Critical Reviews in Oncology/Hematology 94 (2015) 291–301
`
`Recent advances in the treatment of hormone receptor positive HER2
`negative metastatic breast cancer
`Palma Fedele a,∗
`, Laura Orlando a, Paola Schiavone a, Nicola Calvani a, Chiara Caliolo a,
`Annamaria Quaranta a, Angelo Nacci a, Saverio Cinieri a,b
`a Medical Oncology & Breast Unit, “A. Perrino” Hospital, Brindisi, Italy
`b Division of Medical Oncology, European Institute of Oncology, Milan, Italy
`Accepted 5 January 2015
`
`Contents
`
`3.
`
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1.
`2. Advances in the treatment of HR positive metastatic breast cancer before everolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.1.
`Polyendocrine therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.2.
`Targeting angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.3. Multitarget kinase inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.4. CDK4/6 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.5. HDAC inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Everolimus in the treatment of endocrine responsive breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.1. Mtor pathway and endocrine resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.2.
`Phase II studies: neoadjuvant and TAMRAD trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.3.
`Phase III trial: BOLERO2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.4.
`Translational studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`292
`292
`293
`293
`295
`295
`296
`296
`296
`296
`297
`298
`298
`298
`298
`299
`301
`
`Abstract
`
`Endocrine therapy is the recommended systemic therapy for hormone receptor (HR) positive metastatic breast cancer (MBC).
`However so far the limited number of endocrine agents and the onset of endocrine resistance have severely limited the therapeutic options
`for this patients.
`In the last years many targeted agents have been investigated to prevent or overcome endocrine resistance; only a few of them have been
`found effective in HR positive MBC, such as everolimus, CK4/6 inhibitors and HDAC inhibitors.
`Furthermore, translational medicine studies using next generation sequencing technologies have evaluated genetic variations of a broad
`panel of cancer-related genes and explored their correlations with targeted agents benefit. In some studies predictive biomarkers have been
`identified and many ongoing studies are evaluating the efficacy of targeted drugs in HR positive MBC patients selected for biomarkers or
`stratified by pathways amplification.
`© 2015 Elsevier Ireland Ltd. All rights reserved.
`
`Keywords: Targeted agents; Metastatic breast cancer; Endocrine therapy; Endocrine resistance; Next generation sequencing technologies
`
`∗
`
`Corresponding author at: Medical Oncology & Breast Unit, “A. Perrino” Hospital, S.S. 7 Appia, 72100 Brindisi, Italy. Tel.: +39 0831 537217;
`fax: +39 0831 537918.
`E-mail address: minafedele@hotmail.com (P. Fedele).
`
`http://dx.doi.org/10.1016/j.critrevonc.2015.01.001
`1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.
`
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`1. Introduction
`
`Endocrine therapy is the most important systemic therapy
`for hormone receptor (HR) positive advanced breast cancer.
`Patients who present minimal, asymptomatic, non-life-
`threatening disease,
`if estrogen receptor or progesteron
`receptor positive should receive hormonal therapy [1].
`However, intrinsic or acquired endocrine resistance is
`involved in the failure of endocrine therapy.
`Cross talk between estrogen receptor (ER) and growth fac-
`tor receptor pathways, which activate ER, has been identified
`as a mechanism associated with endocrine resistance [2–5].
`Over
`the past years many
`targeted agents, EGFR
`inhibitors, HER2
`inhibitors, PI3K/Akt/mTor
`inhibitors,
`histone deacetylases (HDAC) inhibitors, Src inhibitors, IGF-
`1R inhibitors, multitarget kinase inhibitors, antiangiogenic
`agents, CDK4/6 inhibitors have been investigated in phase
`II and III trials in order to overcome endocrine resistance
`and delay systemic chemotherapy for HR positive metastatic
`breast cancer (MBC) patients [6]. Among these, CDK4/6
`inhibitors and histone deacetylases inhibitors are particularly
`promising based on the results of phase II trials that have
`evaluated their efficacy in metastatic breast cancer patients
`as a first-line treatment or after progression to a previous
`nonsteroidal aromatase inhibitor therapy, respectively [7–9].
`Until now, from preclinical studies to phase III trials,
`everolimus has been found to be the most promising agent in
`the treatment of endocrine resistant breast cancer [10–13].
`Although the drug has been approved for the treatment
`of patients with metastatic breast cancer refractory to previ-
`ous treatment with nonsteroidal aromatase inhibitors, some
`aspects of the treatment with everolimus remain still unre-
`solved and will be further explored in future clinical trials
`
`1. What is the optimal management of everolimus toxicity
`or are there strategies to prevent it?
`2. Is there a role of everolimus in earlier lines of treatment
`(first line, adjuvant setting) or with other endocrine agents
`than exemestane?
`3. Should we give everolimus beyond progression
`metastatic breast cancer patients?
`4. How does everolimus compare to chemotherapy or to
`other endocrine agents than exemestane?
`
`in
`
`Furthermore, genomic sequencing
`investigations have
`evaluated the correlation between predictive biomarkers and
`targeted agents benefit. The results obtained so far with
`the next generation sequencing technologies studies have
`allowed us to identify subsets of patients most likely to bene-
`fit from targeted agents, such as in the case of everolimus and
`HDAC inhibitors, and to generate hypotheses on which to
`design future trials of targeted agents and endocrine therapy
`combinations.
`Herein, we focus on the updated findings in the treatment
`of hormone receptor (HR) positive, Her2 negative, metastatic
`breast cancer.
`
`Table 1
`Advances in the endocrine treatment of ER positive breast cancer in the last
`30 years.
`
`Year
`
`1980s
`1990s
`2000s
`
`2010s
`
`Adjuvant ET
`
`None
`Tam
`Aromatase inhibitors,
`Tam
`Aromatase inhibitors,
`Tam
`
`Metastatic ET
`
`Ovarian ablation, Tam
`Aromatase inhibitors
`Aromatase inhibitors,
`Fulvestrant, Tam
`Aromatase inhibitors,
`Fulvestrant, Tam,
`mTOR inhibitors,
`HDAC inhibitors,
`CK4/6 inhibitors
`
`Abbreviations: ET, endocrine therapy; Tam, Tamoxifene.
`
`2. Advances in the treatment of HR positive
`metastatic breast cancer before everolimus
`
`Metastatic breast cancer is an incurable disease, also if HR
`positive, with median overall survival of almost two years.
`Goals of systemic treatments in HR positive metastatic breast
`cancer are maximizing life quality, minimizing treatment
`related symptoms and impact on patients’ lifestyle, delay-
`ing initiation of chemotherapy [14,15]. Although a subset
`of patients with oligometastatic disease may benefit from an
`intensified locoregional approach, most patients with HR pos-
`itive metastatic breast cancer should receive systemic therapy.
`There are various factors to consider when choosing the most
`appropriate systemic treatment between chemotherapy and
`endocrine therapy: sites and extent of the disease, symptoms,
`disease free and treatment free intervals, patients’ perfor-
`mance status and preference. Non life-threatening disease, if
`hormone responsive, should receive first line endocrine ther-
`apy and in case of response, subsequent lines of hormonal
`therapy. Some of the limitations in the treatment of endocrine
`responsive MBC have been so far the lack of endocrine agents
`to administer in a sequential way and the difficult manage-
`ment of endocrine resistance.
`In fact, as shown in Table 1, there has been a limited
`progress in the endocrine treatment of metastatic breast can-
`cer in the last 30 years. In addition to tamoxifen that in the
`1980s was the first and the only drug for the treatment of
`endocrine positive breast cancer, aromatase inhibitors (AIs)
`were first introduced in the 1990s, while fulvestrant, which
`is the most recent endocrine treatment before everolimus,
`HDAC inhibitors and CK4/6 inhibitors dates back to the
`2000s.
`The occurrence of endocrine resistance has been so far
`one of the most important limitation of endocrine therapy and
`the most frequent reason for chemotherapy administration to
`endocrine positive disease.
`Endocrine resistance can occur de novo (before or imme-
`diately after any endocrine treatment is given) or can be
`acquired during the endocrine treatment, after an initial
`period of response. Several mechanisms of endocrine resis-
`tance have been identified [3]. The primary mechanism
`of the novo or intrinsic resistance to endocrine therapy
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`include deregulation of the ER pathways, such as down
`regulation of ER expression, ER mutations, altered expres-
`sion of ER coregulators. Alterations in cell cycle and in
`molecules involved in the cellular responses to endocrine
`therapies are associated with acquired endocrine resistance,
`such as cyclin amplification or overexpression. Finally, the
`crosstalk between growth factor receptor and estrogen recep-
`tor pathways may mediate the development of resistance to
`endocrine therapy and induce cancer cell growth bypassing
`the ER. For example, increased expression and activation of
`epidermal growth factor receptor (EGFR), human Erb B2
`(HER2), and insulin-like growth factor I (IGF-I) receptors
`drive the proliferation and survival of endocrine resistant
`breast cancer cells through the activation of their down-
`stream signaling pathway components, particularly MAPK
`and phosphoinositol-3-kinase [5].
`Studies that have explored first-line endocrine therapy
`with tamoxifen, anastrozole or fulvestrant in endocrine sen-
`sitive MBC patients (treatment-naive patients or who have
`responded to previous treatment with adjuvant tamoxifen)
`reported PFS between 8 and 11 months [16–18]. Less encour-
`aging were the results for those patients who had shown
`resistance to tamoxifen or to aromatase inhibitors, whose
`median PFS ranges between 3 and 6 months [19,20].
`But have we found the way to improve these results?
`In past years numerous studies have explored the role of
`targeted agents, such as EGFR inhibitors, Her2 inhibitors, Src
`inhibitors, IGF-1R inhibitors in endocrine resistant metastatic
`breast cancer patients. Among these the most promising
`were the EGFR inhibitor gefitinib and the dual EGFR-
`Her2 inhibitor lapatinib. However, the two phase II studies
`by Cristofanilli [21] and Osborne [22], that evaluated the
`potential benefit for combining gefitinib with endocrine ther-
`apy (anastrozole and tamoxifene, respectively) in unselected
`patients with ER positive metastatic breast cancer showed a
`little improvement in PFS and failed to define a central role
`of EGFR blockade to overcome endocrine resistance. In con-
`trast, lapatinib in combination with endocrine therapy was
`more effective in metastatic breast cancer patients with co-
`expression of ER and Her2 [23], whereas in the ER positive,
`Her2 negative population a potential benefit from the addi-
`tion of lapatinib to endocrine therapy were identified for those
`patients who relapsed during adjuvant tamoxifene therapy.
`More recently, several clinical trials have explored differ-
`ent strategies to improve endocrine therapy performance in
`endocrine responsive MBC; combining different endocrine
`agents (Table 2); targeting angiogenesis pathways; admin-
`istering multitarget kinase inhibitors, CDK4/6 inhibitors or
`HDAC inhibitors (Table 3).
`
`2.1. Polyendocrine therapy
`
`The role of polyendocrine therapy combining aromatase
`inhibitors and fulvestrant has been explored in the three dif-
`ferent phase III, randomized clinical trials FACT [25], SoFEA
`[26] e SWOG 0226 [27] (Table 2).
`
`FACT is a open-label study that compared fulvestrant and
`anastrozole in combination to anastrozole alone as first-line
`therapy for patients with receptor-positive postmenopausal
`breast cancer.
`SoFEA, a multicenter, partially blinded study, random-
`ized postmenopausal patients progressing on non steroidal
`AIs to fulvestrant plus anastrozole, fulvestrant plus placebo
`or exemestane alone. Patients should have responded to pre-
`vious non steroidal AIs in metastatic setting for more than 6
`months or received more than 12 months non steroidal AIs
`as adjuvant therapy.
`In the SWOG-S0226 trial, 707 patients with metastatic
`hormone receptor-positive breast cancer were randomized to
`receive anastrozole alone or a combination of anastrozole
`plus fulvestrant. In the three studies fulvestrant was adminis-
`tered intramuscularly, using a 500-mg loading dose on day 1
`followed by 250 mg on days 14 and 28, and 250-mg monthly
`thereafter.
`Of these three studies only the SWOG 0226 showed a sig-
`nificant benefit in PFS from the combination of anastrozole
`plus fulvestrant compared to anastrozole alone (median PFS
`was 15 months in the combination arm and 13.5 months in the
`anastrozole arm; HR, 0.80; 95% CI, 0.68 to 0.94; P = .007).
`However, unlike the other two trials, SWOG 0226 enrolled
`a greater proportion of endocrine-naive patients who were
`diagnosed with de novo metastatic disease. Moreover, the
`progression free survival analysis, according to subgroups,
`showed that patients who benefited most from polyendocrine
`therapy were those who had not received prior treatment with
`tamoxifen (PFS HR, 0.74; 95% CI, 0.59–0.92; P = 0.0055)
`and patients who had a disease free interval between diag-
`nosis and metastatic disease > 10 years. Instead, all patients
`included in the Sofea study had received prior treatment with
`AI and those patients reported a lower PFS.
`These studies suggest that patients who benefit more from
`polyendocrine therapy are those endocrine naive with de novo
`metastatic disease that represent a small proportion of HR
`positive MBC patients.
`
`2.2. Targeting angiogenesis
`
`Tumor angiogenesis plays a critical role in breast cancer
`growth, invasion and metastases.
`Different antiangiogenic agents have been investigating
`in preclinical and clinical breast cancer studies; such as
`the antivascular endothelial growth factor (VEGF) anti-
`body bevacizumab, the VEGF receptor antagonists sunitinib,
`sorafenib, pazopanib, axitinib and the multitargeted antian-
`giogenic tyrosine kinase inhibitors cediranib and vandetanib.
`Until now bevacizumab is the most studied and the only
`antiangiogenic agent approved for the first line treatment of
`Her2 negative MBC, outside the United States.
`Preclinical [28] and clinical studies [29] supported the
`concept that high VEGF levels in tumor tissues from breast
`cancer are associated with a decreased response to endocrine
`therapy. In addition the combination of endocrine therapy and
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`Table 2
`Randomized clinical trials combining different endocrine therapies in HR positive metastatic breast cancer patients.
`
`Study, phase
`
`SoFEA, III [26]
`
`FACT, III [25]
`
`SWOG 0226, III [27]
`
`Year
`
`2013
`
`2012
`
`2012
`
`No. of patients
`
`Prior ET exposure
`
`Treatment
`
`Primary endpoint (months)
`
`723
`
`514
`
`707
`
`Yes
`
`Yes, adjuvant
`
`Yes, adjuvant
`
`Fulv plus Ana
`Fulv plus placebo
`Exe
`
`Fulv plus Ana
`Ana
`
`Fulv plus Ana
`Ana
`
`PFS: 4.4
`4.8
`3.4
`
`TTP: 10.8
`10.2
`
`PFS: 15
`13.5
`
`Abbreviations: HR, hormone receptor; ET, endocrine therapy; Fulv, fulvestant; Ana, anastrozole; Exe, exemestane; PFS, progression free survival; TTP, time
`to progression.
`
`bevacizumab has shown to be active and safe in phase II trials
`in metastatic [29] or locally advanced breast cancer [30].
`Based on this data, the phase III LEA study [31,32]
`addressed the hypothesis that anti vascular endothelial growth
`factor (VEGF) treatment might delay resistance to endocrine
`therapy in patients with hormone receptor positive advanced
`breast cancer.
`The
`study
`randomized 380 metastatic or
`locally
`advanced BC patients to receive endocrine therapy with
`Letrozole 2.5 mg/day or Fulvestrant 250 mg/day every
`
`±
` Bevacizumab 15 mg/kg q3w. The combination
`28 days
`therapy failed
`to demonstrate a statistically significant
`increase in progression free survival that was 14.4 months
`in the endocrine therapy (ET) arm and 19.3 months in
`the endocrine therapy + bevacizumab (ET-B) arm P = 0.126;
`HR(95% CI) 0.83 (0.65–1.06) and in overall survival that was
`51.8 months in the ET arm, 52.1 in the ET-B arm P = 0.518;
`HR(95% CI) 0.87 (0.58–1.32). However, the addition of beva-
`cizumab to endocrine therapy resulted in significantly more
`hematologic and nonhematologic adverse events.
`
`Table 3
`Randomized clinical trials combining endocrine therapy with targeted agents in HR positive metastatic breast cancer patients.
`
`No of patients
`
`Prior ET exposure
`
`Treatment
`
`Primary endpoint (months)
`
`Tam
`Tam plus gefitinib
`Ana
`Ana plus gefitinib
`Let
`Let plus lapatinib
`
`Letrozole
`Letrozole plus Temsir
`Tam
`Tam plus everolimus
`Exe
`Exe plus everolimus
`
`Let or fulv
`Let or fulv plus bavacizumab
`
`Ana plus AZD8931 20 mg
`Ana plus AZD8931 40 mg
`Ana plus placebo
`Fulv
`Fulv plus cediranib
`
`Let
`Let plus palbociclib
`
`Exemestane
`Exe plus entinostat
`
`PFS: 8.8
`10.9
`PFS: 8.4
`14.7
`PFS: 3.0
`8.2
`
`PFS: 8.9
`9.0
`PFS: 4.5
`8.6
`PFS: 3.2
`7.8
`
`PFS: 14.4
`19.3
`
`PFS: 10.9
`13.8
`14
`PFS: 3.7
`7.4
`
`PFS: 10.2
`20.2
`
`PFS: 2.3
`4.3
`
`Study, phase
`
`EGFR inhibitors
`Osborne, II [22]
`
`Cristofanilli, II [21]
`
`Johnston, III [23]
`
`mTOR inhibitors
`Horizon, III [24]
`
`Tamrad, II [12]
`
`Bolero2, III [13]
`
`Year
`
`2011
`
`2010
`
`2009
`
`2013
`
`2012
`
`2012
`
`206
`
`93
`
`1286
`
`1112
`
`111
`
`724
`
`Yes
`
`Yes, adj
`
`Yes, adj
`
`Yes, adj
`
`Yes
`
`Yes
`
`Antiangiogenic agents
`Lea, III [31,32]
`
`2012
`
`380
`
`Yes, adj
`
`Multitarget kinase inhibitors
`2013
`Mint, II [36]
`
`Hyams, II [34]
`
`2013
`
`359
`
`62
`
`Yes, adj
`
`Yes
`
`CDK4/6 inhibitors
`Paloma-1, II [8]
`
`HDAC inhibitors
`Encore 301, II [9]
`
`2014
`
`165
`
`Yes, adj
`
`2013
`
`130
`
`Yes
`
`Abbreviations: ET, endocrine therapy; Tam, Tamoxifene; Fulv, fulvestant; ana, anastrozole; let, letrozole; exe, exemestane; Temsir, temsirolimus; PFS,
`progression free survival; adj, adjuvant.
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`The LEA study, like other studies on chemotherapy plus
`antiangiogenic agents combinations in metastatic breast can-
`cer [33], suggests that we need to improve the outcomes
`of antiangiogenic therapy identifying patients more likely
`to benefit from receiving antiangiogenic drugs using pre-
`dictive biomarkers, such as VEGF gene single nucleotide
`polymorphisms.
`
`2.3. Multitarget kinase inhibitors
`
`Several multitargeted tyrosine kinase inhibitors (TKI)
`have been recently evaluated in combination with and versus
`endocrine therapy in patients with metastatic breast cancer.
`However till now the advantage of this therapies over
`endocrine therapy alone in patients with HR positive HER2
`negative metastastic breast cancer remains largely unknown.
`On this regard the multitargeted antiangiogenic TKI cediranib
`(AZD2171) has shown to have limited activity and increased
`toxicity when combined with fulvestrant in endocrine respon-
`sive MBC patients [34].
`Same results came from the study that evaluated the mul-
`titargeted TKI AZD8931 [35]
`AZD8931 is a small molecule, reversible, equipotent
`inhibitor of EGFR, erbB2 and erbB3, showing, in preclinical
`studies, greater antitumor activity than agents like gefitinib
`or lapatinib.
`The activity of the drug has been evaluated in the phase
`II MINT trial [36], that was conducted in 359 HR positive
`HER2 negative postmenopausal MBC patients, endocrine
`naive, who were randomized to receive anastrozole combined
`with AZD8931 20 mg, 40 mg or placebo.
`Progression free survival outcome were respectively 10.9,
`13.8 and 14 months and the study failed to show that cotarget-
`ing of EGFR, HER2, HER3 pathways and endocrine therapy
`can delay endocrine resistance.
`
`2.4. CDK4/6 inhibitors
`
`CDK4 and CDK6 are kinases that, together with cyclin
`D1, regulate the passage of cells through the cell cycle [37].
`Preclinical studies have shown that breast cancer cells rely on
`CDK4 and CDK6 for division and growth and that selective
`CDK4/6 inhibitors can arrest the cells at this G1/S phase
`checkpoint.
`At least three CDK4/6 inhibitors are currently being eval-
`uated; LY2835219, LEE011 and PD0332991.
`Phase I trial of LY2835219, recently presented at the 2014
`American Association for Cancer Research (AACR) Annual
`Meeting, has demonstrated early activity in heavily pretreated
`women with metastatic breast cancer [38].
`Ribociclib, LEE011,
`is an orally available cyclin-
`dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4
`and cyclin D3/CDK6 cell cycle pathway. It specifically
`inhibits CDK4 and 6 and retinoblastoma (Rb) protein
`phosphorylation. Inhibition of Rb phosphorylation prevents
`CDK-mediated G1-S phase transition, thereby arresting the
`
`cell cycle in the G1 phase, suppressing DNA synthesis and
`inhibiting cancer cell growth. The phase I study [39] pre-
`sented at the AACR-NCI-EORTC International Conference
`on Molecular Targets and Cancer Therapeutics in October
`indicated
`that LEE011
`is effective against drug-
`2013,
`resistant breast cancer in combination with other targeted
`therapies. Based on this results the CDK4/6 inhibitor is cur-
`rently being tested in Phase II and Phase III. The Monaleesa-1
`trial is a phase II randomized pre-surgical pharmacodynamics
`study to assess the biological activity of LEE011 plus letro-
`zole versus single agent letrozole in primary breast Cancer.
`The phase III Monaleesa-2 trial [40] is a randomized double-
`blind, placebo-controlled study of LEE011 in combination
`with letrozole (2.5 mg/day) for the treatment of 500 post-
`menopausal women with hormone receptor positive, HER2
`negative, advanced breast cancer who received no prior ther-
`apy for advanced disease.
`Equally promising are the studies on the CDK4/6 inhibitor
`PD0332991(Palbocliclib).
`Palbociclib is an orally active drug that induces G0/G1
`arrest at the dose of 125 mg/day for 3 weeks of a 4-week cycle,
`as reported in the phase I study [41]. Preclinical research iden-
`tified factors associated with PD0332991 sensitivity: luminal
`ER expression, elevated expression of cyclin D1 and Rb pro-
`tein, and reduced p16 expression.
`The phase II Paloma-1 trial [8] shows that MBC patients
`receiving first line combination of palbociclib at 125 mg once
`daily plus letrozole at 2.5 mg once daily had a median PFS of
`20.2 months compared with a median of 10.2 months for
`patients treated with letrozole alone (hazard ratio = 0.488;
`P = .0004). The biomarker analysis showed that there was no
`significant difference in median progression-free survival for
`the women without gene alterations (26.1 months; HR, 0.299;
`P < .0001) and those with gene alterations (18.1 months; HR,
`0.508; P = .0046), when exposed to the combination of pal-
`bociclib plus letrozole. Median progression free survival was
`worse for those women without the gene alterations who
`received letrozole alone (5.7 vs. 11.1 months).
`Forty-three percent of patients in the combination arm had
`an objective response compared with 33% of patients in the
`control arm. Median overall survival, a secondary endpoint
`in this trial, was 37.5 months in the palbociclib arm compared
`with 33.3 months in the letrozole alone arm (P = 0.21). The
`safety profile was acceptable and manageable with uncom-
`plicated neutropenia, fatigue and anemia as the most frequent
`reported adverse events.
`These results have a large potential to impact patients
`with HR positive metastatic breast cancer. If confirmed in the
`ongoing phase III trials, a CDK4/6 inhibitor plus endocrine
`therapy could be a new standard of care.
`In fact, there are different ongoing phase III trials that are
`evaluating the role of the combination of CDK4/6 inhibitors
`plus endocrine therapy in HR positive metastatic breast can-
`cer patients. In addition to the Monaleesa-2 trial [40], that will
`evaluate the efficacy of LEE011 in combination with letro-
`zole, the Paloma-2 trial [42] is evaluating the combination of
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`
`palbociclib with letrozole and fulvestrant in late-stage MBC
`patients who have failed endocrine therapy. The Penelope-B
`trial [43] is exploring palbociclib in combination with stan-
`dard endocrine therapy in HR-positive breast cancer patients
`with residual disease after neoadjuvant chemotherapy.
`Moreover the open-label phase Ib/II study NCT01872260
`is assessing
`[44]
`the anti-tumor activity of
`the
`two
`double combination
`regimens with
`letrozole plus
`the
`CDK4/6
`inhibitor LEE011 versus
`letrozole plus
`the
`PI3K-alpha inhibitor BYL719 versus the triple combina-
`tion (LEE011 + BYL719 with letrozole) in patients with
`ER+/HER2 negative locally advanced or metastatic breast
`cancer.
`
`2.5. HDAC inhibitors
`
`Histone deacetylation is one of the mechanisms by which
`ER expression is regulated.
`In preclinical models HDAC inhibitors reverse hormone
`resistance in human ERα-negative breast cancer cells through
`the upregulation of ERβ
` expression or modulation of growth
`signaling pathways [45,46].
`The phase II Encore 301 study [9], conducted in women
`with advanced estrogen receptor–positive breast cancer fail-
`ing an aromatase inhibitor, showed that the addition of
`the HDAC inhibitors entinostat to exemestane improve the
`progression-free survival, the primary endpoint of the study
`(4.28 months with entinostat/exemestane vs. 2.27 months
`with exemestane alone; HR 0.73; 95% CI, 0.50 to 1.07,
`P = .055) and overall survival, that was an exploratory end-
`point (28.1 vs. 19.8 months; HR, 0.59; 95% CI, 0.36–0.97;
`P = 036). The regimen was well tolerated; the combination
`was associated with more grade 3/4 fatigue (13% vs. 2%),
`gastrointestinal toxicity (10% vs. 0%) and uncomplicated
`neutropenia (13% vs. 2%).
`The biomarker analysis of 49 patients showed that patients
`who presented hyperacetylation of lysines induced by HDAC
`inhibitors and measured in blood samples had a reduced risk
`of disease progression (median progression-free survival of
`8.54 months on the combination versus 1.92 months with
`exemestane plus placebo).
`We await results from ongoing confirmatory phase III trial
`E2112 [47] to better define the role of HDAC inhibitors in
`preventing or overcoming endocrine resistance in metastatic
`breast cancer and to confirm the change in protein lysine
`acetylation as biomarker of response.
`
`3. Everolimus in the treatment of endocrine