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` Annals of Oncology Advance Access published May 2, 2012
`
`review
`
`Annals of Oncology
`doi:10.1093/annonc/mds075
`
`mTOR inhibitors in the management of hormone
`receptor-positive breast cancer: the latest evidence and
`future directions
`C. Villarreal-Garza1, J. Cortes2, F. Andre3 & S. Verma4*
`1Department of Medical Oncology, Instituto Nacional de Cancerologia, Mexico DF, Mexico; 2Breast Cancer Unit, Vall d’Hebron Institute of Oncology, Vall d’Hebron
`University Hospital, Universitat Auto`noma de Barcelona, Barcelona, Spain; 3Breast Cancer Unit, Department of Medical Oncology, University Paris XI and Institut
`Gustave Roussy, Villejuif, France; 4Department of Medical Oncology, Sunnybrook Odette Cancer Centre, Toronto, Canada
`
`Received 18 December 2011; revised 6 March 2012; accepted 7 March 2012
`
`Background: There is an unmet therapeutic need in endocrine-resistant, hormone receptor (HR)-positive, human
`epidermal growth factor receptor 2-negative advanced breast cancer (BC). Preclinical studies support the hypothesis
`that the mammalian target of rapamycin (mTOR) inhibition could potentially overcome resistance to endocrine therapy.
`Materials and methods: A literature review regarding BC and mTOR inhibitors was undertaken. The reference lists
`from retrieved manuscripts were reviewed to identify further studies.
`Results: Phase II studies have reported that the combination of mTOR inhibitors with endocrine therapy shows
`efficacy in patients with advanced disease that progressed after treatment with aromatase inhibitors. The recent
`findings of the phase III BOLERO-2 confirmed that everolimus in combination with exemestane significantly improved
`progression-free survival and response rate, with a manageable safety profile.
`Conclusions: The addition of everolimus to exemestane for women with HR-positive metastatic BC is now
`considered a new therapeutic strategy. However, a word of caution should be added regarding toxic effects, which
`might limit practical use and compliance. It is essential that clinicians are educated about key recommendations for
`toxicity management and specific guideline dose modifications. Additional research efforts with the addition of these
`compounds in the early-stage setting is greatly needed to improve the survival of patients with HR-positive BC.
`Key words: breast cancer, endocrine resistance, everolimus, mTOR inhibitors, temsirolimus
`
`introduction
`
`Approximately three quarters of all invasive breast tumors are
`estrogen receptor (ER)- and/or progesterone receptor (PR)-
`positive, including at least half of all cancers in premenopausal
`women [1]. The natural history of hormone receptor (HR)-
`positive disease differs from that of HR-negative disease in
`terms of time to recurrence, site of recurrence, and overall
`aggressiveness of the disease. Compared with patients with ER-
`negative tumors, patients with ER-positive tumors experience
`a relatively constant hazard of recurrence over time [2, 3]. In
`women treated with tamoxifen for 5 years, more than half of all
`recurrences occur in years 6–15 after diagnosis [4]. Although
`tamoxifen and aromatase inhibitors (AI) lower the risk of
`recurrence for several years after they are stopped, late
`recurrences and deaths remain a major clinical challenge. In the
`metastatic setting, there are some patients with HR-positive
`disease who have durable response to antiestrogen therapy,
`
`*Correspondence to: Dr S. Verma, Department of Medical Oncology, Sunnybrook
`Odette Cancer Centre, T-Wing, 2nd Floor, 2075 Bayview Avenue, Toronto,
`ON M4N 3M5, Canada. Tel: +1-416-480-5248; Fax: +1-416-480-6002;
`E-mail: Sunil.verma@sunnybrook.ca
`
`although the majority of patients will have a short survival
`of <3 years. This review will focus on the management of HR-
`positive breast cancer (BC), the current standard of care, and
`the new evidence on use of mammalian target of rapamycin
`(mTOR) inhibitors in this setting.
`
`current management of HR-positive early BC
`
`The efficacy of adjuvant tamoxifen for women with ER-positive
`early BC has been clearly demonstrated (supplemental
`Appendix S1, available at Annals of Oncology online). Adjuvant
`tamoxifen treatment has been associated with a 31% reduction
`in the annual BC mortality rate among HR-positive women
`with early BC [4], making it a standard of care for this patient
`population. Guidelines suggest that selected patients could be
`treated with tamoxifen alone, especially those with low risk of
`recurrence [5–7]. However, with the advent of nonsteroidal
`AI—anastrozole and letrozole—and steroidal
`AI—exemestane—the standard of care has been evolving. AIs
`have demonstrated improved activity compared with tamoxifen
`for the adjuvant endocrine treatment of postmenopausal
`patients with HR-positive BC. AIs have been evaluated in
`different adjuvant endocrine settings: as upfront therapy,
`
`ª The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
`All rights reserved. For permissions, please email: journals.permissions@oup.com
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`switch to an AI after 2–3 years of tamoxifen or extended
`therapy following 5 years of tamoxifen.
`The various studies are consistent in demonstrating that
`the use of a third-generation AI in postmenopausal women
`with HR-positive BC lowers the risk of recurrence,
`including ipsilateral breast tumor recurrence, contralateral
`BC, and distant metastatic disease, compared with tamoxifen
`alone when the AI is used as initial adjuvant therapy,
`sequential therapy, or extended therapy. Thus, current
`international guidelines recommend that postmenopausal
`women with early BC receive an AI as initial adjuvant
`therapy, sequential with tamoxifen, or as extended therapy
`in those situations where endocrine therapy is to be
`utilized [7–9].
`
`first-line endocrine therapy for MBC
`
`aromatase inhibitors. Tamoxifen was established in the
`treatment of hormone-responsive metastatic breast cancer
`(MBC) based upon superior response and duration and
`favorable toxicity, when compared in randomized trials to
`high-dose estrogens, androgens, progestins, and the AI,
`aminoglutethimide, in postmenopausal patients
`(supplemental Appendix S2, available at Annals of Oncology
`online). The likelihood of response to tamoxifen is 65% in
`ER- and PR-positive tumors, 30% in ER- or PR-positive ones,
`and <5% in both ER- and PR-negative tumors [10].
`Tamoxifen has been recently displaced by third-generation
`AIs as first-line treatment of advanced HR-positive MBC,
`although double-blinded crossover trials showed no
`difference for either sequence in patients exposed to both
`treatments [11].
`Studies comparing tamoxifen versus AI in the first-line
`metastatic setting were largely conducted at a time when
`adjuvant AI use was uncommon. Two phase III double-blind
`trials compared tamoxifen versus anastrozole in the first-line
`setting for postmenopausal MBC [12, 13]. AI was superior to
`tamoxifen only in those patients with positive HR, with an
`advantage in median progression-free survival (PFS) (10.7
`versus 6.4 months, P = 0.022). A third trial showed a significant
`improvement in median time to progression (TTP) and overall
`survival (OS) in the anastrozole compared with the tamoxifen
`group [18.0 versus 7.0 months, hazard ratio = 0.13, P < 0.01
`and 17.4 versus 16.0 months, hazard ratio = 0.64, P = 0.003,
`respectively] [14].
`A single phase III study that compared letrozole versus
`tamoxifen in the first line setting showed a benefit in PFS
`compared with tamoxifen (9.4 versus 6.0 months) [15].
`Prospectively planned analyses of the intent-to-treat population
`showed that letrozole significantly improved OS compared with
`tamoxifen over the first 24 months of the trial. Exemestane has
`also been studied in the first-line treatment in the metastatic
`setting, and a phase III trial showed superior PFS to tamoxifen
`(9.9 versus 5.8 months); however, this did not translate to
`a longer term benefit in OS [16].
`Two meta-analyses of randomized trials of AIs compared
`with other endocrine therapy as first-line therapy showed
`a significantly superior OS [hazard ratio = 0.89, 95%
`confidence interval (CI) 0.8–0.9] favoring treatment with
`a third-generation AI [17, 18].
`
`2 | Villarreal-Garza et al.
`
`Annals of Oncology
`
`fulvestrant. Fulvestrant is an ER antagonist that has no agonist
`effects. As first-line therapy, fulvestrant (250 mg as a monthly
`injection, without the initial loading dose) has been compared
`with tamoxifen in a phase III non-inferiority trial [19]. The
`non-inferiority of fulvestrant was not established (hazard
`ratio = 1.18, 95% CI 0.98–1.44). A loading dose regimen was
`developed in order to produce a steady-state concentration of
`fulvestrant. The CONFIRM trial showed the superiority of
`high-dose fulvestrant (fulvestrant 500 mg monthly after the
`loading schedule versus fulvestrant 250 mg monthly) [20].
`These results prompted the Food and Drug Administration
`approval of fulvestrant 500 mg.
`FIRST is a phase II trial that evaluated fulvestrant 500 mg
`versus anastrozole as first-line treatment of HR-positive advanced
`BC [21]. Fulvestrant improved TTP compared with anastrozole
`(23.4 versus 13.1 months), (hazard ratio = 0.66; 95% CI 0.5–0.9).
`
`second-line endocrine therapy for MBC
`
`aromatase inhibitors. A lack of complete cross-resistance
`between steroidal and nonsteroidal AIs is supported by several
`studies showing clinical benefit (objective response or stable
`disease for >24 weeks) with exemestane after previous
`nonsteroidal AIs [22]. The opposite sequence was also
`investigated in patients receiving exemestane as first-line
`endocrine treatment: when crossed over to letrozole (n = 17) or
`anastrozole (n = 1) at the time of progression, 55.6% obtained
`a clinical benefit [23].
`
`fulvestrant. As second-line and subsequent therapy, fulvestrant
`(250 mg monthly, without the initial loading dose) appears to
`be as effective as anastrozole in postmenopausal patients with
`advanced tamoxifen-resistant BC, with no difference in TTP or
`OS [24–26]. Fulvestrant has also been compared with
`exemestane in patients whose BC recurred after prior AI
`therapy in the EFECT trial [27]. Here too, there was no
`significant difference between fulvestrant and exemestane for
`median TTP or OS.
`
`mechanisms of resistance to
`antiestrogen treatment
`
`The classic mechanism of action of ER is its nuclear function,
`also referred to as genomic activity, to alter the expression of
`genes important for normal cellular function and tumor growth
`and survival. The ER signaling pathway is also regulated by
`membrane receptor tyrosine kinases, including epidermal
`growth factor receptor (EGFR), human epidermal growth
`factor receptor 2 (HER2), and insulin-like growth factor
`receptor (IGF-1R) [28]. This activation of ER by growth factor
`receptor signaling is referred to as ligand-independent receptor
`activation. These membrane kinases activate signaling pathways
`that eventually result in phosphorylation of ER as well as its
`coactivators and corepressors at multiple sites to influence their
`specific functions [29].
`De novo and acquired resistance to endocrine therapy is
`a major clinical problem in the treatment of BC. Evidence is
`emerging to suggest both genomic and nongenomic
`mechanisms for cross talk in endocrine resistance despite the
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`presence of tamoxifen or AI. Different mechanisms are
`involved when BC cells adapt themselves to escape from the
`manipulations blocking the ER signaling, which includes
`EGFR/HER2, mitogen-activated protein kinase (MAPK),
`extracellular signal-regulated kinase (ERK) 1/2, and
`phosphatidylinositol-3-kinase/protein kinase B (Akt) pathways
`[30]. Estrogen-independent growth properties are mediated at
`least in part through the PI3K/Akt/mTOR pathway and that
`hyperactivation of this pathway account for survival of cells
`despite the presence of continued endocrine blockade.
`
`mTOR pathway
`
`The mTOR is a serine/threonine protein kinase and it is placed
`downstream of the PI3K/Akt pathway (Figure 1). The mTOR
`pathway is mainly involved in the regulation of cell growth and
`proliferation by controlling these processes at the translational
`
`level. It has two main downstream messengers: the ribosomal
`p70 S6 kinase (S6K1) and the eukaryotic translation initiation
`factor 4E-binding protein (4E-BP1) [31]. Both proteins are
`translational activators critical for ribosome biogenesis and
`translation, including the synthesis of proteins necessary for cell
`cycle progression. In addition to its effect on protein translation
`mediated by S6K1 and 4E-BP1, mTOR activation leads to the
`phosphorylation of several downstream effectors and
`transcription factors.
`The PI3K/Akt signaling pathway is dysregulated in a large
`number of human cancers, which in turn up regulates the
`downstream mTOR pathway [32]. Mutations in the catalytic
`domain of PI3K have been identified in 20%–25% of BCs [32,
`33]. Furthermore, 15%–35% of patients with BC have
`a reduced expression of PTEN (phosphatase and tensin
`homolog deleted on chromosome 10), an endogenous inhibitor
`of the PI3K/AKT pathway [34].
`
`Figure 1. PI3K/AkT/mTOR pathway and endocrine genomic and non-genomic cross talk. The PI3K/Akt/mTOR signaling network regulates proliferation,
`migration, cell survival, metabolism, and apoptosis. This network is dysregulated in BC enhancing translation and cellular proliferation. The mTOR proteins
`regulate activities of the translational regulators 4E-BP1 and S6K. mTOR-activated kinase S6K1 phosphorylates and destabilizes the insulin-receptor
`substrate 1 and 2 (IRS1 and IRS2). mTOR2 functions as an upstream regulator of Akt and delivers an additional stimulatory signal to mTOR1.
`Bi-directional cross talk between ER and growth factor receptors (e.g. HER2) mediate signaling via PI3K/Akt and MAPK pathways. These two pathways can
`directly phosphorylate genomic ER resulting in enhanced estrogen-regulated gene transcription. BC, breast cancer; ER, estrogen receptor; mTOR
`mammalian target of rapamycin; PI3k, phosphatidylinositol; PTEN, phosphatase and tensin homolog; S6K1, ribosomal protein S6 kinase; 4EBP1, 4E-
`binding protein.
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`Direct blockade of the mTOR pathway is a new and
`intriguing area in BC therapy, with the potential to modulate
`growth factor- and estrogen-dependent and estrogen-
`independent pathways, which contribute to the pathogenesis
`and progression of breast tumors.
`
`mTOR inhibitors in HR-positive BC
`
`preclinical data
`
`Preclinical studies have shown that BC cells with upregulated
`Akt signaling are resistant to hormonal therapy, but sensitivity
`may be restored by treatment with mTOR inhibitors [35, 36].
`Moreover, in models of estrogen-responsive BC, subnanomolar
`everolimus concentrations reduced the growth of BC cells in
`vitro, and enhanced antitumor activities were observed in
`combination with the AI, letrozole [37].
`
`mTOR inhibitors—neoadjuvant setting
`
`The safety and efficacy of everolimus as monotherapy was first
`evaluated in a preoperative pilot study in 31 postmenopausal
`patients with early BC (Table 1) [38]. Treatment with
`everolimus resulted in a significant 74% mean reduction in
`Ki67 from baseline (P = 0.019). The p-S6 staining was
`significantly reduced independently of Ki67 (P < 0.001). No
`data were reported on pathological response rate in these
`patients, which was not an end point in this pilot study.
`Baselga et al. [39] conducted a randomized, double-blinded
`phase II trial in 270 postmenopausal women with operable ER-
`positive BC. Patients 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 end
`point was clinical response by palpation. Biopsies were
`obtained at baseline and after 2 weeks of treatment. Response
`rate (RR) in the everolimus arm was higher than that with
`placebo (68% versus 59%, P = 0.062; one-sided a = 0.1 level).
`Reductions in phospho-S6 were seen only in the everolimus
`arm. An antiproliferative response, as defined by a reduction in
`Ki67 expression, occurred in 57% patients in the everolimus
`arm versus 30% in the placebo arm (P < 0.01). The use of early
`changes in Ki67 as an intermediate marker of neoadjuvant
`treatment has been addressed in other studies and has
`correlated positively with clinical and/or pathological response
`in early BC with hormone therapy and chemotherapy [40, 41].
`This study showed that everolimus increased the efficacy of
`letrozole in the treatment of newly diagnosed ER-positive BC in
`terms of both clinical and antiproliferative response.
`
`mTOR inhibitors—advanced BC
`
`temsirolimus. Baselga et al. [42] conducted a phase II study in
`92 women that compared the efficacy and safety of daily
`letrozole alone or in combination with daily temsirolimus
`(Table 2). Patients in the temsirolimus group had a longer PFS
`compared with those receiving letrozole alone (18.0 versus 9.5
`months, respectively).
`Given these results, a phase III, randomized double-blind
`trial evaluating temsirolimus in combination with letrozole in
`postmenopausal women with locally advanced or MBC was
`conducted [43]. Nine hundred and ninety-two women were
`
`4 | Villarreal-Garza et al.
`
`Annals of Oncology
`
`randomly assigned in a 1 : 1 ratio to receive oral temsirolimus
`(30 mg daily for 5 days every 2 weeks) or placebo in
`combination with letrozole. There were no differences in
`overall response rates (ORRs), clinical benefit rates (CBRs) and
`PFS between the two groups at the interim analysis, suggesting
`that the addition of temsirolimus to letrozole provided no
`improvement in clinical outcome in postmenopausal women
`with advanced BC or MBC.
`
`everolimus. TAMRAD phase II trial. TAMRAD is a phase II
`trial that enrolled 111 patients with HR-positive HER2-
`negative MBC who had previously received adjuvant therapy
`with an AI [44]. After stratification according to primary or
`secondary hormone resistance (determined by early or late
`progression after previous AI treatment), patients were
`randomly assigned 1 : 1 to receive either tamoxifen alone or
`in combination with everolimus (10 mg/day). The primary
`endpoint of the trial was CBR. In an exploratory analysis, the
`CBR was 42% for the tamoxifen group (TAM) and 61%
`(P = 0.045) for the tamoxifen/everolimus group (RAD/TAM)
`[45]. Similarly, TTP favored the combination group
`(4.5 versus 8.6 months; hazard ratio = 0.54, P = 0.0021), as
`did OS (hazard ratio = 0.45, P = 0.007).
`CBR differences were particularly increased in patients with
`secondary hormone resistance (44% for TAM versus 74% for
`RAD/TAM). Looking at TTP as a function of intrinsic hormone
`resistance, Bachelot noted that among patients with primary
`resistance, TTP was 3.8 months for TAM and 5.4 months for
`the combination (hazard ratio = 0.70, P = non significant).
`Among those with secondary hormone resistance, TTP was
`5.5 months for TAM and 14.8 months for RAD/TAM (hazard
`ratio = 0.46, P = 0.0087). OS was significantly better among
`patients with secondary resistance (hazard ratio = 0.73, P = 0.41
`versus hazard ratio = 0.21, P = 0.002).
`Based on these results, the investigators plan to conduct
`additional studies evaluating the combination of everolimus
`and hormonal therapy as a second-line option for women with
`HR-positive HER2-negative BC.
`
`BOLERO-2 phase III trial. BOLERO-2 is a phase III that
`enrolled 724 women postmenopausal women with advanced
`ER-positive HER2-negative BC who were refractory advanced
`BC (with recurrence or progression following prior therapy
`with letrozole or anastrozole) [47, 49]. After initial presentation
`during 2011 European Society of Medical Oncology conference,
`updated results were reported during San Antonio Breast
`Cancer Symposium 2011, with a median follow-up of 12.5
`months [48]. Patients were randomly allocated in a 2 : 1 ratio
`to receive everolimus 10 mg daily or placebo, with both arms
`receiving exemestane. The primary end point for the trial was
`PFS. No crossover after disease progression was allowed.
`Previous therapies included tamoxifen, fulvestrant, and one
`chemotherapy regimen. By protocol definition, 84% of patients
`had previous sensitivity to hormonal therapy (response or long
`stabilization in the metastatic setting or at least 2 years of
`adjuvant therapy).
`The trial was stopped early after the February 2011
`prespecified interim analysis found a significantly better PFS by
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`local assessment for the combined therapy group: median 7.4
`versus 3.2 months (hazard ratio = 0.44, P < 1 · 10216). Based
`on central assessment, everolimus increased median PFS from
`4.1 to 11.0 months (hazard ratio = 0.36, P < 1 · 10216). The
`consistency of the treatment effect was observed in each of all
`these prospectively defined subgroups with an estimated hazard
`ratio ranging from 0.25 to 0.60. Overall RR and CBR were
`significantly greater in the combination group (12% versus 1%,
`P < 0.0001 and 51% versus 26%, P < 0.0001, respectively).
`Survival was immature at the time of the interim analysis with
`a total of 83 deaths: 11% in the combination arm and 13% in
`the exemestane arm. Although grade 3–4 side-effects were more
`often in the combination arm, this did not translate into
`differences in quality of life.
`This is the first, large phase III study of a targeted agent,
`everolimus, which, in combination with endocrine therapy,
`reported significantly improved PFS, RR, and a manageable
`safety profile. The trial results were reported earlier than
`expected at the first interim analysis as the outcome of
`combination had exceeded the prespecified PFS threshold for
`significance. As a result, OS data are still immature and are
`eagerly anticipated.
`The discordant results between the temsirolimus and
`everolimus trials are not well understood. One reason that
`might explain this is that population was different between
`both studies: the temsirolimus trial included only endocrine
`treatment-naive patients, while the everolimus population
`was composed of patients refractory to a previous treatment
`with AI. In addition, the different outcomes seen between
`studies might be due that temsirolimus was not bioactive
`enough in the study due to a high rate of toxic effects: grade
`3–5 adverse events occurred in 37% versus 11% in the
`temsirolimus and everolimus groups, respectively [43, 49].
`
`sirolimus in MBC. Bhattacharyya et al. [46] recently presented
`the results of a trial that evaluated the addition of tamoxifen
`(TAM) to sirolumus (SIR) in HR-positive HER2-negative
`MBC. The study was done in two groups including 400
`patients: (i) prior exposure to AIs or failed on TAM within
`6 months and (ii) no prior exposure to AIs. The primary
`end points were RR and TTP. The results of the group 1
`showed RR of 4% versus 39% (P = 0.00018) and TTP was 3.3
`versus 11.7 months (hazard ratio = 0.43, P = 0.0023), for
`TAM and TAM/SIR, respectively. Notably, for those patients
`who progressed within 6 months, the magnitude of this effect
`was lower (TTP 2.2 versus 7.4 months, hazard ratio = 0.62,
`P = non significant). For group 2, RR was 33% versus 76%
`(P = 0.0043) and TTP was 9.0 versus 16.0 months (hazard
`ratio = 0.48, P = 0.0028). The conclusion of this study is that
`combination treatment increased RR and TTP while showing
`a greater quality of life adjusted for survival.
`
`biomarkers
`
`Two mTOR activation biomarkers were assessed in 35 patients
`in the primary tumor in the TAMRAD study. pS6K and 4EBP1
`are downstream effectors of the mTOR pathway: pS6K is
`upregulated and 4EBP1 is downregulated by mTOR. Patients
`with high pS6K expression and low 4EBP1 expression showed
`
`doi:10.1093/annonc/mds075 | 5
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`BC,breastcancer;ER,estrogenreceptor;mTOR,mammaliantargetofrapamycin.CR,completeresponse;PR,progressivedisease.
`
`30%;PD:4.3versus9.8%
`50%;Nochange:25versus
`versus9.1%;PR:55versus
`versusplacebo):CR:13%
`
`palpation
`
`Response(everolimus
`
`Responseratebyclinical
`
`placebofor4months
`NeoadjuvantLetrozole+
`Everolimusversus
`
`NeoadjuvantLetrozole+
`
`neoadjuvanttherapy
`BC,eligiblefor
`previouslyuntreatedER+
`
`USA/Europe
`controlled,multicenter
`
`(phaseII)
`
`etal.,2009[39]
`
`Postmenopausal,with
`
`Doubleblind,placebo-
`
`270
`
`NCT00107016
`
`Baselga
`
`(P=0.019)
`Ki67(74%)frombaseline
`significantreductionin
`
`surgery
`biopsiesatdiagnosisand
`
`surgery
`for14daysbefore
`
`earlyBCsomelevelofER+
`
`Everolimusresultedin
`
`PercentreductioninKi67in
`
`Everolimus(5mgdaily)
`
`Postmenopausal,operable
`
`Onearm
`
`31
`
`Pilotstudy
`
`Response/Efficacy
`
`Primaryendpoint
`
`Treatment
`
`Patients
`
`Studydesign
`
`n
`
`Trial
`
`etal.,2011[38]
`
`Macaskill
`
`Reference
`
`Table1.ClinicalstudiesofmTORinhibitorsinHR-positiveBCintheneoadjuvantsetting
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`PFS: 13.2 versus 11.5 versus
`11.6 months; ORR: 40%
`versus 33% versus 45%
`
`PFS: 9.2 versus 9.2 months;
`ORR: 24% versus 24%
`
`CBR: 61.1% versus 42.1%
`(P = 0.045); TTP: 8.6
`versus 4.5 months, hazard
`ratio = 0.54 (P = 0.0021);
`OS: hazard ratio = 0.45
`(P = 0.007); TTP in
`primary resistance: 5.4
`versus 3.8 months,
`hazard ratio = 0.70
`(P = non significant); OS
`in primary resistance:
`hazard ratio = 0.73
`(P = 0.41); TTP in
`secondary resistance: 14.8
`versus 5.5 m, hazard
`ratio = 0.46 (P = 0.0087);
`OS in secondary resistance:
`hazard ratio = 0.21
`(P = 0.002)
`Group 1: RR: 38.8% versus
`4.1% (P = 0.00018); TTP:
`11.7 versus 3.3 months,
`hazard ratio = 0.43
`(P = 0.0023); TTP in
`primary resistance: 7.4
`versus 2.2 months, hazard
`ratio = 0.62 (P = non
`significant); Group 2: RR:
`75.6% versus 32.7%
`(P = 0.0043); TTP: 16
`versus 9 months, hazard
`ratio = 0.48 (P = 0.0028)
`
`Bhattacharyya
`et al., 2011 [46]
`
`Phase II
`
`400
`
`Randomized
`
`ER+, PR+, HER2; Group 1:
`prior exposure to AIs or
`failed on TAM within 6
`months; Group 2: no prior
`exposure to AIs
`
`Tamoxifen +
`Sirolimus versus
`Tamoxifen
`
`RR and TTP
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`PFS
`
`PFS
`
`CBR
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`Table 2. Clinical studies of mTOR inhibitors in HR-positive BC in the metastatic setting
`
`Reference
`
`Trial/Phase
`
`Baselga, et al., 2005 [42]
`
`Phase II
`
`Chow, et al., 2006 [43]
`
`NCT00083993
`(Phase III)
`
`Bachelot, et al., 2010 [44]
`and Bourgier,et al.,
`2011 [45]
`
`TAMRAD
`(Phase II)
`
`n
`
`92
`
`992
`
`111
`
`Study design
`
`Randomized
`phase II
`
`Patients
`
`Randomized,
`double-blind,
`placebo-controlled
`multicenter global
`Randomized
`
`Postmenopausal,
`with locally advanced or
`metastatic BC, first-line
`metastatic
`ER+, PR+, HER22;
`Resistance to AIs
`
`Treatment
`Letrozole + Temsirolimus
`30 mg versus Letrozole +
`Temsirolimus 10 mg versus
`Letrozole
`Letrozol + Temsirolimus
`versus Letrozole + Placebo
`
`Tamoxifen + Everolimus
`versus Tamoxifen
`
`6 | Villarreal-Garza et al.
`
`Primary end point
`
`Response/Efficacy
`
`Ex. 1080-0006
`
`

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` by guest on October 30, 2016
`
`review
`
`the greatest benefit for TTP as a function of biomarker
`expression. These preliminary results of translational analysis
`show a possible correlation between biomarkers of mTOR
`activation and everolimus efficacy.
`
`mTOR resistance
`
`Two key regulatory loops have been described that may limit
`the effectiveness of drugs that have been developed to target
`mTOR in cancer [32]. The mTOR-activated kinase S6K1
`phosphorylates and destabilizes the insulin-receptor substrate
`1 and 2 (IRS1 and IRS2) proteins in insulin-like growth factor
`(IGF)-responsive cells [50]. mTOR inhibition can block the
`negative feedback on IGF-1R signaling interfering on AkT/
`PI3K signaling. The result is an increase in Akt
`phosphorylation, protein kinase activity, and downstream
`signaling, which could potentially counteract the inhibition of
`mTOR [31]. Thus, concern has been raised that loss of this
`negative feedback loop may overcome the antitumor
`effectiveness of mTOR blockade and limit their effectiveness
`[51]. Based on preclinical models, dual inhibition of both
`IGF-1R (with either monoclonal antibodies or tyrosine kinase
`inhibitors) and mTOR results in a superior antiproliferative
`effect over each single strategy, and this combination is now
`under evaluation in phase II trials in patients with BC
`[31, 52].
`In addition, a positive regulatory loop exists involving the
`mTOR2 complex that is activated directly by growth factors
`[53]. In contrast to mTOR1, the mTOR2 complex
`phosphorylates Akt directly, and this is thought to be required
`for full activation of the Akt pathway by mitogenic signals. As
`such, mTOR2 complex functions as an upstream regulator of
`Akt and delivers an additional stimulatory signal to mTOR1.
`However, rapamycin analogs that target mTOR proteins appear
`to specifically only block the mTOR1 complex and do not
`inhibit the mTOR2 complex [54, 55].
`
`toxicity and practical implications
`
`management of toxic effects
`
`The main toxic effects associated with the use of mTOR
`inhibitors are stomatitis, pneumonitis, and metabolic
`abnormalities, as shown in Table 3. These toxic effects can
`influence the practical use of this class of drugs and compliance.
`Since temsirolimus [56] and everolimus [57, 58] have been
`approved for the treatment of metastatic renal cell carcinoma
`since 2007 and 2008, respectively, most of the experience in the
`management of toxic effects related to this compounds come
`from these studies. Recently, an expert group published the
`guidance for management of selected adverse effects associated
`with the use of everolimus for the treatment of metastatic renal
`cell carcinoma [59]. As we integrate these agents in BC, it is
`critical that clinicians are educated about these key
`recommendations and specific guideline modifications. Some
`of the key issues are summarized below:
`
`stomatitis. The efficacy of specific topical corticosteroids and
`mouthwashes in the treatment of chemotherapy-induced
`stomatitis has been reviewed extensively and may be applicable
`
`doi:10.1093/annonc/mds075 | 7
`
`PFS,progression-freesurvival;PR,progesteronereceptor;RR,responserate;TTP,timetoprogression.
`BC,breastcancer;CBR,clinicalbenefitrate;ER,estrogenreceptor;PR,progesteronereceptor;HER2,humanepidermalgrowthfactorreceptor2;mTOR,mammaliantargetofrapamycin;OS,overallsurvival;
`
`Annals of Oncology
`
`0.36(P<1·10216)
`versus4.1,hazardratio=
`Centralassessment:11.0
`0.44(P<1·10216);PFS
`versus3.2,hazardratio=
`
`PFSLocalassessment:7.4
`
`PFS
`
`Response/Efficacy
`
`Primaryendpoint
`
`Exemestane
`
`Everolimusversus
`
`Exemestane+
`Treatment
`
`anastrozole
`Resistancetoletrozoleor
`ER+,PR+,HER22;
`Patients
`
`blind
`
`Randomized,double
`
`Studydesign
`
`724
`
`n
`
`(PhaseIII)
`
`BOLERO-2
`
`Trial/Phase
`
`2011[39,47,48]
`
`Baselgaetal.,
`
`Reference
`
`Table2.(Continued)
`
`Ex. 1080-0007
`
`

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`
` by guest on October 30, 2016
`
`Annals of Oncology
`
`to patients treated with everolimus [60, 61]. The main
`preventive measurements include good oral hygiene, treatment
`of anticipated infectious foci, and avoidance of alcohol- or
`peroxide-containing products, as they may exacerbate the
`condition. In addition, patients should be evaluated for herpes
`and fungal infections, with institution of an antiviral agent or
`an antifungal agent as appropriate.
`
`interstitial pneumonitis. In patients with baseline respiratory
`symptoms or in patients with documented multiple lung
`metastases, a computed tomography scan and lung function
`tests, and arterial oxygen saturation should be carried out
`before everolimus is initiated. A temporary treatment
`interruption may be considered if symptoms are moderate or
`severe; following resolution of symptoms, everolimus may be
`reinitiated at a reduced dosage of 5 mg/day.
`The extent to which prior chest radiation increases the risk of
`mTOR inhibitor-induced noninfectious pneumonitis is
`unclear. A clinical study of patients with metastatic or recurrent
`BC showed prominent radiological findings ipsilateral to
`previous adjuvant radiation fields [62], which suggests that
`previous radiotherapy may be an influencing factor for
`developing everolimus-associated pneumonitis.
`
`metabolic abnormalities. Mild metabolic abnormalities can be
`managed routinely without treatment interruption.
`Intervention at the grade 2 level is recommended, with the
`extent of intervention dependent on the specific metabolic
`abnormality. Patients with underlying diabetes require careful
`monitoring and, potentially, modifications to their
`antihyperglycemic regimen. Optimal glycemic control before
`everolimus initiation is mandated since hyperglycemia
`primarily occurs in patients with abnormal p