2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

MOLECULAR ABERRATIONS IN BREAST CANCER
Fig. 1. Recurrence-free survival (RFS) stratified
by response to therapy, complete pathologic
response (pCR) for the population of 172
patients, excluding all patients receiving neoajuvant
trastuzumab overall and by hormone
receptor (HR)-positive/HER2-negative subset,
HR-negative/HER2-negative (triple-negative)
subset, and HER2-positive subset. All patients
received neoadjuvant chemotherapy with a
doxorubicin regimen followed by a taxane.
RFS for all patients (excluding those receiving
trastuzumab, 37 patients) is shown on the left
and on the right for the receptor subsets. The
solid line represents patients who achieved a
pCR and the dotted lines represent patients
who did not. HR-positive/HER2-negative tumors
are shown in blue, triple negative tumors
are shown in red, and HER2-positive tumors
are shown in green. Reprinted with permission.
© American Society of Clinical Oncology.
All rights reserved. 40
being used as a standard of care. 36 The order of therapy
(surgery or systemic therapy first) does not affect the efficacy
of therapy. 37,38 However, sequencing systemic therapy first
allows the measurement of response to therapy and the safe
capture of tissue specimens during the course of treatment.
The I-SPY TRIAL and others have demonstrated that response
to therapy is predictive of ultimate outcome and that
those with either complete or near-complete response to
chemotherapy in fact have much better outcomes than those
who have large residual cancer burdens. 39-41 Importantly,
this relationship between response to treatment and outcome
is even stronger by tumor subset (Fig. 1)—whether
looking by receptor subtype 40 or by molecular subset. 42
We now have the opportunity to test emerging new agents
in the neoadjuvant setting for women at high risk for
recurrence. To do this efficiently, we need clinical trial
designs that take the heterogeneity of disease into account,
a paradigm for identifying the most effective agents and
their associated predictive biomarkers and a more rapid
path to getting such drugs to market. The I-SPY 2 TRIAL
design is an adaptive clinical trial focused on women at the
time of primary diagnosis with tumors 2.5 cm or larger. The
first step of the process is to generate a molecular profile
from core biopsy of the primary tumor; those women found to
be at high risk for early recurrence, on the basis of a
high-risk classification by the 70-gene profile, are then
randomly assigned to either standard therapy or standard
therapy in combination with a novel agent. The philosophy
of the I-SPY 2 TRIAL is to accelerate the testing of promising
new targeted agents by enabling their first phase II
assessment to be in the neoadjuvant setting. To accomplish
this, the I-SPY 2 TRIAL has established a precompetitive
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