2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

BIOMARKERS AND COLORECTAL CANCER
mutations who received FU/LV reversed the poor survival of
women with tumors harboring zinc-binding mutations and
improved 5-year OS (50% vs. 73%; p � 0.1). No difference in
OS was observed for men in either treatment arm or when
genotype was considered. We conclude that CALGB 89803
demonstrated a lack of survival benefit for patients with
stage III colon cancer when IFL was added to FU/LV. We
now show that in the setting of a large clinical trial, refined
stratification of women, based on domain-specific mutations
of p53 identifies subsets of patients likely to benefit from, or
respond poorly to, adjuvant FU/LV. The interaction of p53
genotype, gender, and adjuvant therapy regimen has the
potential to be paradigm changing in the treatment of colon
cancer, and possibly other malignancies (Table 2).
These data, if validated, suggest that evaluation of p53
genotype and gender may guide clinicians to make rational
choices of adjuvant therapy. Clearly, prospective clinical
trials must be sufficiently large and adequately powered to
ferret out previously undescribed interactions between oncogenes,
tumor suppressor genes, and gender.
In summary, although many studies purporting to demonstrate
either prognostic or predictive value in a variety of
markers (DNA based, protein based, and metabolite based)
have been published, only a few have acquired sufficient
evidence to warrant possible inclusion in clinical decision
making in colon cancer. 46-48 Further, a variety of regulatory
hurdles must be addressed during biomarker development
in the future. 47
The Road Ahead: Companion Diagnostics in
Clinical Trials
As use and interest in laboratory-developed tests continues
to grow, it will be important to work with the FDA to
define the oversight framework that takes into account
higher-risk tests that require more complex validation,
equipment, and software. Regulatory clarity and predictability
will be important to ensure that high-quality tests
reach the market expeditiously.
Authors’ Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Alan P. Venook Abbott
Laboratories (U);
Bristol-Myers
Squibb (U);
Chugai Pharma
(U)
Johanna C. Bendell*
Robert S. Warren*
*No relevant relationships to disclose.
1. Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan,
fluorouracil, and leucovorin as first-line treatment for metastatic colorectal
cancer: updated analysis of overall survival according to tumor KRAS and
BRAF mutation status. J Clin Oncol. 2011;29:2011-2019.
2. De Roock W, Jonker DJ, Di Nicolantonio F, et al. Association of KRAS
p.G13D mutation with outcome in patients with chemotherapy-refractory
metastatic colorectal cancer treated with cetuximab. JAMA. 2010;304:1812-
1820.
3. Tejpar S, Bokemeyer C, Celik I, et al. The role of the KRAS G13D
mutation in patients with metastatic colorectal cancer (mCRC) treated with
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630).
Laboratory tests have been critical to recent advances in
oncology because they can be developed rapidly and targeted
locally. Currently, no controls have been placed on the
marketing claims of theses tests, and limited control of test
development exists. Likewise, there are limited premarket
independent review or postmarket reporting requirements.
These requirements are dependent on state regulations
and/or the laboratory accreditation process. Currently, some
of these functions for laboratories performing molecular
testing, such as postmarket performance, are conducted
voluntarily.
Some sectors are concerned that additional regulation of
molecular testing may harm innovation because associated
regulatory barriers may hinder the pace of progress.
The product lifecycles of molecular testing assays often
differ from those of drugs. This could present issues related
to innovation with new therapies and their companion
diagnostics.
Most molecular testing is performed in laboratories that
meet or exceed the laboratory quality standards currently
set by the Centers for Medicare & Medicaid Services (CMS,
Rockville, MD) under the Clinical Laboratory Improvement
Amendments (CLIA). However, CLIA regulations do not
measure the clinical validity or clinical utility of individual
molecular tests. The FDA does have the authority to ensure
the safety and effectiveness of molecular tests, which includes
an evaluation of clinical validity.
New therapies that are found to be effective in patients
with a specific biomarker profile may require a companion
diagnostic test to be approved by the FDA if these tests are
considered essential for the safe and effective use of a
therapy. Label changes to already approved treatments can
also be required if a companion diagnostic is shown to
improve safety. It will be important to understand how
clinical trials for drugs and their companion diagnostics
should be designed and carried out, validated, and brought
to the clinic. 49,50
Stock
Ownership Honoraria
REFERENCES
Research
Funding
Amgen; Bayer;
Genentech;
ImClone
Systems;
Novartis; Pfizer
Expert
Testimony
Other
Remuneration
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199