2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

MOLECULAR ABERRATIONS IN BREAST CANCER
tify patients who may be refractory to therapy and at
highest risk for metastatic progression. 12 In addition, we
now have access to powerful assay platforms and informatics
tools that can generate and integrate tens of thousands of
gene expression data from very small slices of archival
tumor. This, in turn, creates the opportunity to validate
promising gene signatures and integrate them into a userfriendly,
personalized clinical breast cancer application that
provides prognostic and predictive tools to all patients with
all types of breast cancer.
There are several important questions that have the
potential to be addressed by using new and emerging candidate
signatures. We discuss them in the following sections.
Evidence of Very-Low-Risk Tumors and Tools
for Prediction
Screening has clearly led to an increase in the number of
detected cancers. 13 Many of these tumors are likely to be
indolent, and the term “IDLE tumors” has been suggested to
differentiate tumors that are life-threatening and those that
are not. 13 As shown by Esserman and van’t Veer, it is
possible to identify molecular evidence of such tumors by
defining an “ultra-low” threshold for the 70-gene profile that
could identify tumors that, in the absence of any adjuvant
therapy, would not result in distant progression. By using
two large European data sets, they showed that with the
advent of screening, the incidence of these IDLE tumors has
increased, and that in women with screen-detected cancers,
30% could fit the definition of IDLE tumors and potentially
not need additional therapy. 14 Validation studies are currently
in progress. A tool that successfully predicted indolent
disease would have an enormous and beneficial impact
KEY POINTS
● Breast cancer is made up of several different diseases
with remarkable variation in the risk and timing of
recurrence.
● There are targeted treatments in breast cancer that
are established on the basis of inhibiting overexpressed
estrogen (ER) or HER2 receptors, and these
treatment strategies are being further refined by
using multigene subclassifiers.
● Proliferative lesions are most likely to benefit from
chemotherapy, and the genes turned on by activated
ER are emerging as predictors for sensitivity to
endocrine therapy. Additional signatures are being
developed to predict resistance to either or both
endocrine and chemotherapies.
● Existing and emerging predictive and prognostic biomarkers
are being integrated into clinical trials to
help focus treatments on patient subpopulations
most likely to benefit from systemic therapy.
● New and adaptive clinical trial designs can improve
the efficiency of new drug evaluation, particularly in
the context of biomarkers, and have already begun to
define a new regulatory path that will accelerate the
ability of targeted drug and biomarker pairs to be
used in the adjuvant setting.
for women, reducing the use of toxic therapies in women who
do not need them.
Evidence that Timing of Risk Is Related to
Tumor Biology
There is now a body of literature supporting the notion
that the timing of recurrence is a critical feature of the
biology of HR-positive breast cancer. By using a data set
from the late 1970s from Guy’s Hospital in London, before
the advent of adjuvant therapy and screening, we were able
to newly characterize 349 cases using more modern scoring
of ER and PR (HR), HER2, and grade to develop new tools to
understand the best order of integrating predictors of outcome.
The routinely used staging, histologic and immunohistochemical
features of primary breast cancers, provide
important information about overall relapse risk and timing
of future metastatic recurrence. By using a risk-partitioning
algorithm, we can identify the order in which the standard
clinical information can separate out groups of patients by
the degree and timing of risk. By using a classification and
regression tree approach, which identifies the order of importance
of the clinical variables, the first split in the data is
by node status (0 vs. any). For the node-negative patients,
the groups then split by HR-positive versus triple-negative
(both ER and PR negative) and HER2–positive disease.
HR-positive disease was split by low grade versus others.
The low-grade tumors appear to have late but not early
recurrence risk. 15 The risk-partitioning method identifies
the critical dependencies among variables and opportunities
where molecular information can clearly improve our ability
to fine-tune predictions of both early and late risk, as well as
the benefits of chemotherapy. Curated and analyzed published
breast cancer data sets can serve as an important
resource to validate candidate predictors for use in Clinical
Laboratory Improvement Amendments (CLIA)-certified
laboratories. 16-18 Although our analyses have shown that
tumor proliferative capacity is predictive of early breast
cancer metastasis—but only for HR-positive breast cancer
15-17 —we have also uncovered new predictors of late
metastatic recurrence by HR-positive breast cancer that
need additional validation with respect to routine adjuvant
endocrine therapy use. 15
We have clearly established that the timing of metastatic
recurrence is a critical feature of tumor biology. For HRnegative
tumors and HER2-positive tumors, recurrence risk
is early (within the first 5 years), but for HR-positive breast
cancer, the risk can extend for many years. Others have
demonstrated this as well. The conclusion that emerges is
that HR-positive tumors have a recurrence risk that can
span more than 20 years from the time of diagnosis. For
these patients, signatures that are based largely on the
expression of genes driving cell proliferation are predictive
only of early recurrence. Fortunately, investigators are now
focusing on finding predictors that can be used to identify
HR-positive breast tumors with higher likelihood of recurrence.
Dr. Liu and colleagues have described a 91-gene
signature to look for early recurrence as well as late recurrence,
between 5 and 20 years after diagnosis. 19,20
Sensitivity to Endocrine Therapy
Prediction of HR-positive patients most likely to benefit
from endocrine therapy remains a major clinical challenge to
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