The

Oncologist

Targeting the Phosphoinositide-3 (PI3) Kinase Pathway in

Breast Cancer
JOS BASELGA

Disclosures: Jos Baselga: Consultant/advisory role: Novartis, Merck, Exelixis.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from
commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer
reviewers.

ABSTRACT
The phosphoinositide-3 kinase (PI3K) pathway has
been identified as an important target in breast cancer
research for a number of years, but is new to most clinicians responsible for the daily challenges of breast
cancer management. In fact, the PI3K pathway is probably one of the most important pathways in cancer metabolism and growth. Mutations in the PI3K pathway
are frequent in breast cancer, causing resistance to human epidermal growth factor receptor 2targeted
agents and, possibly, to hormonal agents as well. Available agents that affect the PI3K pathway include monoclonal antibodies and tyrosine kinase inhibitors, as well
as PI3K inhibitors, Akt inhibitors, rapamycin analogs,
and mammalian target of rapamycin (mTOR) catalytic

inhibitors. Multiple PI3K inhibitors are currently under development, including pure PI3K inhibitors, compounds that block both PI3K and mTOR (dual
inhibitors), pure catalytic mTOR inhibitors, and inhibitors that block Akt. It is likely that these agents will
have to be given in combination with other signal inhibitors because anti-mTOR agents and PI3K inhibitors
may result in the activation of compensatory feedback
loops that would in turn result in decreased efficacy.
This article reviews current data related to the PI3K
pathway, its role in breast cancer, the frequency with
which PI3K is aberrant in breast cancer, and the potential clinical implications of using agents that target the
PI3K pathway. The Oncologist 2011;16(suppl 1):1219

INTRODUCTION

AN OVERVIEW OF THE PI3K PATHWAY

The phosphoinositide-3 kinase (PI3K) pathway has been

identified as an important target in breast cancer research
for a number of years, but could be unfamiliar to clinicians responsible for daily breast cancer management.
This article reviews the current data related to the PI3K
pathway, its role in breast cancer, how frequently PI3K is
aberrant in breast cancer, and the potential clinical implications of these findings with the use of agents that
target the PI3K pathway.

The PI3Ks are a family of lipid kinases whose primary biochemical function is to phosphorylate the 3-hydroxyl group
of phosphoinositides [1]. Class IA PI3Ks, deregulated in
cancer, are heterodimers comprised of a regulatory subunit
(referred to as p85) and a catalytic subunit (p110). Activation of PI3Ks is initiated when a growth factor or ligand
binds to its cognate receptor tyrosine kinase (RTK). These
receptors include members of the human epidermal growth
factor receptor (HER) family, and the insulin and insulin-

Correspondence: Jos Baselga, M.D., Ph.D., Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Telephone: 617-643-2438; Fax: 617-643-9686; e-mail: jbaselga@partners.org, AlphaMed Press
1083-7159/2011/$30.00/0 doi: 10.1634/theoncologist.2011-S1-12

The Oncologist 2011;16(suppl 1):1219 www.TheOncologist.com

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Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA

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like growth factor 1 receptor (IGF-1R), among others.

Upon receptor activation, the PI3K heterodimer interacts
with their intracellular portion via p85. Alternatively, an
adaptor molecule may act as an intermediary between an
RTK and p85, such as occurs with insulin receptor substrate
1 (IRS1) downstream of IGF-1R. Binding removes the inhibitory effect of p85 on p110, resulting in full activation of
PI3K. The activated kinase catalyses the phosphorylation
of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol triphosphate (PIP3). PIP3 acts as a docking site
for Akt, a serine/threonine kinase that is the central mediator of the PI3K pathway, and phosphoinositide-dependent
kinase 1. Once localized at the cell plasma membrane, Akt
is phosphorylated and stimulates protein synthesis and cell
growth by activating mammalian target of rapamycin
(mTOR) through effects on the intermediary tuberous sclerosis 1/2 complex. The PI3K pathway is integral to diverse
cellular functions, including cellular metabolism and proliferation, differentiation, and survival (Fig. 1).
Additional evidence of the importance of this path-

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way is the high frequency with which and the multiple

sites where this pathway is aberrantly hyperactivated in
cancer, as illustrated in Figure 1, which shows locations
in the pathway where activating mutations and deletions
have been identified. In addition to the activating components of the pathway, some of the components of the
pathway have an intrinsic inhibitory effect, such as phosphatase and tensin homologue deleted on chromosome
ten (PTEN), for example [2]. PTEN loss activates the
pathway, because PTEN has been charged with the reconversion of PIP3 into PIP2. Mutations also occur at the
level of RTK receptors, mutations in PTEN itself, Akt,
and Ras, among others.

THE PI3K PATHWAY IN BREAST CANCER

The PI3K pathway is frequently aberrantly activated in
breast cancer with mutations occurring in up to one quarter
of breast cancers. The majority of mutations are in PIK3CA,
encoding the catalytic p110 subunit, and are nonrandomly
localized in three hot spots, resulting in single amino acid

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Figure 1. PI3K pathway mutations in cancer.

Abbreviations: BAD, Bcl-2-associated death promoter; GRB2, growth factor receptor-bound protein 2; IRS1, insulin receptor
substrate 1; MDM2, murine double minute 2; mTOR, mammalian target of rapamycin; PDK1, 3-phosphoinositide-dependent
protein kinase 1; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol triphosphate; PTEN, phosphatase and tensin homologue deleted on chromosome ten; RAPTOR, regulatory associated protein of TOR;
RICTOR, rapamycin-insensitive companion of mammalian target of rapamycin; TSC, tuberous sclerosis.

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Table 1. Frequency of mutations in the PIK3CA and PTEN genes in 547 human breast cancers
Mutation
Breast cancer subtype

PIK3CA catalytic domain*

PIK3CA other

PIK3CA total

PTEN

All breast tumors

HR
ERPR
ERPR
ERPR
HER2
Triple negative

73/547 (13.3%)
48/232 (20.7%)
39/186 (21%)
9/41 (22%)
0/5 (0%)
13/75 (17.3%)
12/240 (5.0%)

44/547 (8.0%)
32/232 (13.8%)
22/186 (11.8%)
10/41 (24.4%)
0/5 (0%)
4/75 (5.3%)
8/240 (3.3%)

117/547 (21.4%)
80/232 (34.5%)
61/186 (32.8%)
19/41 (46.3%)
0/5 (0%)
17/75 (22.7%)
20/240 (8.3%)

2/88 (2.3%)
2/58 (3.4%)
1/48 (2.1%)
1/8 (12.5%)
0/2 (0%)
0/10 (0%)
0/20 (0%)

substitutions: E545K and E542K in the helical domain

(exon 9) and H1047R in the kinase domain (exon 20).
These mutations increase enzymatic function, enhance
downstream signaling elements including Akt, and promote oncogenic transformation.
Overall, the proportion of breast tumors exhibiting these
mutations is in the range of 20%25%, depending on the
breast cancer subtype. For example, in hormone receptor
positive tumors, these mutations occur in 30% of cases.
Also, in HER2 disease, mutations are evident in about one
quarter of tumors. Meanwhile, it seems that mutations in triple-negative breast cancer may be less frequent [3] (Table
1). It is important to note that, as more data series are gathered, these numbers could change, but these data trends offer an initial picture on the distribution of these mutations in
the different subtypes of breast cancer. As shown in Table
1, PTEN alterations have been described as well, but may be
less common.
Mutations or amplifications in oncogenes are frequently
associated with adverse outcomes, the classical example of
which has been HER2 amplification. The relationship between PI3K mutation status and clinical outcome is now being studied. In an initial study, investigators at Memorial
Sloan Kettering Cancer Center identified that PI3KCA mutations are associated with favorable clinicopathologic features and better clinical outcomes, including survival
benefits [4]. Consequently, clinical data with PI3K inhibitors and with mTOR inhibitors need to be evaluated carefully with respect to historical series, because patients with
these tumors could have a better outcome. The corollary of
this, though, is that if these patients intrinsically have a less
aggressive form of the disease, it could well be that a less
aggressive therapy, including PI3K inhibitors and hormonal therapies, should be considered.
On the other hand, PI3K mutations may also play a role

in resistance to some of the therapies that block upstream

tyrosine kinase receptors. For example, PI3K mutations
have been implicated as a mechanism of resistance to antiHER2 agents. One study looked at PTEN status and PI3K
mutation status in patients who had been treated with trastuzumab. Tumors with the PTEN deletion of PI3K mutations responded less efficiently to trastuzumab, which
suggests a mechanism of trastuzumab resistance in HER2
breast cancer [5]. This finding is not surprising, because
trastuzumab blocks the signaling pathway upstream from
PI3K. If a downstream mutation exists, it would override
upstream inhibition.
In laboratory experiments, a genomewide small hairpin
RNA screen was used to determine potential mediators of
resistance to lapatinib, a small tyrosine kinase receptor of
HER2. In these assays, PTEN deletion resulted in lapatinib
resistance. One experiment was conducted in cells with different levels of PTEN and PI3K expression, as well as control cells with wild-type PTEN and wild-type PI3K. The
bottom of Figure 2 illustrates cells with p110 overexpression and cells with the two frequent PI3K hotspot mutations. All cells were treated with either trastuzumab,
lapatinib, or a combination of the two. As evidenced in the
figure, cells harboring PI3K mutations or the PTEN deletion were clearly resistant to both trastuzumab and lapatinib
[6] (Fig. 2).
Evidence also exists to suggest that PI3K mutations may
confer resistance to hormonal therapy. In support of this,
hyperactivation of receptors that signal via the PI3K pathway, such as HER1, HER2, and insulin like growth factor
receptor (IGFR) also result in resistance to antiestrogen
therapy [7]. The proposed mechanism of resistance is via
direct induction of estrogen receptor (ER) transcription
(Fig. 3). Additional studies have demonstrated that PI3K

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From 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 6091, with permission.

Baselga

mutations could also mediate resistance to downstream

mTOR inhibitors.

AGENTS TARGETING PI3K

The first agents against the pathway that were studied in the
clinic were rapamycin analogs. These agents work by interfering with mTORC1, which is the complex formed by
mTOR and regulatory associated protein of TOR. Clinical
data are now available to suggest that mTOR inhibition may
play a role in the therapy of breast cancer. In a neoadjuvant
randomized phase II study in patients with newly diagnosed, primary ER breast tumors 2 cm, patients were
randomized to receive either letrozole plus placebo for 16
weeks or letrozole plus daily everolimus (RAD001), a rapamycin analog. The primary endpoint of the trial was response to the combination therapy [8]. Patients who
received the rapamycin analog had a better response rate,
which provided a clear indication that the mTOR inhibitor
may be a potential novel addition to the therapy of breast
cancer.
Because a decrease in the proliferation marker Ki67 has
been proposed as a valid surrogate marker of clinical benefit to antihormonal agents in the neoadjuvant setting, investigators also analyzed changes in Ki67 in the two
therapy groups. Baseline distributions of Ki67 values were
similar in the treatment arms. Using the definition that patients with a ln(Ki67) 1 at day 15 had an antiproliferative
response, 57% of everolimus-treated patients were responders, compared with 30% of placebo-treated patients
(p .01) (Fig. 4). This finding suggested that the combina-

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tion is more efficient at blocking proliferation and correlates with the observed greater clinical benefit of the
combination treatment.
Based on these data, a number of ongoing phase III studies are exploring the efficacy of everolimus in patients with
metastatic ER breast cancer. Although fewer data are
available with trastuzumab and mTOR blockade, a phase I
study was conducted in patients who were largely resistant
to paclitaxel and had prior exposure to trastuzumab. With
the addition of everolimus, the activity demonstrated was
quite remarkable [9]. Based on these findings, additional
studies are being conducted in the HER2 metastatic setting.
Meanwhile, an important pharmacodynamic finding in
the initial metastatic and neoadjuvant studies was the observation that, upon mTOR blockade with everolimus,
there was an increase in the activated phosphorylated form
of Akt (pAkt). Figure 5 shows Akt phosphorylation status
prior to and during therapy, demonstrating an increase in
pAkt in everolimus-treated patients [10] (Fig. 5). We had
identified a potential explanation for what was at first a
counterintuitive finding: S6, a molecule that is immediately
downstream from and activated by mTOR, suppresses signaling of IGF-1R via suppression of IRS1. The blockade of
mTOR and the resulting inhibition of S6 causes a negative
feedback loop effect, and IGF-1R becomes activated,
which in turns results in increased PI3K signaling and activation of Akt (Fig. 6). The activation of this compensatory
pathway (Fig. 7) could be, in part, responsible for the limited activity that this class of agents has shown against
breast cancer to date [11]. In preclinical models, the activation of this compensatory pathway is totally prevented by
anti-IGF-1R monoclonal antibodies and there is strong evidence that combining antiIGF-1R monoclonal antibodies
and mTOR inhibitors results in synergism [12]. This combination is currently being explored in a phase I clinical
trial, and remarkable activity has been observed in patients
with ER luminal B breast cancer [13]. Another equally appealing approach would be the use of PI3K inhibitors in
combination with mTOR inhibitors.

PI3K INHIBITORS UNDER CLINICAL DEVELOPMENT

Current PI3K inhibitors under development are grouped by
their specificity, ranging from pure PI3K inhibitors, to compounds that block both PI3K and mTOR (dual inhibitors),
to pure catalytic mTOR inhibitors, and to inhibitors that
block Akt. Two agents that are discussed in further detail
here are the compounds being developed by Exelixis and
sanofi-aventis: XL147 and XL765.
The XL147 agent is a selective PI3K inhibitor. This
compound is a potent inhibitor of the Class I PI3K family.

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Figure 2. Hyperactivation of the PI3K pathway regulates

trastuzumab and lapatinib sensitivity in HER2 breast cancer
cells.
Abbreviations: HER2, human epidermal growth factor receptor 2; PI3K, phosphoinositide-3 kinase; PTEN, phosphatase and tensin homologue deleted on chromosome ten.
From Eichhorn PJ, Gili M, Scaltriti M et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance
that is reversed by the mTOR/phosphatidylinositol 3-kinase
inhibitor NVP-BEZ235. Cancer Res 2008;68:92219230,
with permission.

15

Targeting PI3K in Breast Cancer

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Figure 4. Phase 2 neoadjuvant everolimus (RAD001) breast cancer study: Change in Ki67.

The agent, which can be administered orally, does not inhibit mTOR or the mitogen-activated protein kinase/extracellular signalrelated kinase kinase pathway, and has
demonstrated preclinical efficacy in PI3K, PTEN, and
KRAS mutant xenografts. Initial phase I studies have demonstrated an adequate safety profile.
In a single-agent dose-escalation study, two XL147 dosing
schedules were investigated. These include 20 days on and 7

days off (21/7) and a continuous daily schedule. The first study
also included a cohort expansion in patients with non-small
cell lung cancer (NSCLC) and lymphoma [14]. A second
study in NSCLC patients is being expanded, combining
XL147 with erlotinib [15]. A third study is combining XL147
with paclitaxel and carboplatin, with cohort expansions in patients with endometrial cancer, ovarian cancer, and NSCLC [16].
In the first study, 48 patients were enrolled by the time

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Figure 3. Strategies to overcome resistance in hormone receptorpositive breast cancer.

Abbreviations: CBP, CREB binding protein; ER, estrogen receptor; ERE, estrogen-responsive element; HER2, human epidermal growth factor receptor 2; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase/extracellular
signalrelated kinase kinase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide-3 kinase; SOS, son of sevenless.
From Di Cosimo S, Baselga J. Management of breast cancer with targeted agents: Importance of heterogenicity. Nat Rev Clin
Oncol 2010;7:139 147, with permission.

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Figure 7. Activation of IRS1 and Akt by mTOR inhibitors is

prevented by the co-administration of anti-IGF-1R monoclonal antibodies.
Abbreviations: IGF1-R, insulin-like growth factor 1 receptor; IRS1, insulin receptor substrate 1; mTOR, mammalian target of rapamycin; PDK1, 3-phosphoinositide-dependent
protein kinase 1; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol
triphosphate; PTEN, phosphatase and tensin homologue deleted on chromosome ten; RAPTOR, regulatory associated
protein of TOR; RICTOR, rapamycin-insensitive companion
of mammalian target of rapamycin; TSC, tuberous sclerosis.

Figure 6. mTOR represses IRS1 under basal conditions.

Abbreviations: IGF1-R, insulin-like growth factor 1 receptor; IRS1, insulin receptor substrate 1; mTOR, mammalian target of rapamycin; PDK1, 3-phosphoinositide-dependent
protein kinase 1; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol
triphosphate; PTEN, phosphatase and tensin homologue deleted on chromosome ten; RAPTOR, regulatory associated
protein of TOR; RICTOR, rapamycin-insensitive companion
of mammalian target of rapamycin; TSC, tuberous sclerosis.

data were presented at the 2009 annual meeting of the

American Society of Clinical Oncology (ASCO). A maximum-tolerated dose (MTD) of 600 mg was determined for

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the 21/7 dosing schedule. The trial is still ongoing with continuous daily dosing. A dose-limiting toxicity of rash was
reported. For the most part, however, the compound is well
tolerated. There is excellent pharmacodynamic clinical evidence of inhibition of the pathway, in addition to evidence
of clinical activity [14].
Clinical responses have been reported in a patient with
NSCLC and also in a proportion of patients with longstanding, stable disease 12 weeks.
Interestingly, the compound also inhibits extracellular signalrelated kinase (ERK) signaling, as seen by immunochemistry [14]. Inhibition of ERK signaling is not
seen with mTOR inhibitors, which actually activate the
pERK pathway, and likewise has not been reported with
other PI3K inhibitors. Potential mechanisms leading to
this lack of ERK activation are unknown.
Another compound, XL765, is a dual mTOR and PI3K in-

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Figure 5. The mTOR inhibitor everolimus increases tumor

pAkt in breast cancer patients.
From Tabernero J, Rojo F, Calvo E et al. Dose- and scheduledependent inhibition of the mammalian target of rapamycin pathway with everolimus: A phase I tumor pharmacodynamic study in
patients with advanced solid tumors. J Clin Oncol 2008;26:1603
1610. Reprinted with permission. 2008 American Society of
Clinical Oncology. All rights reserved.

Targeting PI3K in Breast Cancer

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under discussion at the time of this presentation, it is likely

that the phase I study will be a classical 33 dose escalation, and then the phase II study will have 50 patients accrue
to each arm. The key eligibility criteria will include postmenopausal patients with ERPR tumors with metastatic
breast cancer. Eligible patients will also be refractory to a
nonsteroidal aromatase inhibitor. The primary objective of
the phase I study is to determine the MTD; the phase II objective will be the objective response rate and progressionfree survival rate at 3 months.
Another phase I/II study is planned with XL147 in patients
who have received trastuzumab and who have failed to respond to treatment. One treatment arm will consist of XL147
in combination with trastuzumab, and the other treatment arm
will consist of XL147 in combination with trastuzumab and
paclitaxel. The phase I and phase II studies will each accrue 25
patients to each arm and are being conducted with the goal of
answering important therapeutic questions.
The primary endpoint of the phase I study is the MTD of
XL147 in combination with each regimen (trastuzumab or
trastuzumab plus paclitaxel). The phase II primary endpoint is
the objective response rate. Eligible patients will have metastatic HER2 breast cancer, and will have progressed on at
least one prior trastuzumab-containing regimen. Tumor biopsies will be requested in the phase II trial, when feasible.

REFERENCES

Kalinsky K, Jacks LM, Heguy A et al. PIK3CA mutation associates with

improved outcome in breast cancer. Clin Cancer Res 2009;15:5049 5059.

Berns K, Horlings HM, Hennessy BT et al. A functional genetic approach

identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007;12:395 402.

Eichhorn PJ, Gili M, Scaltriti M et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/
phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008;

Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:

16551657.

Wellcome Trust Sanger Institute. Catalogue of Somatic Mutations in Cancer (COSMIC). Available at: http://www.sanger.ac.uk/genetics/CGP/
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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 6091.

CONCLUSIONS
Mutations in the PI3K pathway are frequent in breast
cancer and result in resistance to HER2-targeted agents
and, possibly, to hormonal agents as well. Anti-mTOR
agents have clinical activity against breast cancer, but activation of feedback loops may result in decreased efficacy.
In phase I studies, the PI3K inhibitors XL147 and
XL765 have been shown to effectively block the PI3K and
ERK pathways, and they have demonstrated signs of clinical activity. Phase II clinical trials with XL147 are under
way in two settingsin hormone-refractory disease and
also in patients who have failed trastuzumab. Trial results
are awaited to determine the role of these new agents in
clinical practice.

68:92219230.

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hibitor. In terms of mTOR inhibition, this is a catalytic inhibitor of TORC1 and TORC2, as opposed to the rapamycin
analogs described above that target solely TORC1. Like
XL147, the agent is designed for oral administration and has
demonstrated clinical efficacy in a variety of models.
There are a number of phase I clinical trials currently
under way with XL765. The first study is looking at different dosing schedules daily or twice a day [17]. Other
studies are investigating XL765 in combination with temozolomide in glioblastoma multiforme patients [18], and in
combination with erlotinib, with expansions in NSCLC patients [19]. At the time of the last report at the 2009 ASCO
meeting, 51 patients had been enrolled. An MTD of 50 mg
twice daily was identified, and the first study is still enrolling on a daily schedule.
With XL765, dose-limiting toxicities have included
transaminase elevations at higher dose levels. These were reversible and not seen at lower levels. Excellent pharmacodynamic activity has been observed in normal and tumor tissue,
and some evidence of clinical antitumor activity has been observed as well, including in patients with KRAS-mutant colorectal cancer. Impressive inhibition of the pathway was seen
by examining pAkt and pEBP1. Similar findings were also observed with respect to ERK inhibition.
Based on these promising initial clinical data, phase II
studies are now open or about to be open to enrollment for
patients with ER/progesterone receptor (PR) breast cancer, and in those with HER2 disease. Although these trials
will initially enroll a wide patient population, potential enrollees will eventually undergo real-time advanced tumor
genotyping in order to select for patients with tumors with
either PI3K mutations or PTEN deletions. Hence, it is anticipated that a number of patients in each cohort will have
PI3K mutations, so that patients with a higher likelihood of
benefiting may be included in the study.
A phase I/II randomized study of letrozole and XL147
versus letrozole and XL765 is also planned. This interesting
design will pose the question of whether it is better to inhibit
PI3K alone or PI3K and mTOR when given in combination
with hormonal therapy. Although the study design was still

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Di Cosimo S, Baselga J. Management of breast cancer with targeted agents:

Importance of heterogenicity. Nat Rev Clin Oncol 2010;7:139 147.

IGF-1R antibody dalotozumab (DALO) in patients (pts) with advanced

solid tumors. J Clin Oncol 2010;28(15 suppl):3008.

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 2637.

14 Shapiro G, Kwak E, Baselga J et al. Phase I dose-escalation study of

XL147, a PI3K inhibitor administered orally to patients with solid tumors.
J Clin Oncol 2009;27(15 suppl):3500.

Andre F. Multicenter phase I clinical trial of daily and weekly RAD001 in

combination with weekly paclitaxel and trastuzumab in patients with
HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab. J Clin Oncol 2008;26(suppl):1003.

11 Tabernero J, Rojo F, Calvo E et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: A
phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008;26:16031610.
12 Di Cosimo S, Scaltriti M, Val D et al. The PI3-K/AKT/mTOR pathway as
a target for breast cancer therapy. J Clin Oncol 2007;25(suppl 18):3511.
13 Di Cosimo S, Bendell JC, Cervantes-Ruiperez et al. A phase I study of the
oral mTOR inhibitor ridaforolimus (RIDA) in combination with the

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16 Wheler JJ, Traynor AM, Bailey HH et al. A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with paclitaxel (P) and carboplatin (C) in patients with advanced solid
tumors. Mol Cancer Ther 2009;8(suppl 1):B247.
17 LoRusso P. A phase I dose-escalation study of the safety, pharmacokinetics
(PK), and pharmacodynamics of XL765, a PI3K/TORC1/TORC2 inhibitor
administered orally to patients (pts) with advanced solid tumors. J Clin Oncol 2009;27(15 suppl):3502.
18 Wen PY, Omuro AM, Batchelor TT et al. A Phase 1 safety and pharmacokinetic study of XL765 (SAR245409), a novel PI3K/TORC1/TORC2 inhibitor, in combination with temozolomide (TMZ) in patients (pts) with
malignant glioma. Mol Cancer Ther 2009;8(suppl 1):B265.
19 Janne PA, Felip E, Cedres S et al. A phase 1 safety and pharmacokinetic
(PK) study of PI3K/TORC1/TORC2 inhibitor, XL765 (SAR245409), in
combination with erlotinib in patients (pts) with advanced solid tumors.
Mol Cancer Ther 2009;8(suppl 1):A254.

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10 Atzori F, Tabernero J, Cervantes A et al. A phase I, pharmacokinetic (PK)

and pharmacodynamic (PD) study of weekly (qW) MK-0646, an insulinlike growth factor-1 receptor (IGF1R) monoclonal antibody (MAb) in patients (pts) with advanced solid tumors. J Clin Oncol 2008; 26(15 suppl):
3519.

15 Faulkner N, LoRusso PM, Guthrie T et al. A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients with advanced solid tumors. Mol Cancer Ther
2009;8(suppl 1):C197.