2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

mately 40% of patients with colorectal cancer have alterations
in the PI3K pathway including mutations and loss of
phosphatase and tensin homolog (PTEN) activity. 15,16 Multiple
agents that affect this pathway are in development,
including PI3K inhibitors, mammalian target of rapamycin
(mTOR) inhibitors, and AKT inhibitors. For patients with
colorectal cancer, studies have been reported looking at
mTOR inhibitors 17 and AKT inhibitors. 18 It remains to be
seen whether there is any association with outcomes with
these agents in patients who have documented abnormalities
in this pathway, but biomarker studies are underway.
c-MET
Overexpression of the c-met receptor in colorectal cancers
is associated with a poor prognosis. 19 c-MET activation is
associated with colon cancer tumorigenesis and metastasis,
and in preclinical studies inhibition of c-met decreases colon
tumor spread. 20 c-MET is also involved in signal transduction
when growth factor receptors such as EGFR and vascular
EGFR (VEGFR) are activated. 21 The combination of
c-MET and EGFR inhibition has shown in a randomized
phase II study improved time to progression and OS in
patients with non-small cell lung cancer with c-met overexpression.
22 c-MET inhibitors are currently under investigation
for patients with colorectal cancer. A phase I study of
IFL, cetuximab, and c-MET inhibitor ARQ-197 showed very
promising results in pretreated disease. 23 First- and secondline
studies are ongoing with inhibitors of the c-MET pathway.
We await further data on the correlation in patients
with colorectal cancer between c-MET expression and outcomes
with treatment with c-MET pathway inhibitors.
Ready for Prime Time: Conclusion
As you can see, the era of personalized medicine has
arrived for patients with colorectal cancer. We are already
using markers to help guide clinical decisions. The markers
we have will only continue to grow from here. We need to
continue to find new markers, which can be done only if
correlative biomarker studies are included in clinical trials.
We are at only the beginning of fully realizing the potential
of personalized biomarker status to deliver the best treatment
to our patients.
Robert S. Warren, MD: Personalized Oncology for
Colorectal Cancer: Stop the Train
The application of molecular biomarkers to prognosis, and
markers that are predictive of benefit from specific chemotherapeutic
regimens, is receiving tremendous interest on
the part of patients, clinicians, and the pharmaceutical
industry. Patients’ wishes, on the one hand, successful
therapeutics, and on the other hand, avoiding potentially
toxic therapy if the chance of benefit is remote; clinicians
search for guidance in the care of their patients who have
exhausted most standard therapy options, and the keen
interest of the pharmaceutical and biotechnology companies
in developing drugs that are effective, even if only in a
subset of patients with colorectal cancer, are all driving the
interest in the application of prognostic and predictive
biomarkers. Identifying biomarkers that would permit personalized
therapies and more successfully targeted drug
development may save lives and require many fewer millions
of dollars in drug development and in standard clinical
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trials. If fact, a review of PubMed shows papers describing
more than 60 new biomarkers for cancer just in 2011. Most
are retrospective studies, small and inadequately powered
to perform multivariable analysis in combination with more
thoroughly examined potential markers.
As a measure of the increasing interest in this pursuit, it
may be noteworthy that in PubMed, searching under “colon
cancer biomarkers,” 560 papers were published in 2008,
whereas 1,228 were published in 2011. Under “personalized
oncology,” 43 papers were published in 2008, whereas 161
papers were published in 2011.
The questions that Dr. Bendell so nicely discussed focus
on a few of these: KRAS/BRAF mutations and the activity of
EGFR antibodies (MoAby), the utility of gene expression
arrays in determining prognosis (generally in advanced
colorectal cancer), and the impact of microsatellite instability
on prognosis and response to chemotherapy. Despite a
plethora of research publications, the U.S. Food and Drug
Administration (FDA), the National Comprehensive Cancer
Network (NCCN), and ASCO 24,25,26 have recommended the
standard use of very few markers. The important question
here is why? Are there guidelines for the development,
verification, and validation of markers to hasten their application
to the clinic? Following is a summary of definitions
and a process to permit moving forward, part of a paper that
gives a good perspective on the challenges we face in this
pursuit 26 : biomarker—a characteristic that is objectively
measured and evaluated as an indicator of normal biologic
processes, pathogenic processes, or pharmacologic responses
to a therapeutic intervention; diagnostic biomarkers—early
detection biomarkers and disease classification; predictive
biomarkers—predict patients likely to have an adverse
event to a specific agent and predict patients likely to
respond to a specific agent; outcome biomarkers—forecast
response, progression, and recurrence; assay validation—
the process of assessing the assay and its performance
characteristics and determining the optimal conditions that
will generate a reliable, reproducible, and accurate biomarker
assay for the intended application; clinical qualification—linking
a biomarker (using data obtained by a
biomarker assay) with meaningful biologic or clinical outcomes;
high-quality biospecimens (collection methods, quality
assessment), accurate detection of markers (reference
standards, analytic performance and methods), useful patient
annotation, design of new bioinformatics approaches to
the study of biomarkers, and the application of optimized
retrospective and prospective study designs (adaptive clinical
trials).
The goal of this discovery process is to “elucidate the
physiologic, toxicological, and pharmacologic, or clinical significance
of the test results.” 26 The tools that we need to
query our patients’ genomes and their tumors have developed
rapidly. Analysis of DNA copy number by comparative
genomic hybridization (CGH), mutation detection, epigenetic
profiling, gene expression profiling, determining splice
variants of significant genes and functional proteomics and
metabolomics are becoming routine on frozen or paraffinfixed
tumors. High-density single nucleotide polymorphism
(SNP) arrays (containing 500,000 to 1,000,000 individual
SNPs) permit an in-depth analysis to the host genome.
Clearly, these methods are not rate limiting in terms of
progress toward individualized cancer care. Even the most
robust of assays associated with therapeutic response or