Biology Reference
In-Depth Information
risk of contralateral breast cancer was demonstrated in
both carriers and non-carriers of the BRCA mutations
treated with chemotherapy. The benefit of adjuvant
tamoxifen treatment was only significant in patients
without BRCA1 or 2 mutations.
219
Similarly in ovarian cancer patients receiving primary
chemotherapy, BRCA mutation carriers had higher
tumor response rates compared to patients with
sporadic ovarian cancers.
220
BRCA1 mRNA expression
has also been shown to be associated with efficacy of
neoadjuvant cisplatin-based chemotherapy in patients
with muscle-invasive bladder cancer. Response to treat-
ment was higher in patients with low or intermediate
BRCA1 levels. Median survival was also significantly
higher in patients with low or intermediate levels (168
months versus 34 months in patients with high levels,
P
of multiple myeloma patients undergoing autologous
bone marrow transplantation carriers of the variant T
allele of XRCC3 Thr241Met had increased time to
treatment failure compared with homozygous wild-
type carriers
169
and in a study of patients with advanced
NSCLC treated with cisplatin/gemcitabine survival
was significantly higher in patients harbouring
XRCC3 241 Met/Met versus patients with Thr/Met
or Thr/Thr.
225
In patients with metastatic breast
cancer enrolled into clinical trials of high-dose chemo-
therapy and autologous stem-cell transplantation,
XRCC1 Arg399Gln or XRCC3 Thr241Met polymor-
phisms were associated with increased breast-cancer-
free survival and progression-free survival. Patients
carrying one variant genotype or combinations of any
two variant genotypes had significantly poorer survival
compared with patients carrying zero variants.
116
Polymorphisms in the ATM gene are not associated
with resistance to chemotherapy in patients with
advanced NSCLC.
98
In malignant melanomas of the
oral cavity, decreased Ku70/80 expression was found
to influence disease progression.
226,227
In patients with
advanced rectal carcinoma, expression pattern of Ku
protein was correlated not only with tumor radiosensi-
tivity but also with disease-free survival.
228
A signifi-
cant correlation between the expression of Ku70, p53
and tumor radiosensitivity in rectal cancer patients
was demonstrated in another study.
229
Although it is difficult to draw any conclusions, early
evidence suggests that SNPs within DSB-repair genes
are important in cancer. Though some of the results
from currently published studies appear to contradict
one another this may be due to differences within the
study designs. Alternatively variant alleles may have
dissimilar effects for different tumor types or stages,
treatment regimes or patient populations, and few
studies have analyzed the collective effect of several
SNPs in combination. BRCA1 gene alterations have
been the most investigated and the results so far are
promising.
0.002).
221
In addition another study has shown that
on multivariate analysis high BRCA1 mRNA expression
is associated with increased progression-free survival
with first-line docetaxel-based chemotherapy in
NSCLC.
222
Similar results were demonstrated in another
study in advanced NSCLC treated with cisplatin-based
regimens. Patients with high BRCA1 expression demon-
strated a better response rate and survival if an anti-
tubulin agent was included in the regimen.
223
Recently,
it has been demonstrated that both overall survival
and progression-free survival is significantly improved
in BRCA1 mutant TT homozygotes with advanced
gastric cancer treated with taxane and cisplatin.
115
ΒΌ
Other DSB Repair Genes
In patients with pancreatic cancer treated with
chemotherapy, radiotherapy or chemoradiation, a study
of 378 patients investigated the effect of six SNPs of the
RecQ1, RAD54L, XRCC2, and XRCC3 genes. An
increased survival for the RecQ1 159 AA and the
RAD54L 157 CC genotypes compared with the AC
and CC, and the CT and TT genotypes was seen in
that study. On the other hand, a significantly reduced
survival was associated with the variant alleles of
XRCC2 Arg188His and XRCC3 A17893G in subgroup
analysis. When analyzed together, an increasing
number of adverse alleles were associated with a signif-
icantly decreased survival.
224
In another study, SNPs
within RecQ1, RAD54L, ATM, LIG3, LIG4, XRCC1,
XRCC2, and XRCC3 were evaluated in 92 patients
with potentially resectable pancreatic cancer treated
with neoadjuvant concurrent gemcitabine and radio-
therapy. The RecQ1 A159C,RAD54LC157T,XRCC1
Arg194Trp, and ATM T
e
77C genotypes were signifi-
cant. Patients with none of the adverse genotypes had
a mean survival time of 62.1 months whereas those
with 1, 2, or
DNA REPAIR AND CHEMOTHERAPY-
IND
UCED TOXICITY (
TABLE
12.5
)
In addition to their effect on tumor response to
chemotherapy and radiotherapy DNA repair alterations
may affect normal tissue tolerance to DNA damaging
agents. SNPs that reduce expression or activity of their
encoded proteins resulting in inefficient removal of
damaged DNA may lead to accumulation of DNA
damage within normal tissue and increased normal
tissue toxicity. The predominant acute toxicities of
chemotherapy are directed towards the bone marrow
and the gastrointestinal tract. In addition, toxicity to
3 at-risk alleles had median survival times
of 27.5, 14.4, and 9.9 months, respectively.
224
In a study
