2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

date. With the advent of gene expression profiling, several
gene signatures of endocrine sensitivity, including the
HOXB13:IL17RB ratio 21,22 and the Sensitivity to Endocrine
Therapy (SET index), 23 have been identified. In addition,
the estrogen-regulated gene GREB1 has been shown to be a
critical regulator of hormone-dependent breast cancer
growth and may serve as a marker of endocrine therapy
sensitivity 24 Bianchi and colleagues from Italy recently
presented evidence that a signature of four estrogen-related
genes and 12 mitotic kinase genes has the potential to
predict resistance/sensitivity to hormone therapy. 20 The fact
that many signatures are emerging on the basis of the same
biologic principles, and can be generated from the tissue
sample at the time of diagnosis, suggests that these types of
signatures are likely to validate and find their way into
clinical trials and practice. By using the neoadjuvant approach,
even more discriminatory signatures are likely to
emerge. These predictors will not only identify women at
risk, but we hope will also suggest targeted strategies, based
on timing of treatments as well as novel agent combinations,
that will substantially improve outcomes specifically for the
groups at risk.
Identifying Risk and Response to Therapy in
HR-Negative Tumors
For HR-negative tumors and HER2-positive tumors, the
risk of recurrence is early, largely in the first 5 years. In
these tumors, proliferation does not seem to be a driver, as
the majority of tumors are indeed proliferative. In this
population, immune-based signatures seem to have the most
predictive signatures, and they can predict risk within the
first 5 years. 15 Importantly, there is evidence that in some
patients with node-negative, HR-negative disease, risk is
quite low as a result of high immune responsiveness. This
has been shown independently in several studies. 25 We have
also recently identified immune- and cytokine-based gene
expression levels capable of identifying early-stage HRnegative/triple-negative
breast cancer at the lowest risk for
developing early or late metastatic recurrence. 18 Both of
these signatures have been translated to CLIA-certified
RNA-based assay platforms and preliminarily validated
with our retrospective collection of formalin-fixed paraffinembedded
breast tumor–derived RNA samples, 18,25 and
have been shown to be able to predict HR-negative and
triple-negative metastatic outcome. 15,18 There is clearly a
spectrum of risk that is modified by the expression of
immune-related genes, suggesting that there is an important
component of immune responsiveness that drives outcome
in HR-negative tumors. This conclusion is further
supported by the identification of the T-cell/macrophage
signature that confers chemoresistance, described in the
following section.
Immunity and Sensitivity to Chemotherapy: T-Cell and
Macrophage Signatures
Leukocyte infiltration into breast tumors has been observed
in the context of both protumorigenic inflammation
and anticancer immunosurveillance. Thus, beyond just the
composition of the immune infiltrate, the immune context of
these leukocytes (their distribution, density, architecture,
and interactions) must be analyzed to understand their
prognostic significance. Although the mechanisms involved
in leukocyte infiltration into tumors are poorly character-
188
ESSERMAN, BENZ, AND DEMICHELE
ized, a recent study found high endothelial venules (HEVs),
blood vessels normally found in lymphoid tissues specialized
in lymphocyte recruitment, in a variety of solid tumors. 26
High densities of HEVs in breast cancers correlated with a
more pronounced infiltration by T cells and conferred a
lower risk of relapse and significantly longer metastasisfree,
disease-free, and overall survival rates. 26
T lymphocytes—in particular CD8-positive T lymphocytes—are
a crucial component of cell-mediated immunity.
Several studies have examined the prognostic value of
tumor-infiltrating lymphocytes (TILs) and/or CD8-positive
TILs in breast cancer. 27,28 Interestingly, high TILs are
associated with better responses to chemotherapy and improved
disease-specific survival, particularly in HR-negative
tumors.
We, and others, have shown that high numbers of tumorassociated
macrophages (TAMs) are associated with high
grade, HR-negative breast cancers and poor outcomes. 29,30
Recently, we proposed a gene expression signature related to
cytotoxic T-cell (Tc) responses and major histocompatibility
complex class II expression that might serve as a surrogate
for an anticancer immune microenvironment in breast cancer.
31 Others have proposed combinations of macrophage
and T-cell markers as markers of poor outcomes on the basis
of both mouse and human studies. 32,33 These results illustrate
the importance of understanding the immune context
of leukocytes within the tumor microenvironment, and the
opportunity we may have to improve outcomes by targeting
the immune microenvironment as part of our therapeutic
strategy.
Trials that Focus on Development of Drug-Biomarker
Pairs and Response to Treatment in the
Neoadjuvant Setting
Increasingly, it is clear that all drugs will not benefit all
patients with breast cancer. As new targeted drugs are being
tested, more and more trials are incorporating biopsies
before and after treatment to both determine predictors to
therapy response and also assess pharmacodynamics. Biopsy
at the time of presentation of metastatic disease is
increasingly becoming the standard of care, given that 20%
to 35% of metastatic lesions are discordant from the primary
tumor on the basis of HR or HER2 status. 34,35 However, this
is problematic on several fronts. First, it is challenging to
perform biopsies of metastatic lesions: There are associated
risks depending on the location of these lesions. Second, the
standard setting for testing new drugs is in patients with
metastatic disease, often when they have experienced failure
with first- and second-line treatments. Novel therapies
may be less effective once tumors have progressed through
several treatment regimens, and serial biopsies performed
with subsequent lines of therapy compound the risk. Finally,
effective agents have resulted in longer control of metastatic
disease, but rarely cure. Those same agents, when administered
at the time of primary diagnosis, have resulted in cure.
Trastuzumab is the prime example of this phenomenon. 4,5
Determining appropriate end points in the metastatic setting
that predict curative potential when administered at
the time of diagnosis has been challenging.
One approach to determining which biologically defined
tumors are most likely to benefit from which therapy is to
introduce new agents at the time of diagnosis. This approach
is feasible because neoadjuvant therapy is increasingly