Biology Reference
In-Depth Information
ERCC1 and Other Solid Tumors
In ovarian cancer, high ERCC1 mRNA correlated to
platinum resistance.
148,149
A study of patients with
locally advanced cervical cancer treated with radical
radiotherapy alone has shown that poorer overall
survival is seen in women with low ERCC1 mRNA
expression levels. On multivariate analysis (including
adjustment for pre-treatment hemoglobin level)
ERCC1 protein expression status as measured using
FL297 antibody was significantly associated with over-
all survival.
150
Additionally, in the neoadjuvant setting
women treated with platinum-based neoadjuvant
chemotherapy for locally advanced cervical cancer
with low ERCC1 expression have been shown to have
a longer disease-free survival and a better response to
neoadjuvant chemotherapy.
151
The expression level of
ERCC1 has been shown not to be associated with
response to chemotherapy in patients with advanced
breast cancer treated with paclitaxel and cisplatin
chemotherapy or overall survival.
152
In patients with nasopharyngeal cancer treated with
radiotherapy alone, a high ERCC1 protein score was
associated with a statistically significant lower rate of
locoregional recurrence compared with tumors with
a low score. No association was seen with distant
failure-free rate or overall survival.
153
In patients treated for locally advanced bladder
cancer with adjuvant cisplatin-based chemotherapy
high ERCC1 gene expression is associated with poorer
overall progression-free survival.
154
ERCC1 N118N (500C
response rate compared to the Lys/Gln or Gln/Gln
genotypes.
163
In another study of patients with meta-
static colorectal cancer treated with irinotecan-based
regimens XPD (codon751) alleleic variants were not
independently associated with outcome or grade 3
or 4 hematological or gastrointestinal toxicity.
109
In advanced NSCLC patients treated with platinum-
based chemotherapy no relation between the Lys751Gln
polymorphism and survival
105
or response to treat-
ment
164
or Asp312Asn polymorphism and treatment
response
128
has been demonstrated. In another study
in NSCLC, the variant (Asn) genotype at codon 312
was associated with decreased overall survival in
patients with advanced disease treated with platinum-
based chemotherapy.
103
A trend towards better response
was also seen in patients with the XPD 312 polymor-
phism with locally advanced NSCLC treated with gem-
citabine/cisplatin.
165
A meta-analysis of 12 studies of patients treated with
platinum-based chemotherapy for NSCLC found no
association between XPD Asp312Asn and XPD
Lys751Gln and response to treatment.
134
This has been
corroborated by an additional meta-analysis of 17
studies, including 2097 individuals from similar patient
groups, and no significant association was observed
with progression-free or overall survival.
135
In glioma
no associations were demonstrated with XPD 312
polymorphisms.
166
In bladder cancer treated with platinum-based che-
moradiotherapy associations between SNPs in several
DNA repair genes (XPC Lys939Gln, XPD Lys751Gln,
XPG Asp1104His, XRCC1 Arg399Gln, and XRCC3
Thr241Met) and the clinical response and survival
were evaluated. Combined genotypes with at least one
variant allele in XPD or XRCC1 were significantly asso-
ciated with improved cancer-specific survival compared
with remaining groups.
167
The Lys751Gln polymor-
phism also predicts response to chemotherapy in elderly
patients with acute myeloid leukemia. Disease-free and
overall survival at one year was significantly higher for
Lys/Lys homozygotes compared with Gln/Gln homo-
zygotes in that study.
168
In multiple myeloma patients
undergoing autologous bone marrow transplantation,
carriage of Lys751Gln was associated with increased
time to treatment failure compared with homozygous
wild-type carriers.
169
In a customized ERCC1-based
chemotherapy trial, patients were randomized to the
control arm of cisplatin/docetaxel or to the experi-
mental arm where docetaxel was combined with
cisplatin or gemcitabine according to ERCC1 levels;
the effect of ERCC2 polymorphisms on response was
analyzed retrospectively. In gemcitabine/cisplatin-
treated patients, time to disease progression was signif-
icantly higher in patients with the Lys751Gln genotype
of ERCC2 than in those with the Lys751Lys genotype.
T) polymorphisms were found
not to impact on survival of patients with castrate-resis-
tant prostate cancer or survival of a subgroup of patients
treated with radiotherapy.
117
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Excision Repair Cross-Complementing Enzyme
Group 2 (XPD/ERCC2)
The XPD/ERCC2 is a DNA helicase that unwinds
DNA in the 5' to 3' direction. Polymorphisms in codons
156 (C156A), 312 (Asp312Asn), and 751 (Lys751Gln) are
well characterized. The Gln/Gln 751 and the Asn/Asn
312 genotypes are associated with suboptimal DNA
repair
155
e
159
and increased radiation induced DNA
single-strand breaks in irradiated lymphocytes.
160
In
preclinical studies, the Lys751Gln polymorphism
predicts sensitivity to several anticancer agents.
161
In
gastric cancer patients treated with chemoradiotherapy
and surgery, Lys751Gln polymorphism predicts clinical
outcome. Lys/Lys genotype may be associated with
increased DNA repair and resistance leading to
increased incidence of relapse compared to Lys/Gln
and Gln/Gln genotype.
162
However in metastatic colo-
rectal cancer, Lys/Lys genotype correlated to higher
