Biology Reference
In-Depth Information
TABLE 12.2 Nucleotide Excision Repair as a Predictive Marker in Human CancersdCont'd
Cancer type
Treatment
Repair enzyme
Results
Reference
NSCLC
Cisplatin/gemcitabine
ERCC2
TTP with Lys751Gln genotype
170
[
NSCLC
Cisplatin/vinorelbine
ERCC2
TTP with Lys751Lys genotype
170
[
NSCLC
Cisplatin/
gemcitabine/docetaxel
ERCC2
Lys751Lys genotype associated with
170
[
survival
NSCLC
Gemcitabine/
docetaxel
ERCC2
Wild type (Lys) genotype codon 751
associated with
171
survival but
risk of
[
[
grade 4 neutropenia
Abbreviations: NSCLC, non-small-cell lung cancer; CRC, colorectal cancer; AML, acute myeloid leukemia; MM, multiple myeloma; GI, gastrointestinal; SNP, single
nucleotide polymorphism; CRT, chemoradiotherapy; RT, radiotherapy; Cx, chemotherapy; BMT, bone marrow transplant; RR, response rate; DFS, disease-free
survival; PFS, progression-free survival; OS, overall survival;
increased;
decreased.
[
Y
away from the lesion, release of the excised oligomer,
repair synthesis to fill in the resulting gap (RPA, RFC,
PCNA, Pol
d
/
3
), and ligation (ligase I). In TCR, translo-
cating RNA polymerase II may be used to detect lesions
in the template, CSA and CSB may also be involved in
DNA damage recognition. Subsequent steps in TCR
pathway are similar to GGR.
99
treated with adjuvant cisplatin-based chemotherapy
was demonstrated.
123
The IALT Biology Study used
immunohistochemical analysis to determine the expres-
sion of the ERCC1 protein in the surgical specimens.
ERCC1 expression was positive in 335 tumors (44%)
and negative in 426 tumors (56%) in that study. A signif-
icant benefit from cisplatin-based adjuvant chemo-
therapy was associated with the absence of ERCC1
expression. Adjuvant chemotherapy significantly pro-
longed survival among patients with ERCC1-negative
tumors but not among patients with ERCC1-positive
tumors.
124
However, in another study in advanced
NSCLC patients treated with either cisplatin/gemcita-
bine or single agent gemcitabine, no correlation between
ERCC1 expression levels and response to chemotherapy
(even when only the subgroup of cisplatin-treated
patients was investigated) was found. However median
survival time was significantly longer in patients with
low ERCC1 mRNA levels, and low ERCC1 level was
an independent prognostic factor for survival. The
predictive effect of ERCC1 expression was more signifi-
cant in the group of patients treated with cisplatin/gem-
citabine regimens.
125
Similarly in a separate study in
NSCLC, in patients treated with gemicitabine/cisplatin
chemotherapy, median overall survival was also signifi-
cantly longer in patients with low ERCC1 expression
tumors (61.6 weeks) compared to patients with high
expression tumors (20.4 weeks). There was a trend
toward decreased response in tumors with high
ERCC1 mRNA levels, though this did not reach statis-
tical significance.
126
Another study customized chemotherapy based on
ERCC1 mRNA expression levels. The control arm
received docetaxel and cisplatin chemotherapy whereas
in the experimental arm patients received either the
combination of docetaxel and cisplatin if their ERCC1
mRNA levels were low, or docetaxel plus gemcitabine
if their levels were high. The response rate for patients
with low ERCC1 levels was 56.6% compared with
40.4% for patients in the control arm. Within the control
Excision Repair Cross-Complementing Enzyme
Group 1 (ERCC1)
The XPF/Mus 81 family of structure-specific endonu-
cleases are dimeric DNA endonucleases that process
bulky DNA lesions in NER. XPF-ERCC1 endonuclease
cleaves DNA 5' of the lesion whereas XPG cleaves DNA
3' of the lesion. XPF
e
ERCC1 may also be involved in
recombinational DNA repair and in the repair of inter-
strand crosslinks has two domains: a conserved central
domain that binds to ssDNA/dsDNA junctions with
a defined polarity, preferring a 5' single stranded over-
hang andmediates interactionwith XPA and a C-terminal
domain that binds to the C-terminal domain of XPF.
Preclinical studies confirm that ERCC1 mRNA expres-
sion levels or ERCC1 protein expression levels may corre-
late with cisplatin resistance in human cancer cell lines.
Moreover, in cisplatin resistant OVCAR10 cancer cell
line, depletion of ERCC1 by antisense oligonucleotide
or siRNA restored sensitivity to cisplatin.
122
Accordingly,
several clinical studies have investigated ERCC1 mRNA
expression or ERCC1 protein expression in human
tumors and have attempted to correlate this expression
with tumor response and/or overall survival. In
addition, clinical studies have also evaluated the predic-
tive significance of ERCC1 genetic polymorphism.
99
ERCC1 and Lung Cancer
In the International Adjuvant Lung Cancer Trial
(IALT), an absolute benefit of 4.1% in 5-year overall
survival among 1867 patients with NSCLC who were
