2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

with the mTOR pathway. 44 The combined treatment led to
an impressive 6.5 month extension of PFS. 43
There are four additional classes of PI3K pathway inhibitors
in clinical development: dual PI3K-mTOR inhibitors,
PI3K inhibitors that do not inhibit mTOR, AKT inhibitors,
and mTOR catalytic inhibitors (also called pan-mTOR inhibitors
because they inhibit mTORC2 in addition to mTORC1)
(Fig. 1). The future will tell if these newer agents are
effective and tolerable pathway inhibitors or are able to
overcome feedback inhibition normally observed with
mTORC1 inhibitors.
Of critical importance will be the identification of populations
in which the benefits of these PI3K pathway inhibitors
will justify their manageable but real toxicity–the current
assumption is that PI3KCA-mutated cancers and PTENdeficient
cancers will be at the top of the list. This would
suggest that this family of compounds may find a role in all
three types of breast cancer.
Recently, there has been growing interest in combining
PI3K with MEK pathway inhibitors. Many cancers sensitive
to PI3K pathway inhibitors show tumor stasis rather than
regression. The MEK pathway can represent an escape
route in the presence of effective downregulation of the PI3K
pathway. Therapeutic inhibition of both pathways is under
clinical investigation with the use of MEK and PI3K inhibitors
(Table 1).
Instability of the genome is inherent to the great majority
of human cancer cells and is instrumental for tumor progression.
It has been proposed as a fundamental hallmark of
cancer. 45
Although PARP inhibitors have clearly demonstrated
striking antitumor activity in BRCA mutation carriers with
advanced breast cancer, their activity in sporadic triplenegative
breast cancer, alone or in combination with chemotherapy,
has been less consistent. Myelosuppression has
been an obstacle to their development. It remains uncertain
whether PARP inhibitors will find an application beyond the
treatment of BRCA-mutated tumors.
Strategies directed at hallmarks of cancer in early development
for MBC. Cyclin-dependent kinase inhibitors target
evasion from growth suppressors by directly interfering with
the cell cycle, downstream of the receptor tyrosine kinase
signaling cascades. Several CDK inhibitors are in phase I or
II trials, in combinations with either endocrine therapy in
luminal cancers or chemotherapy for basal-like cancers. A
randomized trial of letrozole with or without a CDK-4, -6
inhibitor 25 has generated promising results. 46
A similar anticancer strategy is inhibition of Aurora
kinases. These serine/threonine kinases play an essential
role in cellular proliferation, through control over chromatid
segregation. Agents targeting Aurora kinases have entered
early clinical trials.
Proapoptotic agents aim at antagonizing “resistance to
cell death,” and a number of them are in phase I clinical
trials (Table 1). Triple-negative breast cancer seems to be a
priority given the high prevalence of p53 mutations seen in
this subtype.
Strategies directed at epigenetic aberrations or at downregulation
of key intracellular targets. As our understanding
of the deregulation of epigenetic mechanisms evolves, growing
interest in targeting these aberrations has emerged.
Histone deacetylase inhibitors are progressing from phase I
to phase II trials with interesting results seen when these
36
SLEDGE, CARDOSO, WINER, AND PICCART
agents are combined with endocrine agents or anti-HER2
drugs.
Heat shock protein 90 (HSP90) represents another interesting
anticancer target in MBC. 47 A molecular chaperone,
HSP90 plays a vital role in the intact function of several
oncogenic proteins and, thus, promotes key molecular events
in malignant progression. Several agents have been tested
with promising results in HER2-positive MBC.
Antihormone strategies. The androgen and prolactin receptors
are being explored in advanced breast cancer. The
androgen receptor (AR) has recently been shown to play a
role in HER2-positive/estrogen receptor-negative breast
cancers, which can get stimulated by testosterone and also
show upregulation of the Wnt signaling pathway. 48 Moreover,
AR positivity has been found in approximately 20% of
triple-negative breast cancers, 49 and a phase II study with
bicalutamide for ER-negative breast cancer expressing AR
has recently been performed.
Targeting Breast Cancer Stem Cells
The identification of a cellular subpopulation in breast
cancer with a specific immunophenotype (i.e., CD44 �
CD24 - ) 50 bearing a tumor-initiating capacity was the first
identification of cancer stem cells (CSCs) in the setting of a
solid tumor. Ever since, a detailed exploration of this cellular
compartment of breast cancer has been undertaken, and
this expanding knowledge provides novel therapeutic targets
51 for this therapy-resistant cellular population.
One of the fundamental aspects of CSCs is their capacity
for self-renewal, mediated through well-conserved developmental
signaling pathways 52 (the Notch, Hedgehog, and
Wnt pathways) amenable to therapeutic targeting. The
Notch signaling pathway, frequently deregulated in breast
cancer, 53 can be targeted by gammasecretase inhibitors
(Table 2). These small molecules block the translocation of
the intracellular part of the Notch receptor to the nucleus
and corresponding signaling pathway activation. The
Hedgehog signaling pathway has also been shown to promote
the tumor-initiating ability of breast CSCs. 54 A class of
compounds called Smo-antagonists has entered clinical trials
(Table 2).
A second approach targeting breast CSCs is based on
high-throughput screening methods. A population of breast
cancer cells enriched for CSCs are screened either for
druggable targets through shRNA/siRNA technology or
through the testing of extended small molecule compound
collections. Based on the latter approach, Gupta and colleagues
55 recently discovered that salinomycin is able to
eradicate breast CSCs.
Targeting the Tumor Microenvironment
Tumor cells are integrated into their microenvironment,
constantly interacting with it. 56 These components are
appealing therapeutic targets, with antiangiogenic factors
being the most clinically advanced. The failure of bevacizumab,
a humanized monoclonal antibody targeting
VEGF-A, to extend OS of MBC patients 23,57 should not be
regarded as a proof of failure of the concept of antiangiogenic
therapy in breast cancer. The assumption that bevacizumab
administration potentiates the delivery of higher intratumor
chemotherapy concentrations proved incorrect. 58 Moreover,
the redundancy of different angiogenic mechanisms and
proangiogenic factors could explain this clinical failure, as