Biomedical Engineering Reference
In-Depth Information
denoted LCS6 (for SNP rs
1764370; rs stands for reference SNP)
and consists of a thymidine (T) to guanine (G) base change. The
LCS6 nucleotide change alters the binding capability of Let-7 to the
KRAS
6
mRNA and this loss of transcript silencing results in
KRAS
over
expression in
in vitro
models [100].
. recently demonstrated that the LCS6 G allele
had a worse OS and PFS than the T/T genotype carriers, in 130
patients with mCRC treated with salvage cetuximab/irinotecan
and
Graziano
et al
WT tumors [101]. Around the same time,
another study, contradicted these results, publishing that the WT
LCS6 genotype (T/T) had a worse objective response rate (ORR 9%)
compared with patients with the T/G or G/G genotype (42%;
KRAS
WT and
BRAF
=
0.02) [102]. Although there was a trend to improved PFS and OS
in those patients with a G allele, these results were not statistically
significant. Possible reasons for the conflicting results are that
P
KRAS
exon 61, known to harbor activating mutations, and
were not
sequenced in the latter study. The non-responders to cetuximab
among the LCS6 T/T genotype patients could be partly attributed to
the presence of unidentified
BRAF
mutations. This could
also explain the differences in survival analyses. These studies were
both retrospective studies and ultimately require larger prospective
controlled studies utilizing other accepted predictive markers before
the LCS6 polymorphism can be accepted as a predictive marker of
anti-EGFR moAbs efficacy.
KRAS
and
BRAF
7.4.3
Genetic Mutations Affecting the EGFR Gene
7.4.3.1
Somatic EGFR gene mutations
Somatic
gene mutations are found in approximately 5-15%
of unselected white patients and in 25-35% of unselected Asian
patients with non-small cell lung cancer (NSCLC) [103, 104]. Also,
the
EGFR
gene has somatic mutations in 30-50% of patients with
glioblastoma (GBM) [9]. However, these mutations in the
EGFR
gene
rarely occur in CRC. When DNA from 293 colorectal cancers were
screened for
EGFR
mutations within the tyrosine kinase domain
only one mutation was identified [9]. Moroni
EGFR
also detected only
one mutation (3.2%) among 31 patients with metastatic colorectal
cancer who had responded to cetuximab [8]. The patient harboring
this mutation achieved stable disease for 24 weeks with cetuximab
and chemotherapy treatment. This mutation was a heterozygous
et al.
