2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Is There Currently an Established Role for
the Use of Predictive or Prognostic Molecular
Markers in the Management of Colorectal
Cancer? A Point/Counterpoint
By Alan P. Venook, MD, Johanna C. Bendell, MD, and Robert S. Warren, MD
Overview: The term “personalized oncology” means different
things to the oncologist than to the patient. But fundamentally,
the phrase creates the expectation that decisions can be
informed by the unique features of the patient and patient’s
cancer. Much like determining antibiotic sensitivities in urinary
tract infections, the oncologist is expected to choose the
right treatment(s), for each individual patient.
Numerous methods can be used to “personalize” management
decisions, although truly useful biomarkers continue to
escape our grasp. Positron Emission Tomography in patients
with GI stromal tumors or genotyping of c-kit in chronic
myelogenous leukemia cells can guide the use of imatinib,
these scenarios represent a minority of patients. The promise
of individualized therapy, however, has led to the commercialization
of numerous assays to probe patient’s genetic
make-up and that of the tumor. Breast cancer management
THE TERM “personalized oncology” means different
things to the oncologist than to the patient. But fundamentally,
the phrase creates the expectation that decision
making can be informed by the unique features of the
patient and of that patient’s cancer. Much like culturing the
urine in a urinary tract infection and determining antibiotic
sensitivities, it implies that oncologists can pick just the
right treatment, or combination of treatments, for each
specific patient.
There are numerous tools that can be used to “personalize”
management decisions, although for much of the last
decade the truly useful biomarkers were few and far between.
Although positron emission tomography imaging in a
patient with a GI stromal tumor patient or mutational
analysis of chronic myelogenous leukemia cells could direct
the proper decision about whether to use imatinib, these
scenarios represented a distinct minority of patients. The
promise, however, led to the commercialization of numerous
assays to probe a patient’s genetic make-up and/or the
cancer. We now know that gene recurrence scores can
“personalize” breast cancer management in some patients,
and more recently we have capitalized on mutations in
non-small cell lung cancers and melanomas to subdivide
these patients into subsets of diseases. We have shown
recently that some of these infrequent mutations can be
targeted successfully by small-molecule inhibitors.
Despite the high incidence of colorectal cancer and our
relatively long-standing grasp of the molecular pathways in
colorectal cancer—the polyp-to-malignancy transformation—the
management of disease in patients with colorectal
cancer for years is mostly empiric and movement toward
“personalization” has been incremental. Now, however, the
availability of newer imaging modalities and commercial
assays for genetic mutational analysis of tumor specimens
has put the oncologist and oncologic surgeon in the crossfire
with patients and families who believe the era of “personalization”
is here.
Now the debate: The medical oncologist (Johanna Bendell)
has benefitted from the analysis of gene recurrence scores.
More recently the analysis of germline or tumor-associated
mutations in non-small cell lung cancer and melanoma has led
to clinically meaningful molecular subsets of these diseases,
guiding the successful targeting of such cancers with smallmolecule
inhibitors.
Despite the high incidence of colorectal cancer and our
relatively long-standing grasp of the molecular pathways in
colorectal carcinogenesis, the management of these patients
remains mostly empiric and movement toward “personalization”
has been slow and incremental. Now, however, molecular
imaging and commercial assays for genetic makeup of
tumor specimens has put the oncologist and oncologic surgeon
in the crossfire with patients and families who believe
the era of “personalization” is here.
wants the surgeon (Robert Warren) to carefully collect
tumor tissue of the patient undergoing surgery. Always a
willing collaborator, the surgeon—mindful of cost and the
pathologist’s time—asks what makes the medical oncologist
think these tests will be helpful. The patient expects a
compromise that will help “personalize” care.
Johanna Bendell, MD: Ready for Prime Time
As part of the referral to the surgeon, the medical oncologist
lists a number of specific tissue acquisition needs and
handling instructions to the surgeon. The message: these
are the biomarkers we will use to decide how to treat this
patient and here are the data to support our decision.
KRAS
Many of the biomarkers currently in use or under active
investigation are based around research done with epidermal
growth factor receptor (EGFR) pathway inhibitors.
These include KRAS, BRAF, and rash. The data from the
CRYSTAL trial, where patients were randomly assigned in
the first-line setting to receive fluorouracil (FU), leucovorin
(LV), and irinotecan (IFL; FOLFIRI) with or without cetuximab,
is well known. 1 This trial showed that the addition of
cetuximab improved response rate (49% vs. 39%; p � 0.0038)
and progression-free survival (8.9 vs. 8.0 months; p � 0.05).
For the patients with wild-type KRAS status, who comprised
37% of the patients, the benefit of cetuximab over no cetuximab
was greater for response rate (57.3% vs. 39.7%; p �
From the Department of Medicine (Hematology/Oncology); Department of Surgical
Oncology, University of California San Francisco Helen Diller Comprehensive Cancer
Center, San Francisco, CA; Gastrointestinal Oncology Research, Sarah Cannon Research
Institute, Nashville, TN.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Robert S. Warren, MD, Professor of Surgery, Chief, Surgical
Oncology, University of California, San Francisco, 1600 Divisadero St., Room A-723, San
Francisco, CA 94115; email: robert.warren@ucsfmedctr.org.
© 2012 by American Society of Clinical Oncology.
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