2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

BIOMARKERS AND COLORECTAL CANCER
Determination of BRAF status is important at the outset
for guidance in terms of prognosis. As of today, do not order
BRAF until the tumor is known to be KRAS wild type; by
convention, KRAS mutant cancers do not have BRAF mutations.
And I reserve the right to change the above recommendation.
The BRAF story teaches us that we should not rush to
judgment on the utility of biomarkers until the correct,
adequately powered trials have been performed. To determine
whether a biomarker is predictive, where the biomarker
status can be used to determine whether a patient
will or will not benefit from treatment, a four-arm trial must
be done. The arms of the trial will include patients who do
and do not receive active therapy and patients who do and do
not have the presence of the biomarker. Trials that include
only the presence or absence of a biomarker can tell us only
whether that biomarker is prognostic, when the biomarker
is associated with better or worse outcomes, no matter what
the treatment.
Rash: Acneiform Skin Change to EGFR Inhibitors
Biomarkers not only include tests on tumor and blood, but
also the reaction an individual patient may have to therapy.
Skin rash reaction to EGFR inhibitors is an example. It has
been well established that worsened skin reaction to EGFR
inhibitors is associated with improved outcome to treatment.
Data from the PRIME study, in which patients were
randomly assigned to receive FOLFOX with or without
panitumumab found that wild-type KRAS patients receiving
panitumumab who had a grade 2 to 4 skin reaction compared
with patients who had a grade 0 to 1 skin reaction had
improved progression-free survival (11.1 vs. 6.0 months; p �
0.001) and OS (28.3 vs. 11.5 months; p � 0.0001). 7 Given the
importance of skin rash reaction to outcomes, the EVEREST
study attempted to increase the dose of cetuximab therapy
on the basis of rash. Patients received IFL and cetuximab,
and patients who developed only grade 0 to 1 rash were
randomly assigned to receive high-dose versus low-dose
cetuximab. 8 Though the response rate was improved in the
high dose patients (30% vs. 16%), there was no difference in
OS. At the moment, we can say that the individual patient
biomarker of skin reaction to EGFR inhibitors can help us
predict improved outcomes with higher-grade rash.
When you see our patient in follow-up, take note of the
extent of acne. If it is quite severe, make sure the patient
knows that is a good sign.
Node-Negative Colon Cancer: Mismatch Repair
The use of adjuvant chemotherapy for patients with stage
II colon cancer has been the subject of much debate, and the
ability to identify patients who would be more or less likely
to benefit for adjuvant chemotherapy is needed. The status
of DNA mismatch repair (MMR) seems to be a biomarker to
guide the choice to use adjuvant chemotherapy for these
patients. It is known that patients with tumors that are
deficient in MMR (dMMR) have a better overall prognosis
than those who have proficient MMR (pMMR). A pooled
analysis of 457 patients and then 1,027 patients with stage
II or III colon cancer found that patients with pMMR status
had a benefit from adjuvant chemotherapy with a diseasefree
survival HR of 0.67 (95% CI, 0.48 to 0.93), whereas
patients with dMMR status derived no benefit from FU-
based chemotherapy (HR � 1.10; 95% CI, 0.42 to 2.91). 9
Further, for the stage II patients with dMMR there seemed
to be a worse OS with the use of FU adjuvant chemotherapy
(HR � 2.95; 95% CI, 1.02 to 8.54).
When you refer the patient to the medical oncologist for
discussion of adjuvant therapy for stage II disease, please
also ask the pathologist to determine MMR status. If the
tumor is dMMR, the use of adjuvant chemotherapy will be
discouraged.
Recurrence Score
Although there are numerous gene signatures in development,
the assay with the most supporting data is a 12-gene
recurrence score. The recurrence score was derived from
tumor samples from 1,851 stage II or III patients who
received FU adjuvant chemotherapy or surgery alone, identifying
a set of 12 genes that appeared to be associated with
risk of disease recurrence. 10 This recurrence score was then
analyzed in 1,436 tumor samples from patients with stage II
cancer treated with or without FU chemotherapy on the
QUASAR trial. 11 Patients with a recurrence score greater
than 40 had a 25% rate of 3-year disease recurrence compared
with patients with a recurrence score less than 30 who
had a 3-year disease recurrence rate of 8%. However, although
the recurrence score seems to identify patients with
an increased risk of disease recurrence, when the recurrence
score was applied to look for patients who would then have
benefit from adjuvant chemotherapy, no conclusion could be
drawn. Larger prospective trials are needed.
I expect the recurrence score to be helpful in some patients,
but let me discuss the ramifications of the score with
the patient before we send the specimen, since the importance
of the score is a function of the philosophy of the
patient and oncologist. In general, though, we should get as
much information as we can.
Up-and-Coming Biomarkers
EGFR Ligands
Amphiregulin and epiregulin are ligands of EGFR. A
study of examining DNA, RNA, and protein expression
profile in 110 patients who received cetuximab found that
patients with increased expression of amphiregulin and
epiregulin had an increased rate of disease control. 12 Further,
a retrospective analysis of IFL-refractory patients
treated with cetuximab and IFL for metastatic colorectal
cancer found that patients with high epiregulin levels plus
KRAS wild-type status showed a response rate of 58%
compared with 40% for KRAS wild type alone, and a median
progression-free survival of 36 weeks compared with 24
weeks. 13 Another analysis for patients treated on the NCIC
CO.17 study of cetuximab versus best supportive care
showed that patients who had KRAS wild-type and high
epiregulin had a much improved HR for OS benefit compared
with the KRAS wild-type only or total population
(HR � 0.46 vs. 0.55 vs. 0.70, respectively). 14 The combination
of KRAS and EGFR ligand status appears promising to
select patients who will have the most benefit from anti-
EGFR therapy.
Phosphoinositide 3-Kinase and Phosphatase and Tensin Homolog
The phosphoinositide 3-kinase (PI3K) pathway is likely
the most commonly activated pathway in cancers. Approxi-
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