2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

consortium to facilitate the testing of agents against a
backdrop of comprehensive tumor profiling, with the ability
to use the adaptive design process to enrich enrollment on
the basis of standard markers. The biomarker design of the
trial allows the evaluation of three levels of biomarkers. The
first are standard or investigational device exemption (IDE)
approved, which are integral markers used in the adaptive
randomization. These include hormone and HER2 receptors,
the U.S. Food and Drug Administration (FDA)—approved
70-gene profile, other measures of HER2 overexpression
(fluorescent in situ hybridization and expression array) and
volume on magnetic resonance imaging. The second level
comprises “qualifying” biomarkers. These are biomarkers
that have promise in predicting response to a specific agent,
but require validation in a CLIA-approved testing environment.
This includes cell line predictors that predict response
and can be read by expression array, or other specific
phosphoprotein that is thought to be a key target of a
particular agent. These markers, if they prove to be predictive
of response, would potentially be used as integral
markers in future trials of the agent and the data generated
from their evaluation in the I-SPY 2 TRIAL can be used to
support an IDE application. The last layer is the exploratory
biomarkers. These include hypothesis-generating markers
from new platforms such as RNAseq. The platforms being
Authors’ Disclosures of Potential Conflicts of Interest
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used to characterize tumors in the trial include Agilent
Technologies (Palo Alto, CA) and Affymetrix (Santa Clara,
CA) expression arrays, reverse phase protein arrays,
genome-wide association study (GWAS), and RNAseq.
The goal of the trial is to graduate agents and biomarker
pairs with a predicted likelihood of success in phase III
trials. 7 Going forward, if an agent is shown to improve the
chance of obtaining a pathologic complete response and this
observation can be confirmed in a separate neoadjuvant
trial, the FDA is willing to consider awarding accelerated
approval on the basis of these data. 43 This provides a
regulatory path forward for accelerating successful agents to
the neoadjuvant or adjuvant settings, in which they are
likely to provide the greatest benefit. Indeed, it is about time
that we design our trials around the biomarkers that characterize
risk and response to treatment. The I-SPY 2 TRIAL
is one such effort directed at more rapidly and efficiently
finding better options for patients with breast cancer. Furthermore,
this platform provides the opportunity to validate
several of the emerging markers described in the first
portion of this article, and to help us move faster toward the
time when we will be able to provide precision medicine
approaches to reduce the suffering and death associated
with a diagnosis of breast cancer.
Stock
Ownership Honoraria
Laura Esserman Agendia
Christopher Benz*
Angela DeMichele*
*No relevant relationships to disclose.
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