Biology Reference
In-Depth Information
However, in patients treated with cisplatin/vinorelbine,
the opposite effect was observed and patients with
Lys751Lys had a longer time to progression. When doce-
taxel was added to gemcitabine/cisplatin, patients with
Lys751Lys also had better survival.
170
ERCC2 poly-
morphs may also predict toxicity to chemotherapy. In
a phase II trial of patients with advanced NSCLC treated
with docetaxel and gemcitabine chemotherapy the wild
type (Lys) ERCC2 genotype at codon 751 was associated
with prolonged survival and a significantly higher risk
of grade 4 neutropenia.
171
In a study of patients with high-risk superficial
bladder cancer treated with Bacillus Calmette-Guerin
(BCG) immunotherapy the variant genotype of ERCC2
(312) AA polymorphism was associated with a high
risk of recurrence and shorter recurrence-free survival.
No association was seen between ERCC2 Lys(751)Gln
polymorphism and recurrence in that study.
Preclinical and clinical studies discussed here
provide evidence that ERCC1 and ERCC2 are promising
predictive biomarkers and influence response to chemo-
therapy and prognosis for many different tumor types
and treatment regimes. While many studies suggest
the variant alleles are associated with improved
response, others have found the opposite. Although
variation in results may be due to different patient pop-
ulations, tumor types and treatment regimes, larger
prospectively designed studies are essential to confirm
current data.
METHYLGUANINE
METH
YLTRANSFERASE (
TABLE
12.3
)
The cytotoxicity of methylating (dacarbazine, temo-
zolomide), and chloroethylating (bis-chloroethyl nitro-
surea and streptozotocin) agents is directly related to
their ability to alkylate guanine at the O
6
position,
resulting in GC to AT transition mutations. The
“suicide enzyme” MGMT, otherwise known as AGT,
is the key enzyme that repairs these lesions. MGMT
performs this activity by transferring the alkyl group
from the O
6
position of guanine to its own internal
cysteine residue, thus repairing the DNA lesion. This
stoichiometric reaction, however, results in irreversible
inhibition of MGMT and hence endogenous MGMT
depletion.
172,173
Promoter methylation is an important
mechanism for silencing MGMT expression. The loss
of MGMT expression promotes tumorigenesis.
174
However MGMT silencing increases sensitivity to alky-
lating agents in certain tumors. For example, in
malignant glioma MGMT promoter methylation is
Other NER Factors
AT dinucleotide insertion or deletion in intron 9 of the
XPC gene in NSCLC had a significant impact on
response to platinum based chemotherapy.
164
A study
in esophageal cancer examined the impact of XPA,
XPC, XPD, XPG, ERCC1, ERCC6, CCNH, and RAD23B
polymorphisms on clinical outcomes. Although no
significant individual association with clinical outcome
was found there was a significant trend for better
survival with a decreasing number of putative high-
risk alleles. Compared with individuals with five or
more putative risk-alleles, individuals with four risk
alleles and individuals with three or fewer risk alleles
had a significantly reduced risk of death.
106
TABLE 12.3 Methylguanine Methyltransferase (MGMT) as a Predictive Marker in Human Cancers
Cancer type
Treatment
Results
Reference
High grade glioma
Alkylating chemotherapy
Promoter methylation associated with improved disease response
and survival
175, 176
High grade astrocytoma
Bis-chloroethylnitrosurea
Low level is predictive marker of survival
177
GBM
CRT (TMZ)
Benefit from TMZ only seen with methylated promoter
178
e
180
GBM
CRT (TMZ)
[
Survival with promoter methylation
179
GBM
TMZ (inoperable)
Better tumor response with hypermethylation
176
Low grade glioma
TMZ
Methylation associated with radiological response to Cx and TTP
192
Melanoma
Dacarbazine
Expression level associated with disease stabilization, PFS and OS
193
Melanoma
TMZ
Methylation correlates with tolerance to TMZ.
S/E with
194
[
methylated promoter
CRC
Oxaliplatin-based
TT genotype of MGMT
535
T polymorphism correlates with
151
>
worse PFS than GG
þ
GT genotypes
Abbreviations: CRC, colorectal cancer; GBM, glioblastoma; CRT, chemoradiotherapy; RT, radiotherapy; Cx, chemotherapy; TMZ, temozolomide; S/E, side effects;
MGMT, methylguanine methyltransferase; PFS, progression-free survival; OS, overall survival; TTP, time to progression;
[
increased;
Y
decreased.
