8 Diabetic coma: A reappraisal after five years

Cancer Treatment Reviews xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

New Drugs

Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer Eva Maria Ciruelos Gil ⇑ Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain

a r t i c l e

i n f o

Article history: Received 18 December 2013 Received in revised form 14 March 2014 Accepted 17 March 2014 Available online xxxx Keywords: Luminal type Breast cancer Phosphatidylinositol 3-kinase PI3K AKT Mammalian target of rapamycin mTOR Estrogen receptor Endocrine therapy Endocrine resistance

a b s t r a c t Approximately 70 75% of breast cancers express the estrogen receptor (ER), indicating a level of dependence on estrogen for growth. Endocrine therapy is an important class of target-directed therapy that blocks the growth-promoting effects of estrogen via ER. Although endocrine therapy continues to be the cornerstone of effective treatment of ER-positive (ER+) breast cancer, many patients with advanced ER+ breast cancer encounter de novo or acquired resistance and require more aggressive treatment such as chemotherapy. Novel approaches are needed to augment the benefit of existing endocrine therapies by prolonging time to disease progression, preventing or overcoming resistance, and delaying the use of chemotherapy. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a key intracellular signaling system that drives cellular growth and survival; hyperactivation of this pathway is implicated in the tumorigenesis of ER+ breast cancer and in resistance to endocrine therapy. Moreover, preclinical and clinical evidence show that PI3K/AKT/mTOR pathway inhibition can augment the benefit of endocrine therapy in ER+ breast cancer, from the first-line setting and beyond. This article will review the fundamental role of the PI3K/AKT/mTOR pathway in driving ER+ breast tumors, and its inherent interdependence with ER signaling. In addition, ongoing strategies to combine PI3K/AKT/mTOR pathway inhibitors with endocrine therapy for improved clinical outcomes, and methods to identify patient populations that would benefit most from inhibition of the PI3K/AKT/mTOR pathway, will be evaluated. Ó 2014 Elsevier Ltd. All rights reserved.

Introduction Breast cancer is a heterogeneous disease, presenting as several diverse clinical and histologic varieties. Approximately 70 75% of breast cancers express estrogen receptor a (ERa), and are considered ER-positive (ER+) [1–3], indicating some level of estrogen dependence for tumor growth. This provides a rationale for ER-targeted therapy for these patients. Endocrine therapies block the growth-promoting effects of estrogen via the ER through several different mechanisms, and comprise the following major classes: (1) selective ER modulators (e.g. tamoxifen), which have dual agonistic/antagonistic effects on ER transcription, depending on the tissue; (2) selective ER downregulators (e.g. fulvestrant), which downregulate expression of the ER; (3) aromatase inhibitors (e.g. letrozole, anastrozole, exemestane), which inhibit estrogen biosynthesis in postmenopausal patients; and (4) gonadotropin-releasing

⇑ Tel.: +34 659 228 621; fax: +34 914 603 310. E-mail address: [email protected]

hormone analogs, which inhibit estrogen biosynthesis in premenopausal patients. Endocrine therapy was the first class of target-directed therapy approved for the treatment of breast cancer, and continues to be the cornerstone of treatment for ER+ breast cancer due to its effectiveness and favorable toxicity profile [2,3]. Despite this, not all patients with advanced ER+ breast cancer derive benefit from endocrine therapy and many encounter either no response initially, or, more probably, experience eventual disease progression following an initial response. Overall, an estimated 20–40% of patients with advanced ER+ breast cancer respond to endocrine therapy, with a median duration of response of approximately 8– 14 months [4]. Upon disease progression, treatment options include other classes of endocrine therapies, chemotherapy, and/ or treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with the aromatase inhibitor exemestane [5]. New approaches are needed to increase the efficacy and extend the use of existing endocrine treatments in order to improve patient outcomes. Such new approaches would augment the benefit of existing endocrine therapy by prolonging time

http://dx.doi.org/10.1016/j.ctrv.2014.03.004 0305-7372/Ó 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.03.004

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E.M. Ciruelos Gil / Cancer Treatment Reviews xxx (2014) xxx–xxx

to disease progression, preventing or overcoming resistance to endocrine treatment, and delaying the use of chemotherapy. The potential of phosphatidylinositol 3-kinase (PI3K)/AKT/ mTOR pathway inhibition to enhance clinical response and extend the duration of endocrine therapy is currently the focus of many preclinical and clinical studies. The PI3K/AKT/mTOR pathway is a key intracellular signaling system that drives cellular growth and survival. Hyperactivation of this pathway is implicated in the tumorigenesis of ER+ breast cancer [6–14] and resistance to endocrine therapy [15–19]. This article will review the fundamental role of the PI3K/AKT/ mTOR pathway in driving ER+ breast tumors, and the inherent interdependence with ER signaling. In addition, strategies to combine pathway inhibitors with endocrine therapy for improved patient outcome, and methods to identify patient populations that would benefit most from inhibition of the PI3K/AKT/mTOR pathway will be evaluated. The PI3K/AKT/mTOR pathway in ER+ breast cancer PI3K/AKT/mTOR pathway signaling drives cellular growth and survival The PI3K/AKT/mTOR pathway plays a crucial role in multiple cellular processes, including proliferation, growth, and survival (Fig. 1), and is the focus of several recent comprehensive reviews [20–24]. The PI3K protein family is a group of signaling enzymes that are activated in response to growth factor receptor tyrosine kinases (RTKs) and G-protein-coupled receptor signaling. They are most potently activated by the insulin receptor tyrosine kinase (InsR) and the related insulin-like growth factor 1 receptor (IGF-1R) [25]. The PI3K protein family comprises 3 classes of lipid kinase that catalyze the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). Class IA PI3Ks are the most frequently implicated in human cancer, and are found as heterodimers of a regulatory and a catalytic subunit. Several isoforms have been described for each subunit: three catalytic subunit isoforms (p110a, p110b, and p110d), and five regulatory subunit isoforms (p50a, p55a, p55c, p85a, and p85b). PIP3, the product of PI3K catalytic activity, is an important transmitter of cellular signaling that functions to activate downstream signaling components, such as phosphoinositide-depen-

dent kinase 1 (PDK1) and AKT, by directly binding their pleckstrin homology domain. PDK1 binds PIP3 at the plasma membrane and phosphorylates AKT, which is then free to phosphorylate numerous targets in the nucleus and cytoplasm, thereby promoting cellular growth, proliferation, and angiogenesis, and preventing apoptosis. Through negative regulation of the tuberous sclerosis (TSC) complex (TSC1 and TSC2), activated AKT stimulates the mTORC1 complex, a key regulator of cellular growth and protein synthesis that includes mTOR and a regulator binding partner, raptor. In addition, AKT phosphorylates Mdm2, a protein that binds to and blocks the activation of the p53 tumor suppressor protein, and negatively regulates the pro-apoptotic Bcl-2 family members BAD and BAX and forkhead transcription factors such as FOXO to promote cell survival. The enzymatic activity of PI3K is antagonized by the phosphatase and tensin homolog (PTEN), a protein that catalyzes the dephosphorylation of PIP3, and by inositol polyphosphate-4phosphatase type II (INPP4B), a protein that catalyzes the dephosphorylation of PIP2. The PI3K/AKT/mTOR pathway is frequently altered in ER+ breast cancer Many of the protein components of the PI3K/AKT/mTOR pathway are encoded by oncogenes or tumor suppressor genes, depending on whether they activate or suppress pathway signaling. In breast cancer, PI3K/AKT/mTOR is the most frequently activated signaling pathway [15], and pathway activation promotes tumor growth [24] and progression [14]. Furthermore, alterations in the genes encoding several nodes of the PI3K/AKT/ mTOR pathway are frequently found in ER+ breast cancer (Table 1). These include activating mutations or amplifications in the genes encoding IGF-1R and InsR (41–48% of ER+ breast cancers) [12,13], p110a PI3K (28–47%) [6–10,18], PDK1 (22%) [15,26], human epidermal growth factor receptor 2 (HER2; 10%) [27,28], and AKT1 (2.6–3.8%) [7,29,30], and loss of function or reduced expression of the genes encoding PTEN (29–44%) [6,10,14,19], and INPP4B (8.4–37.7%) [31,32]. Mutations in PIK3CA, the gene encoding p110a PI3K, are more common in ER+ breast cancer than in any other breast cancer subtype. These mutations occur early and are selected for in the

Fig. 1. PI3K/AKT/mTOR and ER pathway cross-talk.

Please cite this article in press as: Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.03.004

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E.M. Ciruelos Gil / Cancer Treatment Reviews xxx (2014) xxx–xxx Table 1 Frequency of genetic alterations of the PI3K/AKT/mTOR pathway in ER+ breast cancer. Gene (protein)

Effect on signaling

Frequency in ER+ breast cancer (%)

Activating mutations or amplifications IGF1R (IGF-1R) and INSR (InsR) [12,13] PIK3CA (p110a PI3K) [6–10,18] PDK1 (PDK1) [15,26] ErbB2 (HER2) [27,28] AKT1 (AKT1) [7,29,30]

Activation of IGF-1R/InsR signaling (upstream of PI3K) Hyperactivation of PI3K signaling Hyperactivation of PDK1 signaling (upstream of AKT) Hyperactivation of HER2 signaling Hyperactivation of AKT1 signaling

41–48 28–47 22 (of all breast tumors) 10 2.6–3.8

Loss-of-function mutations or reduced expression PTEN (PTEN) [6,10,14,19] INPP4B (INPP4B) [31,32]

Hyperactivation of PI3K signaling Hyperactivation of PI3K signaling

29–44 8.4–37.7

HER2, human epidermal growth factor receptor 2; IGF-1R, insulin-like growth factor 1 receptor; INPP4B, inositol polyphosphate-4-phosphatase type II; InsR, insulin receptor tyrosine kinase; mTOR, mammalian target of rapamycin; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog.

progression of ER+ breast cancer [33,34]. The frequency of alterations in the PI3K/AKT/mTOR pathway in ER+ breast cancer tumors implies an important role for PI3K signaling in the maintenance of ER+ breast cancer. The PI3K/AKT/mTOR and ER signaling pathways intersect at multiple junctures and display a high level of interdependence There is significant cross-talk between the PI3K/AKT/mTOR pathway and the ER pathway, with direct and indirect interaction occurring at multiple nodes within each pathway (Fig. 1). Activation of the ER signaling pathway by PI3K/AKT/mTOR Signaling through the PI3K/AKT/mTOR pathway activates estrogen-independent ER transcriptional activity [35–37], thereby promoting cellular proliferation in the absence of estrogen (e.g. during aromatase inhibitor treatment) [38,39]. This occurs through the direct phosphorylation of ERa at serine 167 by either AKT or S6 kinase 1 (S6K1; a downstream effector of mTOR) [35,36]. In addition, Ras/PI3K/AKT signaling (through c-Jun phosphorylation) activates the activator protein 1 transcription factor, which cooperates with ER transcriptional activity [37]. Activation of the PI3K/AKT/mTOR signaling pathway by ER The ER promotes the transcription of several genes that encode upstream effectors of the PI3K/AKT/mTOR pathway, including receptor ligands, RTKs, and signaling adaptors [15,37]. There is also evidence for activation of the PI3K/AKT/mTOR pathway though extranuclear ER signaling. For example, estrogen-bound ERa activates PI3K/AKT signaling in cells by directly binding to the p85a regulatory subunit of PI3K [40]. In addition, estrogen stimulation in cells activates PI3K signaling through IGF-1R. This was shown to increase pAKT levels and the interaction between p85 PI3K and the IGF-1R effector insulin receptor substrate 1 (IRS-1) [41]. In patients with ER+ breast cancer, treatment with the aromatase inhibitor letrozole has been shown to reduce tumor levels of PI3K and the phosphoproteins pmTOR and pS6 [18,42]. Thus, estrogen deprivation may be effective in decreasing PI3K/AKT/ mTOR pathway signaling [37]. Hyperactivation of PI3K/AKT/mTOR signaling as a potential mechanism of resistance to endocrine treatment Currently, the only clinically proven mechanism of developing resistance to endocrine therapy is HER2 overexpression. However, only around 10% of hormone receptor-positive (HR+) breast cancers overexpress HER2, and thus the mechanism of resistance for the majority of patients with HR+ breast cancer has not been

elucidated [27,43]. Several mechanisms of endocrine resistance in ER+ breast cancer have been proposed [44]. These include loss of ER expression over time, which is thought to occur in 20% of patients following endocrine treatment and results in hormoneindependent growth [43,45]; dysregulation of ER co-activators; expression of truncated (products of splice variants) or posttranslational modified ER; and increased growth factor receptor signaling (e.g. IGF-1R). Emerging evidence points to hyperactivation of the PI3K/AKT/ mTOR pathway being a key mechanism of endocrine resistance in ER+ breast cancer, and one that could allow for ER+ breast cancer cells to adapt to estrogen deprivation [15–17]. ER levels are inversely correlated with PI3K activation scores in ER+ tumor samples; low ER levels and high PI3K activity are associated with resistance [46]. Correspondingly, loss of PTEN expression is associated with low ER levels and poor outcome [47–49]. In ER+ breast cancer cell lines, PI3K/AKT/mTOR pathway inhibition significantly increased ER gene expression and the expression of ER-inducible target genes, and increased sensitivity to tamoxifen treatment [46]. Thus, PI3K/AKT/mTOR pathway hyperactivation may contribute to endocrine resistance through the downregulation of ER expression, thereby promoting hormone-independent growth. Inhibiting the PI3K/AKT/mTOR pathway may provide a mode of reversing this process by increasing ER levels, and thereby restoring hormone dependence and sensitivity to endocrine therapy.

PI3K/AKT/mTOR pathway inhibitors in ER+ breast cancer Given the fundamental role of PI3K/AKT/mTOR pathway signaling in the maintenance of ER+ breast tumors and its emerging role in resistance to endocrine therapy, strategic inhibition of pathway signaling must be considered in the treatment of ER+ breast cancer. This rationalizes the use of endocrine therapy and PI3K/AKT/mTOR pathway inhibition in combination. Several agents targeted to one or more nodes of the PI3K/AKT/ mTOR pathway are currently being evaluated for the treatment of ER+ breast cancer in clinical trials (Table 2). These targets include centrally located effectors such as pan-PI3K inhibitors (BKM120 [buparlisib], GDC-0941 [pictilisib]), a-isoform-specific PI3K inhibitors (BYL719, GDC-0032), the dual PI3K/mTOR inhibitor GDC-0980, mTOR inhibitors (everolimus, ridaforolimus), and AKT inhibitors (MK2206, AZD5363). In addition, targets upstream of the PI3K/AKT/mTOR pathway, such as RTKs, and downstream of the PI3K/AKT/mTOR pathway are of interest. These include fibroblast growth factor receptor (FGFR) inhibitors (AZD4547, dovitinib) and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors (PD-0332991 [palbociclib], LEE011, LY2835219) [50,51]. A number of studies are evaluating

Please cite this article in press as: Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.03.004

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E.M. Ciruelos Gil / Cancer Treatment Reviews xxx (2014) xxx–xxx

Table 2 Comparative potencies of selected PI3K/AKT/mTOR pathway inhibitors in clinical trials for the treatment of ER+ breast cancer, by target. Compound

Assay, units

p110a

p110b

p110c

p110d

mTOR(C1/C2)

AKT(1,2,3)

mTOR inhibitors Everolimus [106] Ridaforolimus [107] Pan-PI3K inhibitors Buparlisib [108] Pictilisib [109]

IC50, nM IC50, nM

– –

– –

– –

– –

5–6a <1

– –

IC50, nM IC50, nM

52 3

166 33

262 75

116 3

4610 580

– –

Isoform-specific PI3K inhibitors BYL719 [110] GDC-0032 [111]

IC50, nM Ki, nM

5 <1

1156 9

290 <1

250 1

>9100 –

– –

IC50, nM

5

27

14

7

17(Ki)

–

IC50, nM IC50, nM

– –

– –

– –

– –

– –

8/12/65 3/7/7

Dual PI3K/mTOR inhibitors GDC-0980 [112] AKT inhibitors MK2206 [113] AZD5363 [114]

FKBP, FK506-binding protein; IC50, half maximal inhibitory concentration; mTOR, mammalian target of rapamycin; mTORC1/2, mTOR complex 1/2; PI3K, phosphatidylinositol 3-kinase. a Binding to FKBP-12 or FKBP-12 in complex with mTOR.

the ability of PI3K/AKT/mTOR pathway inhibitors to augment endocrine therapy, either following endocrine resistance or as a first-line treatment. Rationale for PI3K/AKT/mTOR pathway inhibition following resistance to endocrine therapy Preclinical evidence Hyperactivated PI3K/AKT/mTOR signaling associated with lower levels of ER has been observed in human ER+ breast tumor samples [46]. As low ER levels are associated with resistance to endocrine therapy [52,53], PI3K/AKT/mTOR pathway inhibition in these ER+ tumors might reverse the loss of ER expression and restore ER signaling and sensitivity to endocrine therapy, and improve patient outcomes [54–56]. In addition, an inverse functional relationship has been observed in cell lines, where treatment with the PI3K activator IGF-1 decreased ER expression and transcriptional activity, and treatment with the dual PI3K/mTOR inhibitor BEZ235 increased ER expression and transcriptional activity [46]. These findings imply that PI3K/AKT/mTOR pathway inhibition could re-establish ER expression and activity in ER-negative breast cancers, effectively restoring ER+ status. Combining the PI3K/AKT/mTOR pathway inhibitors buparlisib, everolimus, or BGT226, with fulvestrant reversed resistance to endocrine therapy by promoting apoptosis in estrogen-deprived MCF7 cells [57]. In addition, treatment with BEZ235 promoted apoptosis in letrozole-resistant, ER+, aromatase-expressing MCF7/AROM-1 cells with hormone-independent growth. These letrozole-resistant cells were more sensitive to everolimus than their letrozole-sensitive progenitors, and exhibited an upregulated AKT/mTOR/S6K1 pathway [17]. This suggests that AKT/mTOR/ S6K1 signaling has a key role in acquired resistance to letrozole and that there is a dependence on this pathway for cell survival. Thus, PI3K/AKT/mTOR pathway inhibition might restore hormone sensitivity to ER+ breast cancer, reverse endocrine resistance, and promote apoptosis. In addition, although endocrine therapy leads to cell cycle arrest, it does not cause a high level of apoptosis, a probable reason that treatment is not successful in the long term. Targeting the pro-survival PI3K/AKT/mTOR pathway could improve clinical outcomes [57]. This provides a clear rationale for including PI3K/AKT/mTOR pathway inhibitors in later lines of endocrine therapy, following the development of resistance. The aforementioned preclinical studies are promising; however, preclinical investigations might not fully or accurately represent endocrine resistance in human tumors or correctly predict

response to treatment. Several completed and ongoing studies are focused on inhibition of the ER and PI3K/AKT/mTOR signaling pathways in patients who have developed resistance to endocrine therapy. Clinical evidence Most studies evaluating PI3K/AKT/mTOR pathway inhibitors following endocrine resistance have centered on the first-generation mTOR inhibitors everolimus and temsirolimus. Two key studies in the advanced setting, BOLERO-2 and TAMRAD, have evaluated everolimus in patients who have progressed on aromatase inhibitor treatment. BOLERO-2 examined everolimus in combination with exemestane following progression on an aromatase inhibitor. BOLERO-2 was a randomized Phase III study of 724 postmenopausal women with HR+/HER2-negative (HER2 ) metastatic breast cancer who had experienced progression on treatment with non-steroidal aromatase inhibitors (letrozole or anastrozole; progression during or within 12 months of treatment). Results showed that the combination of everolimus and exemestane significantly prolonged progression-free survival (PFS) (7.8 versus 3.2 months) and response rate compared with exemestane alone [5,58]. In addition, a subgroup analysis of BOLERO-2 patients receiving first-line treatment for advanced breast cancer (137 patients; 21%) revealed that the combination of everolimus and exemestane more than doubled PFS compared with exemestane alone (11.5 versus 4.1 months), providing support for this treatment as a first-line therapy for advanced disease following recurrence during or after adjuvant endocrine therapy [59]. TAMRAD was an investigation of everolimus in combination with tamoxifen following progression on an aromatase inhibitor [60]. This was a randomized Phase II study in postmenopausal women with HR+/HER2 aromatase inhibitor-resistant metastatic breast cancer in a small population (111 patients). It was found that the addition of everolimus to tamoxifen significantly increased clinical benefit rate (61% versus 42%), prolonged time to progression (8.6 versus 4.5 months), and increased overall survival (70% versus 46%) in the intent-to-treat population compared with tamoxifen alone. This combination was particularly effective in patients with secondary endocrine resistance, meaning those patients relapsing more than 6 months after stopping adjuvant aromatase inhibitor treatment or those responding to aromatase inhibitors for 6 months or more in the metastatic setting [60]. These results suggest that PI3K/AKT/mTOR pathway inhibitors can augment the efficacy of existing endocrine therapy in later

Please cite this article in press as: Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.03.004

E.M. Ciruelos Gil / Cancer Treatment Reviews xxx (2014) xxx–xxx

lines of treatment, following the development of endocrine resistance. Based on the results of the BOLERO-2 study, the United States Food and Drug Administration (FDA) approved everolimus in combination with exemestane for the treatment of HR+ breast cancer following progression on letrozole or anastrozole in July 2012 [61]. Several ongoing studies will determine the efficacy of endocrine therapy plus everolimus or another first-generation mTOR inhibitor, ridaforolimus (Table 2), in the treatment of postmenopausal women with ER+ breast cancer who have experienced progression on prior lines of endocrine treatment (Table 3).

Rationale for combining endocrine therapy with PI3K/AKT/mTOR pathway inhibition prior to the development of endocrine resistance There is a body of evidence indicating that the combination of ER and PI3K/AKT/mTOR pathway inhibition may also be beneficial in early lines of treatment, prior to the development of acquired resistance.

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Preclinical evidence Hyperactivation of the PI3K/AKT/mTOR pathway has been shown to be a requirement for adaptation to hormone-independent growth in the ER+ breast cancer cell line MCF-7 after long-term estrogen deprivation (LTED), a model of endocrine resistance that mimics the low estrogen levels seen in patients treated with aromatase inhibitors [62]. Furthermore, BEZ235, a dual PI3K/mTOR inhibitor, prevented cells from acquiring hormone independence in all four LTED cell lines tested and increased apoptosis in three out of four LTED cell lines tested [62]. Similarly, selective inhibition of p110a through RNA interference led to growth reduction (>90%) and apoptosis (50%) in estrogen-deprived MCF-7 cells [63]. Thus, PI3K/AKT/mTOR pathway inhibition prevents the development of hormone-independent cells by causing cell death, providing a strong rationale for the combination of PI3K/AKT/mTOR inhibitors and endocrine therapy in early lines of treatment. Clinical evidence The clinical utility of PI3K/AKT/mTOR pathway inhibition in combination with endocrine therapy has also been evaluated in

Table 3 Ongoing clinical trials of PI3K/AKT/mTOR pathway inhibitors in breast cancer, tested specifically in HR+ populations [86]. Study drug(s)

Phase

NCT number

PI3K/AKT/mTOR pathway inhibitors in the first-line setting Everolimus + letrozole II NCT01698918 (BOLERO-4)a Pictilisib + paclitaxel II NCT01740336 MK-2206 + current endocrine therapy I NCT01344031 regimen MK-2206 + anastrozole II NCT01776008 AZD5363 + paclitaxel II NCT01625286 (BEECH)

Patient population Postmenopausal women with ER+ metastatic breast cancer Women with HR+/HER2 locally recurrent or metastatic breast cancer Postmenopausal women with ER+ metastatic breast cancer currently being treated with endocrine therapy with no evidence of disease progression PIK3CA mutant ER+/HER2 stage II–III breast cancer in the neoadjuvant setting Women with ER+ advanced or metastatic breast cancer

PI3K/AKT/mTOR pathway inhibitors following resistance to endocrine therapy Everolimus + exemestane II NCT01698918 Postmenopausal women with ER+ metastatic breast cancer (BOLERO-4)a Everolimus + exemestane II NCT01783444 Postmenopausal women with ER+ locally advanced, recurrent, or metastatic breast cancer (BOLERO-6) after recurrence or progression on prior letrozole or anastrozole Everolimus + exemestane + LEE011 II NCT01857193 Postmenopausal women with ER+/HER2 locally advanced or metastatic breast cancer with recurrence or progression on or after treatment with a non-steroidal aromatase inhibitor Everolimus + exemestane III NCT01626222 Postmenopausal women with HR+/HER2 locally advanced or metastatic breast cancer (4EVER) progressing following prior therapy with non-steroidal aromatase inhibitors Everolimus + exemestane III NCT00863655 Postmenopausal women with ER+ locally advanced or metastatic breast cancer who are (BOLERO-2) refractory to letrozole or anastrozole Everolimus + exemestane IV NCT01743560 Postmenopausal women with HR+/HER2 locally advanced or metastatic breast cancer with recurrence or progression on or after treatment with a non-steroidal aromatase inhibitor Everolimus + letrozole + lapatinib II NCT01499160 Postmenopausal women with advanced HR+ breast cancer that is resistant to endocrine therapy Everolimus + fulvestrant II NCT00570921 Postmenopausal women with HR+ advanced or metastatic breast cancer after failure of (BRE-43) aromatase inhibitor therapy Everolimus + fulvestrant II NCT01797120 Postmenopausal patients with HR+ metastatic breast cancer resistant to aromatase inhibitor (PrE0102) therapy Everolimus + tamoxifen II NCT01298713 Postmenopausal women with ER+/HER2 metastatic breast cancer that is resistant to aromatase inhibitor therapy Ridaforolimus + dalotuzumab II NCT01234857 Postmenopausal women with ER+/HER2 locally advanced or metastatic breast cancer who have received at least one line of endocrine therapy for metastatic disease Ridaforolimus + dalotuzumab + exemestane II NCT01605396 Postmenopausal women with ER+/HER2 locally advanced or metastatic breast cancer refractory to letrozole or anastrozole Buparlisib + fulvestrant I NCT01339442 Postmenopausal women with ER+ metastatic breast cancer Buparlisib + fulvestrant III NCT01610284 Postmenopausal women with HR+/HER2 locally advanced or metastatic breast cancer who (BELLE-2) are resistant to aromatase inhibitor therapy Buparlisib + fulvestrant III NCT01633060 Postmenopausal women with HR+/HER2 locally advanced or metastatic breast cancer who (BELLE-3) are resistant to mTOR inhibitor therapy Pictilisib or GDC-0980 + fulvestrant II NCT01437566 Postmenopausal women with ER+ locally advanced or metastatic breast cancer who are (FERGI) resistant to aromatase inhibitor therapy BYL719 + letrozole I NCT01791478 Postmenopausal women with HR+/HER2 metastatic breast cancer BYL719 + letrozole or exemestane I NCT01870505 Postmenopausal women with HR+ locally advanced unresectable or metastatic breast cancer GDC-0032 + letrozole and/or fulvestrant I NCT01296555 Postmenopausal women with HR+ locally advanced or metastatic breast cancer ER+, estrogen receptor positive; HER2 , human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; mTOR, mammalian target of rapamycin; mTORC1/2, mTOR complex 1/2; PI3K, phosphatidylinositol 3-kinase. a The BOLERO-4 trial will investigate everolimus in both the 1st- and 2nd-line treatment of women with ER+ metastatic breast cancer. Patients will start with everolimus + letrozole treatment, followed by everolimus + exemestane after disease progression.

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the first-line setting, with studies showing that complete inhibition of mTOR signaling may be an effective strategy to fight de novo endocrine resistance. RAD2222 was a randomized Phase II trial examining letrozole in combination with everolimus in 270 postmenopausal women with treatment-naïve ER+ early-stage breast cancer [18]. The combination of neoadjuvant letrozole and everolimus for 4 months led to an increase in response rate compared with letrozole alone (68% versus 59%) and an antiproliferative response (as measured by a reduction in Ki67 levels) was observed in a significantly higher proportion of patients in the combination group than in the letrozole alone group (57% versus 30%) [18]. However, HORIZON, a large, randomized Phase III trial of letrozole with or without temsirolimus for the first-line treatment of advanced breast cancer, was terminated in 2006 due to lack of efficacy [64]. This is proposed to be due to incomplete inhibition of mTOR signaling as a result of an intermittent dosing schedule for temsirolimus versus continuous daily dosing for everolimus [18,65]. In addition, although the combination of temsirolimus and letrozole is associated with a higher incidence of toxic events than letrozole alone [66], the occurrence of adverse events with the combination arm of the HORIZON study was lower than those seen in studies with daily continuous everolimus, providing further support for incomplete pathway activation [5,60,64]. More studies are needed to fully elucidate the benefit to patients of the upfront combination of endocrine therapy and PI3K/AKT/ mTOR pathway inhibition, especially given the promising preclinical data. Studies such as the UNIRAD and SWOG/NSABP S1207 Phase III randomized studies in patients with early ER+, HER2 breast cancer at high risk of relapse are evaluating the role of everolimus in combination with endocrine therapy in the adjuvant setting, and may provide an evidence base for the use of these agents in patients prior to the development of secondary hormone resistance [67,68]. In addition, BOLERO-4, an ongoing, single-arm, Phase II clinical study in postmenopausal women with ER+ metastatic breast cancer (NCT01698918; Table 3), will examine the effect on PFS of everolimus treatment in the first-line setting and beyond. Patients previously untreated for metastatic disease will receive everolimus plus letrozole as first-line treatment, followed by everolimus plus exemestane upon disease progression [69]. This study will help to determine which lines of therapy are most appropriate for the addition of PI3K/AKT/mTOR pathway inhibition to endocrine therapy, as well as assessing the potential benefit of PI3K/AKT/mTOR inhibition in all lines of treatment, as a mainstay of endocrine therapy.

Considerations for patient and inhibitor selection PI3K/AKT/mTOR pathway alterations as predictors of outcome and response to treatment The role of PI3K alteration as a marker for patient outcome is currently unconfirmed. Genetic alterations in the PI3K/AKT/mTOR pathway are not consistently correlated with clinical outcome after endocrine therapy, with several studies identifying PIK3CA mutations as predictors of improved outcome [29,70,71], poorer outcome [8,72], or having no correlation with outcome [7,73,74]. PIK3CA mutation was found to be a prognostic variable within the HER2+ population in the CLEOPATRA trial, in which PI3K mutations correlated with poorer outcomes independently from treatment received [75]. Evidence of a correlation between prognosis or response to endocrine therapy and alterations in other elements of the PI3K/AKT/mTOR pathway is also mixed [76–80]. There has been greater success in the study of PI3K/AKT/mTOR pathway alterations as molecular predictors of response to pathway inhibition. In breast cancer cell lines and in vivo xenograft models, mutation of PIK3CA has been shown to correlate with sen-

sitivity to pictilisib [81]. Furthermore, apoptosis induced by buparlisib, everolimus, or the dual PI3K/mTOR inhibitor BGT226, was highest in cells with PIK3CA mutation and PTEN loss [57]. In the BOLERO-2 study, next-generation sequencing showed that patients who had minimal genetic variations in the PI3K/ AKT/mTOR or FGFR pathways, or CCND1, benefitted most from everolimus treatment [82]. This demonstrated the feasibility of large-scale genomic sequencing of participants in these types of clinical trials, and the value of PI3K/AKT/mTOR pathway alterations as predictors of sensitivity to everolimus [83,84]. Going forward, it will be important to identify patients who will benefit most from PI3K/AKT/mTOR pathway inhibition, which would allow for the optimization of therapeutic index with reduced toxicity for patients treated [85]. For this reason, PI3K/AKT/mTOR pathway alterations are being investigated as potential biomarkers for response to treatment in several ongoing and upcoming clinical studies of pathway inhibitors. The ongoing BELLE-2 and FERGI studies (Table 3) include exploratory biomarker assessments. These exploratory biomarker studies will identify alterations in tumor molecular profiles to look for potential associations with clinical response and disease progression, resistance to prior endocrine therapy, and response to study treatment. In addition, large-scale genomic datasets such as the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer Project are compilations of sequencing information, including gene expression, and pharmacologic profiles for numerous anticancer agents, from a multitude of human cancer cell lines, which could prove useful in the identification of biomarkers to predict drug sensitivity and aid in participant selection in future clinical trials [86,87]. Treatment drawbacks and next-generation PI3K pathway inhibitors There are many factors to consider when suggesting a PI3K inhibitor clinical trial for a given patient, including toxicities (as mentioned above), level of inhibition, feasibility for combining with other therapies, molecular nature of the tumor, among others. Most PI3K pathway inhibitors are in early clinical development, and consequently, there are limited clinical data comparing efficacy and toxicity across different classes of PI3K pathway inhibitor. As a class, PI3K pathway inhibitors are associated with several drug-related toxicities (Table 4), including fatigue, nausea, and diarrhea. Hyperglycemia is a common on-target effect that is unsurprising given the important role of the PI3K/AKT/mTOR pathway in insulin signaling. This has resulted in the exclusion of patients with diabetes mellitus from clinical trials with these compounds. Other drug-related toxicities include rare cardiac effects, which have been reported with pictilisib [88]. Additionally, mood disorders are a frequently reported adverse event with buparlisib [89], resulting in the exclusion of individuals with a historic or current mood disorder from clinical studies of buparlisib. This toxicity may occur due to the ability of buparlisib to cross the blood–brain barrier, and it is thought that buparlisib may be useful in the treatment of brain metastases [90]. mTOR inhibitors have an overlapping but distinct safety profile from PI3K inhibitors, with drug-related toxicities including stomatitis, rash, fatigue, diarrhea, interstitial pneumonitis, and anorexia – a consideration when adding these agents to endocrine therapy in ER+ breast cancer [5,60]. Another consideration for the use of mTOR inhibition (e.g. by everolimus) to augment endocrine therapy in ER+ breast cancer is the well-described feedback loop. mTOR inhibition activates a negative feedback loop, through S6K and IRS-1, whereby AKT activation is enhanced, superseding mTOR inhibition [91,92]. This provides a rationale for combining mTOR inhibitors with IGF-1R inhibition for complete blockade of the pathway in order to circumvent the feedback loop [93], a hypothesis that is currently being tested in a randomized Phase II clinical

Please cite this article in press as: Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.03.004

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E.M. Ciruelos Gil / Cancer Treatment Reviews xxx (2014) xxx–xxx Table 4 Summary safety and preliminary activity of Phase I clinical studies of selected single-agent PI3K/AKT/mTOR pathway inhibitors in patients with advanced solid tumors. Compound

Manufacturer

Dosing

MTD

DLTs

Common AEs

Activity

Oral, QW or continuous, QD

– –

QW: stomatitis, fatigue QD: hyperglycemia

Rash and erythema, stomatitis/ mucositis, fatigue, nausea

Intravenous, intermittent (days 1–5 and 14–18 of a 28-day schedule)

18.75 mg

Mouth sores

Mouth sores, rash

Partial response in 4/92 pts (4%); stable disease in 12/92 pts (13%) Partial response in 4/32 pts (13%)

Oral, continuous, QD

100 mg

Fatigue/asthenia, anorexia, diarrhea, hyperglycemia, nausea, rash

Partial response in 3/66 pts (5%); stable disease in 28/66 pts (42%)

Oral, BID or QD, intermittent (days 1–21 of a 28day schedule) or continuous

BID: 450 mg QD: 400 mg

Hyperglycemia, skin rash, epigastric pain, mood disorder, joint pain BID: Pleural effusion, decreased carbon monoxide diffusing capacity, thrombocytopenia, hyperglycemia QD: Headache, nausea, fatigue, myalgia, ECG T-wave inversion, rash

Hyperglycemia, diarrhea, nausea

Partial response in 2/97 pts (2%)

Oral, continuous, QD

400 mg

Hyperglycemia, nausea, vomiting, and diarrhea

Oral, continuous, QD

–

Hyperglycemia, fatigue

Hyperglycemia, nausea, diarrhea, decreased appetite, vomiting, fatigue Diarrhea, hyperglycemia, fatigue, nausea, decreased appetite, vomiting

Partial response in 7/39 pts (18%); stable disease in 17/39 pts (44%) Partial response in 5/34 pts (15%)

Oral, intermittent (days 1–21 of a 28day schedule)

–

Hyperglycemia, rash

Fatigue, diarrhea, decreased appetite, nausea, rash mucositis, hyperglycemia, vomiting, constipation

Partial response in 3/33 pts (9%)

Merck

Oral, QDa

60 mg

Rash

AstraZeneca

Oral, BID, intermittent (days 1–4 of each week) or continuous

BID intermittent: 480 mg BID continuous: 320 mg

–

Skin rash, nausea, fatigue, hyperglycemia Hyperglycemia, rash, diarrhea

Stable disease in 9/71 pts (13%) Partial response in 2/92 pts (2%); stable disease in 1/92 pts (1%)

mTOR inhibitors Everolimus Novartis [115] Ridaforolimus [116]

Merck

Pan-PI3K inhibitors Buparlisib [89] Novartis

Pictilisib [88]

Genentech

Isoform-specific PI3K inhibitors BYL719 [117] Novartis

GDC-0032 [118]

Genentech

Dual PI3K/mTOR inhibitors GDC-0980 Genentech [119]

AKT inhibitors MK2206 [120] AZD5363 [121]

AE, adverse event; BID, twice daily; DLT, dose-limiting toxicity; ECG, electrocardiogram; MTD, maximum tolerated dose; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; QD, once daily; QW, once weekly. a An oral 300 mg QW regimen is currently under evaluation.

study of ridaforolimus and dalotuzumab in ER+ breast cancer (NCT01605396) [94]. Direct inhibition of PI3K could be used to avoid feedback signaling. Next-generation inhibitors that may circumvent feedback signaling include dual mTOR/PI3K inhibitors (GDC-0980), pan-isoform PI3K inhibitors (buparlisib, pictilisib), isoform-specific PI3K inhibitors (BYL719, GDC-0032), and AKT inhibitors (MK2206, AZD5363; Table 2). Ongoing clinical studies with next-generation pathway inhibitors are described in Table 3. Isoform-specific PI3K inhibitors may be superior to pan-PI3K inhibitors in terms of safety and efficacy given the roles of each isoform in both key physiologic and pathologic cellular processes. Indeed, p110a is thought to be the PI3K catalytic subunit predominantly responsible for glucose homeostasis [95], while it has been suggested that p110b has an important role in driving tumorigenesis in some PTEN-deficient tumors [96]. Therefore, in these PTEN-deficient tumors, a p110b-specific inhibitor would maintain efficacy with theoretically less hyperglycemia. On the other hand, isoform-specific PI3K inhibitors have a relatively narrow activity profile, and may require careful patient selection based upon potential biomarkers of sensitivity or resistance. For example,

theoretically, p110a inhibitors may be less well suited for the evaluation of tumors with high rates of either PTEN alterations. Novel combination therapies showing promise in ER+ breast cancer As mentioned earlier, aside from PI3K pathway inhibitors, other novel targeted agents have recently emerged as potential combination partners for the potentiation of hormone therapy. CDK4/6 controls entry into cell cycle progression by regulating the activity of retinoblastoma protein (Rb) [97]. Palbociclib/PD0332991 (Pfizer) is a highly active oral CDK4/6 inhibitor with particular activity in luminal ER+ cell lines, and has exhibited synergy with tamoxifen in vitro [97]. Interim data from a Phase II study in which palbociclib was combined with letrozole in patients (N = 165) with untreated postmenopausal ER+ advanced or metastatic breast cancer showed that median PFS increased from 7.5 months with letrozole alone to 26.1 months in combination, with an objective response rate of 34% versus 26%; the rate of hematologic toxicities also increased [50]. Activation of the PI3K pathway augments D-cyclin abundance, which activate CDK4/6

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E.M. Ciruelos Gil / Cancer Treatment Reviews xxx (2014) xxx–xxx

kinase activity, and phosphorylate Rb, thus facilitating proliferation [98,99], and providing a rationale for combining PI3K and CDK4/6 targeted agents in patients with HR+ breast cancer. LEE011 (Novartis) is a dual CDK4/6 inhibitor that induces cell-cycle arrest and senescence, leading to antitumor activity [100]. LEE011 in combination with the PI3Ka inhibitor BYL719 has demonstrated enhanced antitumor activity compared with either agent alone in PIK3CA-mutant breast cancer models that are both sensitive and resistant to BYL719 [101]. In addition to the Phase III program in combination with letrozole, LEE011 is also being investigated in Phase Ib/II clinical studies in combination with BYL719 and letrozole in patients with ER+, HER2 advanced or metastatic breast cancer (NCT01872260), and in combination with exemestane with or without everolimus in patients with ER+, HER2 advanced breast cancer (NCT01857193). Anti-estrogen resistance can be induced by elevated IGF-1R signaling, which activates the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK signaling pathways [102]. Preclinical data suggest that inhibiting ER and IGF-1R signaling in ER+ breast cancer may lead to greater suppression of cell proliferation than is achieved by blocking either pathway alone [103]. Similarly, in vitro preclinical data have demonstrated that PI3K pathway inhibitors were more potent when combined with a MEK inhibitor, suggesting that therapeutic targeting of the PI3K/AKT/mTOR and the MEK/ERK signaling pathways may be effective in reversing aromatase-inhibitor-resistance in ER+ breast cancer [104]. A randomized Phase II study of ganitumab/AMG479 (Amgen), a human monoclonal antibody against IGF-1R, with exemestane or fulvestrant in postmenopausal women with HR+ advanced or metastatic breast cancer demonstrated no improvement in PFS [103]. Furthermore, only a limited clinical benefit was seen with the combination of ganitumab with everolimus despite the reported synergism between IGF-1R and mTOR inhibitors, with on-target pS6 reduction, but no effect on AKT upregulation [105]. The results of the aforementioned Phase II clinical study of ridaforolimus and dalotuzumab in ER+ breast cancer remains to be seen. However, the combination of an IGF-1R and PI3K inhibitor may provide more effective blockade of these interlinked and parallel pathways. A Phase Ib/II study evaluating ganitumab in combination with BYL719 in patients with PIK3CAmutated or PIK3CA-amplified solid tumors, including HR+ breast cancer (NCT01708161) is underway. Conclusions and future directions Although endocrine therapy is currently the cornerstone of treatment for ER+ breast cancer, the de novo and acquired resistance that occurs in many patients with advanced disease necessitates new approaches to treatment. Evidence from preclinical and clinical studies shows that PI3K/AKT/mTOR pathway inhibition can augment endocrine therapy in ER+ breast cancer, from the firstline setting and beyond. Upfront treatment with PI3K/AKT/mTOR pathway inhibitors and endocrine therapy may combat de novo resistance to endocrine therapy, prevent the occurrence of acquired resistance, and work synergistically with existing endocrine treatments to kill ER+ breast cancer cells. Moreover, the continued use of PI3K/AKT/mTOR pathway inhibitors in later lines of endocrine therapy can re-sensitize ER+ breast cancer to endocrine therapy, provide tumor-killing activity, extend time to progression, and defer chemotherapy. Therefore, a new approach whereby PI3K/AKT/mTOR pathway inhibition provides the mainstay of treatment, and augments the efficacy of endocrine therapy in successive lines of treatment, could improve clinical outcomes for patients with ER+ breast cancer. Ongoing studies will explore the efficacy of next-generation PI3K/AKT/mTOR pathway inhibitors in combination with existing endocrine treatments and with inhibitors of upstream and down-

stream effectors. Key considerations to be addressed in future studies include determining which is the optimal treatment combination, whether total blockade or partial inhibition of the PI3K/ AKT/mTOR pathway is preferable, and if isoform-specific or panPI3K inhibition will be more beneficial to patients with ER+ breast cancer. Future studies will also focus on identifying new methods of pre-selecting patients who will benefit most from treatment, such as defining molecular signatures for biomarker screening and large-scale genomic screening. Conflict of interest statement Dr. Ciruelos has nothing to disclose. Acknowledgments Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Anna A. Federman PhD for her medical editorial assistance with this manuscript. References [1] Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the surveillance, epidemiology, and end results database. Breast Cancer Res Treat 2002;76:27–36. [2] Cleator S, Ahamed E, Coombes R, Palmieri CA. Update on the treatment of patients with hormone receptor-positive breast cancer. Clin Breast Cancer 2009;2009(Suppl. 1):S6–S17. [3] Davies E, Hiscox S. New therapeutic approaches in breast cancer. Maturitas 2011;68:121–8. [4] Johnston SR. New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res 2010;16:1979–87. [5] Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520–9. [6] Perez-Tenorio G, Alkhori L, Olsson B, et al. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res 2007;13:3577–84. [7] Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008;68:6084–91. [8] Ellis MJ, Lin L, Crowder R, et al. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat 2010;119:379–90. [9] Campbell IG, Russell SE, Choong DY, et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 2004;64:7678–81. [10] Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, et al. PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol Cancer Ther 2011;10:1093–101. [11] Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554. [12] Fu P, Ibusuki M, Yamamoto Y, et al. Insulin-like growth factor-1 receptor gene expression is associated with survival in breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression. Breast Cancer Res Treat 2011;130:307–17. [13] Law JH, Habibi G, Hu K, et al. Phosphorylated insulin-like growth factor-i/ insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 2008;68:10238–46. [14] Saal LH, Johansson P, Holm K, et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci U S A 2007;104:7564–9. [15] Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 2011;13:224. [16] Barone I, Cui Y, Herynk MH, et al. Expression of the K303R estrogen receptor-alpha breast cancer mutation induces resistance to an aromatase inhibitor via addiction to the PI3K/Akt kinase pathway. Cancer Res 2009;69: 4724–32. [17] Cavazzoni A, Bonelli MA, Fumarola C, et al. Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones. Cancer Lett 2012;323:77–87. [18] Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009;27:2630–7. [19] Shoman N, Klassen S, McFadden A, Bickis MG, Torlakovic E, Chibbar R. Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen. Mod Pathol 2005;18:250–9.

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Please cite this article in press as: Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.03.004