus 10 mg/day plus
`exemestane 25 mg/day compared with exemestane 25 mg/day
`alone in postmenopausal women with HR+, HER2− advanced
`breast cancer with recurrence or progression after previous
`therapy with letrozole or anastrozole.22 Patients were randomly
`assigned 2:1 to receive everolimus (n=485) or placebo (n=239),
`in addition to open-label exemestane, in a blinded manner.22
`Randomization was stratified according to the presence of vis-
`ceral metastasis (yes or no) and sensitivity to previous hormonal
`therapy (yes or no).22 The primary efficacy analysis, reported
`at a median follow-up of 7.1 months, resulted in an estimated
`57% risk reduction for progression-free survival (HR 0.43;
`95% CI 0.35–0.54; P,0.001, local assessment, Table 1).22 This
` corresponded to a clinically meaningful 4.1-month prolongation
`in median progression-free survival from 2.8 months to
`6.9 months.22 At a median follow-up of 12.5 months, a 56%
`reduction in risk of progression was identified (HR 0.44; 95%
`CI 0.36–0.53; P,0.0001, local assessment), corresponding to
`a 4.2-month prolongation in median progression-free survival
`from 3.2 months to 7.4 months (Table 1).23 Recently, at a median
`follow-up of 18 months, the median progression-free survival
`was 7.8 months compared with 3.2 months (HR 0.45; 95% CI
`0.38–0.54, P,0.001, local assessment), for the combination
`therapy versus exemestane only therapy (P,0.001).24 Central
`assessment of median progression-free survival at 7.1 months,
`12.5 months, and 18.0 months was consistent with local
`assessments.22–24 In addition, the objective response rate was
`significantly higher with combination therapy that with exemes-
`tane only therapy after 18 months of follow-up (12.6% versus
`1.7%; P,0.0001).26 Respectively, the most common grade 3
`or 4 adverse events were stomatitis (8% versus 1%), anemia
`(6% versus ,1% ), dyspnea (4% versus 1%), hyperglycemia
`(4% versus ,1%), fatigue (4% versus 1%), and pneumonitis
`(3% versus 0%) for everolimus plus exemestane compared
`with exemestane alone.22
`There has been a series of exploratory subanalyses of dif-
`ferent patient populations in the BOLERO-2 study. In patients
`younger than 65 years of age, everolimus plus exemestane was
`found to lower the risk of progression by 62% (HR 0.38; 95%
`CI 0.30–0.47) compared with exemestane alone.27 In patients
`$65 years of age, the risk of progression was reduced by 41%
`(HR 0.59; 95% CI 0.43–0.80).27 The improvement in median
`progression-free survival with everolimus plus exemestane
`
`in patients ,65 years of age and $65 years of age was 6.83
`months and 8.31 months, respectively.27 Also, an analysis of
`patients with visceral metastases showed that treatment with
`everolimus plus exemestane reduced the risk of progression
`by 53% in patients with visceral metastasis at baseline (HR
`0.47; 95% CI 0.37–0.60), whereas the risk reduction was 59%
`in those without baseline visceral metastasis (HR 0.41; 95%
`CI 0.31–0.55).28 Everolimus plus exemestane also reduced
`the risk of progression by 61% (HR 0.39; 95% CI 0.25–0.62)
`in patients who had recurrence after neoadjuvant or adjuvant
`therapy.29 Additionally, using the European Organization for
`Research and Treatment of Cancer Quality of Life Question-
`naire-Core 30 scale to evaluate patients’ health-related quality
`of life, the time to deterioration (ie, worsening) was longer
`with everolimus plus exemestane than with exemestane alone
`(8.3 months versus 5.8 months, P=0.0084).30
`A recent randomized, double-blind, placebo-controlled
`Phase II study demonstrated that continuation with everolimus
`10 mg/day was beneficial in patients with HER2− breast cancer
`and bone metastases.31 An exploratory analysis of the BOLE-
`RO-2 study showed that everolimus plus exemestane signifi-
`cantly lowered bone turnover marker levels at 6 and 12 weeks
`relative to baseline, irrespective of the presence or absence of
`baseline bone metastasis, whereas treatment with exemestane
`alone increased the levels of these markers.32 Even though
`progression of disease in bone was more severe in patients
`with baseline bone metastasis than in the overall population,
`progression in bone was significantly less severe in patients
`treated with everolimus plus exemestane than in those treated
`with exemestane alone.32 Patients with bone-only metastasis
`had a significant improvement in median progression-free
`survival with everolimus plus exemestane than with exemes-
`tane alone (12.88 months versus 5.29 months).28 Following
`these analyses, the long-term effects of mTOR inhibition with
`everolimus plus exemestane on bone health in postmenopausal
`women with HR+ locally advanced or metastatic breast cancer
`were assessed in the Phase IIIb, multicenter, open-label 4EVER
`study (NCT01626222).33 The preliminary results of 4EVER
`supported the findings of BOLERO-2, suggesting that everoli-
`mus provides a bone-protective effect that includes reduction of
`bone turnover and a reversal in the increased bone resorption
`associated with exemestane therapy.33
`Two additional ongoing Phase II studies investigating the
`efficacy and safety of everolimus combined with endocrine
`therapy in postmenopausal women with HR+ advanced or
`metastatic breast cancer are currently being conducted. The
`multicenter, open-label BOLERO-4 (NCT01698918)34 trial
`will assess the safety and efficacy of first-line therapy with
`
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`mtoR inhibitors in advanced breast cancer
`
`everolimus 10 mg/day plus letrozole 2.5 mg/day in postmeno-
`pausal women with ER+, HER2− metastatic breast cancer,
`and the beneficial effects of continuing everolimus plus
`endocrine therapy (exemestane 25 mg/day) beyond initial
`disease progression.35 The multicenter, open-label, random-
`ized BOLERO-6 (NCT01783444)36 trial is also underway
`and will compare the efficacy and safety of everolimus plus
`exemestane and everolimus or capecitabine monotherapy in
`postmenopausal women with HR+, HER2− advanced breast
`cancer who progressed on prior anastrozole or letrozole thera-
`py.37 These studies are expected to be completed in 2015, and
`their results should provide further evidence supporting the
`use of mTOR inhibitors, such as everolimus, in combination
`with endocrine therapy to improve outcomes in postmeno-
`pausal women with HR+, HER2− breast cancer.
`
`Conclusion and future directions
`Although the clinical trial with temsirolimus did not show
`any benefit, potentially because of issues related to dosing or
`patient selection, the clinical trials with everolimus and siroli-
`mus provide important insight into the clinical usefulness
`of targeting the mTOR pathway to enhance the efficacy of
`available hormonal therapies and to overcome or minimize
`endocrine resistance in breast cancer. Therefore, use of
`mTOR inhibitors might delay the need for chemotherapy.
`Despite clinical evidence demonstrating the clinical use-
`fulness of mTOR inhibitors in the treatment of patients with
`breast cancer, limited research has been done on identifica-
`tion of biomarkers that can be used to identify patients who
`are most likely to benefit from these agents. Recent results
`from a translational study of the TAMRAD trial indicated
`that the benefit derived from everolimus therapy was greater
`in patients with low PI3K, low liver kinase B1, or high phos-
`phorylated 4E binding protein 1 expression.38 Additionally,
`a retrospective exploratory biomarker analysis of the
`BOLERO-2 trial used next-generation sequencing to analyze
`numerous cancer-related genes and to determine if there were
`correlations between exon sequence or gene copy number
`variations and the efficacy of everolimus (ie, improvement in
`progression-free survival).39 The four most frequently altered
`genes/pathways were not predictive of everolimus efficacy
`when assessed individually, but a greater benefit from everoli-
`mus was seen in patients with minimal genetic alterations in
`the PIK3CA/phosphatase and tensin homolog/cyclin D1 or
`fibroblast growth factor receptor 1/2 genes combined (76%
`of the next-generation sequencing population).39 The findings
`of TAMRAD and BOLERO-2 provide useful information
`that may have important implications for the future clinical
`
`management of patients with breast cancer (ie, patient selec-
`tion and identification of combinations of novel targeted
`therapies). However, these results will need to be validated
`in prospective studies of independent patient cohorts.
`First-generation mTOR inhibitors, such as everolimus,
`appear to exert their inhibitory effects on the mTOR path-
`way by specifically targeting mTOR complex 1 (mTORC1)
`without binding to mTOR complex 2 (mTORC2).10 However,
`specific inhibition of mTORC1 by these agents may result in
`induction of prosurvival feedback loops, such as the PI3K-
`Akt pathway; this may explain why the antitumor activity
`of first-generation mTOR inhibitors is modest when admin-
`istered alone.10 This limitation of first-generation mTOR
`inhibitors has led to development of the second generation
`of mTOR inhibitors, which includes adenosine triphos-
`phate-competitive inhibitors that block both mTORC1 and
`mTORC2, as well as dual PI3K/mTOR inhibitors. Dual
`mTORC1/2 inhibitors currently in the early stages of clinical
`development include INK128, CC-223, OSI-027, AZD8055,
`AZD2014, and Palomid 529. However, caution should be
`taken with the use of second-generation mTOR inhibitors,
`because global inhibition of the PI3K/Akt/mTOR pathway
`may result in greater toxicity.
`With the US Food and Drug Administration approval of
`everolimus to treat postmenopausal women with advanced
`HR+, HER2− breast cancer in combination with exemestane
`after failure of treatment with letrozole or anastrozole,
`everolimus is the first and only targeted agent approved for
`combating endocrine resistance. Inhibiting mTOR when
`treating patients with HR+, HER2− breast cancer is expected
`to improve treatment outcomes and might help to maintain
`quality of life.
`
`Acknowledgments
`The author thanks Lauren D’Angelo, Janardhan Sampath,
`Matthew Grzywacz, and ApotheCom, Yardley, PA for
`their editorial and technical support (funded by Novartis
`Pharmaceuticals Corporation) in the development of this
`manuscript.
`
`Disclosure
`FA has received grant support from and is a member of
`the scientific advisory board for Novartis Pharmaceuticals
` Corporation. The author reports no other conflicts of interest
`in this work.
`
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`mtoR inhibitors in advanced breast cancer
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