2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TREATMENT OF ADVANCED BREAST CANCER
metastatic setting. If not previously used, an anthracycline
is an appropriate option. The taxanes (particularly weekly
paclitaxel) are a mainstay of treatment and one of the most
commonly employed first-line regimens, particularly as a
backbone for new treatment approaches with combined
biologic agents. Other active agents include capecitabine,
gemcitabine, eribulin, and vinorelbine. The platinum salts,
both carboplatin and cisplatin, are also used in patients with
metastatic triple-negative disease. 22
A variety of biologic agents have been evaluated in patients
with triple-negative disease in conjunction with chemotherapy.
Bevacizumab was commonly administered with
a taxane for metastatic triple-negative disease, but the
benefits of this approach have been called into question
based on the results of recent trials and a meta-analysis, and
the FDA withdrew approval for bevacizumab as a treatment
for MBC. 23,24 Although there is great interest in the PARP
inhibitors, and an initial randomized phase II clinical trial
suggested a substantial benefit when iniparib was combined
with carboplatin-based chemotherapy; 25 a subsequent phase
III trial failed to support these preliminary results. 26
HER2-Positive Breast Cancer
Trastuzumab, a humanized monoclonal antibody directed
against HER2, plus chemotherapy represents the standard
first-line approach for patients who have ER-negative disease
or have had progression on endocrine therapy. 4 In
initial trials, trastuzumab was combined with a taxane, but
more recent studies have suggested that other chemotherapeutic
agents, such as vinorelbine, yield similar results. 27
Recent evidence suggests that continued suppression of
HER2 with trastuzumab is useful even after disease progression.
28
Lapatinib, a small molecule tyrosine kinase inhibitor
directed against EGFR and HER2, is also approved for
the treatment of HER2-positive breast cancer in combination
with capecitabine. 29 Many patients receive a combination
of lapatinib and capecitabine at some point in their
treatment course, after the first or second trastuzumabbased
regimen, and subsequently return to trastuzumab. Of
interest, the combination of trastuzumab and lapatinib
Table 1. Targeting Breast Cancer Cells (Cont’d)
Compound Molecular Target Clinical Trials Pharmaceutical
Entinostat (SNDX-275 or
MS-275)
HSP90
Tanespimycin (17-AAG) HSP90–Geldanamycin
derivative
AUY922 HSP90 (nongeldanamycin
derivative)
HDAC class I -Phase II with lapatinib in trastuzumab resistant HER2� MBC (NCT01434303) Syndax
-Phase II with azacitidine in MBC (NCT01349959)
-Phase II exemestane � entinostat in HR� MBC ( NCT00676663)
-Phase II trial completed (ENCORE 301) of continuing AI upon progression of HR� MBC with the
addition of entinostat (NCT00828854)
-Phase II with trastuzumab in HER2� MBC (NCT00817362) completed (02.01.2012) Infinity
-Phase II with trastuzumab in trastuzumab pretreated HER2� MBC (NCT00773344) completed
-Phase I/II trial monotherapy in HER2� or ER� MBC (NCT00526045) Novartis
-Phase I/II with trastuzumab in HER2� MBC (NCT01271920)
-Phase I/II trial with lapatinib and letrozole in HER2� MBC (NCT0136194)
Retaspimycin (IPI-504)
AR
HSP90 -Phase II with trastuzumab in trastuzumab pretreated HER2� MBC (NCT00817362) completed Infinity
Bicalutamide AR -Phase II monotherapy in AR�ER-PR- MBC (NCT00468715) AstraZeneca
Abiraterone
PRL
-Phase II abiraterone � exemestane in ER� MBC after AI failure (NCT01381874) Johnson & Johnson
LFA 102 PRL-R -Phase I monotherapy in PRL� MBC (NCT01338831) Novartis
Abbreviations: MBC, metastatic breast cancer; AI, aromatase inhibitor; BC, breast cancer; MoAb, monoclonal antibody; EGFR, epidermal growth factor receptor; CNS,
central nervous system; GSK, GlaxoSmithKline; PTEN, phosphatase and tensin homolog; HDAC, histone deacetylase; AR, androgen receptor; FGF, fibroblast growth
factor; VEGFR, vascular endothelial growth factor receptor; PI3K, phosphatidylinositol 3-kinase; CDK, cyclin-dependent kinase; ER, estrogen receptor; PR,
progesterone receptor; IGF, insulin-like growth factor.
without chemotherapy has also been shown to be an active
regimen and substantially more effective than lapatinib
alone. 30
The development of central nervous system (CNS) disease
is a major challenge that is faced by more than a third of all
women with HER2-positive metastatic disease. As women
live longer with HER2-positive metastatic disease, the incidence
of CNS disease increases. Treatment options include
whole brain irradiation, stereotactic radiosurgery, surgery,
and a number of systemic approaches. Of the available
medical therapies, single-agent lapatinib results in rare
objective responses, but a combination of capecitabine plus
lapatinib appears to be more active. 31
The development of trastuzumab (and, subsequently,
lapatinib) for MBC is an example of the problem of leaving
unanswered questions in the metastatic setting once therapy
has moved to the adjuvant setting. It took almost a
decade to gather evidence about the best dose and regimen
(weekly and 3-weekly regimens with a loading dose are
similar), the best timing of introduction, the best agent to
combine it with (several options now known to exist), and
the efficacy of this treatment beyond progression. For patients
with ER-positive, HER2-positive disease, the combination
of aromatase inhibitor therapy with HER2-targeted
therapy is superior to aromatase inhibitor therapy alone.
This combination may be considered as an alternative to a
chemotherapy plus HER2-targeted therapy in selected patients.
Treatment Future: Newer Targeted Agents in
Metastatic Breast Cancer
Gene-expression profiling analysis studies 32 have fundamentally
changed the way we think about breast cancer,
which is now considered a group of diseases with distinct
genetic and epigenetic alterations. The translation of this
improved molecular knowledge into effective molecularlytargeted
agents is slower than expected. The advent of
next-generation sequencing technologies has generated new
enthusiasm, 33 with the promise of better identification of the
molecular defects responsible for carcinogenesis.
33