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regimens. For this reason the development and application of individualized therapy
has been the goal of several studies within the last decade.
DNA microarray analysis was used to analyze the transcriptional profi le of
HCT116 CRC cells that were treated with 5-FU or oxaliplatin and selected for resis-
tance to these agents (Boyer et al. 2006 ). Bioinformatic analyses identifi ed sets of
genes that were constitutively dysregulated in drug-resistant cells and transiently
altered following acute exposure of parental cells to drug. Functional analysis of
three genes identifi ed in the microarray study (prostate-derived factor, calretinin,
and spermidine/spermine N1-acetyl transferase) revealed their importance as novel
regulators of cytotoxic drug response. These data show the power of this novel
microarray-based approach to identify genes which may be important biomarkers of
response to treatment and/or targets for CRC.
Panitumumab (Amgen’s Vectibix) is a recombinant, human IgG2 kappa MAb
that binds specifi cally to the human EGFR is indicated as a single agent for the treat-
ment of EGFR-expressing, metastatic CRC with disease progression on or follow-
ing fl uoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. A
companion diagnostic, TheraScreen K-RAS Mutation Kit (QIAGEN), which was
used in the pivotal clinical trial for panitumumab, is available in 22 EU countries.
The kit detects seven mutations in codons 12 and 13 of the K-RAS oncogen. Patients
with CRC bearing mutated K-RAS do not benefi t from cetuximab, whereas patients
with a tumor bearing wild-type K-RAS do benefi t from cetuximab (Karapetis et al.
2008 ). The mutation status of the K-RAS gene has no infl uence on survival among
patients treated with best supportive care alone. Launch of this companion diagnos-
tic in 2008 marked the fi rst time that the European Commission licensed a bowel
cancer treatment with the stipulation that a predictive test should be carried out. In
2009, the FDA updated the “indication and usage” section of the labels of Vectibix
and Erbitux (ImClone/Bristol-Myers Squibb) to note that retrospective analyses of
metastatic CRC have not shown a treatment benefi t for the EGFR inhibitors in
patients whose tumors had KRAS mutations in codon 12 or 13, and that the use of
the drugs is not recommended for the treatment of CRC patients with these muta-
tions. Physicians can now eliminate anti-EGFR antibodies as a treatment option for
patients with mutated KRAS tumors and redirect those patients to alternative thera-
pies, avoiding unnecessary treatments in patients who are unlikely to benefi t. Other
activating RAS mutations may also be negative predictive biomarkers for anti-
EGFR therapy in patients with metastatic CRC. In patients who had metastatic CRC
without RAS mutations, improvements in overall survival have been observed with
panitumumab plus oxaliplatin, fl uorouracil, and leucovorin (FOLFOX4) therapy
(Douillard et al. 2013 ).
In general, CRC prognosis is based on clinical staging, with roughly 40 % of
cases diagnosed in early or localized stages. Patients with stage I and II colon cancer
are often considered cured following surgery. Nevertheless, some 15–20 % of these
individuals eventually have recurrence of the disease. Therefore, efforts are being
made to defi ne the molecular changes associated with recurrence and decreased
survival. Since high tumor grade is not a biomarker of higher recurrence risk in
stage II colon cancer, suggests that other biomarkers, such as Genomic Health’s
10 Personalized Therapy of Cancer