ERCC1 as a biomarker for bladder cancer patients likely to benefit from adjuvant chemotherapy
Jong-Mu Sun
0
Ji-Youn Sung
Se Hoon Park
0
Ghee Young Kwon
Byong Chang Jeong
Seong Il Seo
Seong Soo Jeon
Hyun Moo Lee
Jisuk Jo
Han Yong Choi
Ho Yeong Lim
0
0
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine
,
Seoul
,
South Korea
Background: The role of adjuvant chemotherapy and the value of molecular biomarkers in bladder cancer have not been determined. We aimed to assess the predictive and prognostic values of excision repair crosscomplementation 1 (ERCC1) in identifying appropriate patients who may potentially benefit from adjuvant chemotherapy for bladder cancer. Methods: A retrospective analysis was performed on 93 patients with completely resected transitional cell carcinoma of the bladder. ERCC1 expression was assessed by immunohistochemistry. ERCC1 expression was analyzed in 57 patients treated with adjuvant gemcitabine plus cisplatin chemotherapy and 36 who were not treated. Results: Among 93 patients, ERCC1 expression was positive in 54 (58.1%) and negative in 39 (41.9%). ERCC1 positivity was significantly associated with longer survival (adjusted hazard ratio for death, 0.12, 95% confidence interval [CI] 0.014-0.99; P = 0.049) in the group without adjuvant chemotherapy while ERCC1 positivity was associated with shorter survival among patients who have received adjuvant chemotherapy (adjusted hazard ratio for death, 2.64; 95% CI 1.01-6.85; P = 0.047). Therefore, clinical benefit from adjuvant chemotherapy was associated with ERCC1 negativity as measured by overall survival (test for interaction, P = 0.034) and by disease-free survival (test for interaction, P = 0.20). Conclusions: Among patients with completely resected transitional cell carcinoma of the bladder, those with ERCC1-negative tumors seemed to benefit more from adjuvant gemcitabine plus cisplatin chemotherapy than those with ERCC1-positive tumors. Future prospective, randomized studies are warranted to confirm our findings.
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Background
Many patients with locally advanced bladder cancer
relapse and subsequently die of their disease, even
after potentially curative surgery, because of occult
micrometastases present at diagnosis. Perioperative
chemotherapy has been investigated for patients who
undergo cystectomy for locally advanced transitional
cell carcinoma of the bladder, and clinical benefit
from neoadjuvant cisplatin-based chemotherapy has
been demonstrated in several randomized trials [1-3].
Although two meta-analyses showed favorable results
for adjuvant chemotherapy for bladder cancer [4,5], no
randomized trial has demonstrated the efficacy of
adjuvant chemotherapy for overall survival because of small
sample size, or early stoppage of patient entry [6-9]. In
practice, however, many physicians administer adjuvant
chemotherapy despite its weak evidence [10,11]. Further
research investigating the effect of adjuvant
chemotherapy on bladder cancer survival is of high importance
considering its current practice .
Cisplatin is the most important adjuvant chemotherapy
agent for bladder cancer and is usually administered with
gemcitabine. Its cytotoxicity is attributed to the
formation of DNA adducts, which cause inter- and intrastrand
cross-linking that inhibits DNA replication.
Cisplatininduced DNA adducts are removed by the
nucleotideexcision repair pathway, and the excision repair
crosscomplementation 1 (ERCC1) protein is rate-limiting
in the nucleotide excision repair pathway. Its increased
expression is associated with resistance to cisplatin-based
chemotherapy in various tumor types [12-17].
In addition to its predictive role for cisplatin-based
chemotherapy, ERCC1 has significant prognostic value
because high ERCC1 expression is associated with longer
survival in patients who do not receive chemotherapy after
complete resection for non-small cell lung cancer [15,18].
ERCC1 has also been supported by studies that
demonstrate cancers with extensive geno- mic alterations have
more malignant phenotype and increased growth rates,
and ERCC1 may be representative of the intrinsic DNA
damage-repair ability of the cell [18,19].
In this study, we sought to determine whether ERCC1
protein expression is an important factor in predicting
the clinical outcome of completely resected bladder
cancer. To assess the predictive and prognostic value of
ERCC1 and to define the subgroup of patients who are
most likely to benefit from adjuvant chemotherapy,
patients classified by history of adjuvant chemotherapy
were analyzed.
Methods
Patients and treatment
The initial study population comprised of 137 patients
treated with radical cystectomy and bilateral pelvic
lymphadenectomy as definitive treatment for clinically
localized urothelial cancer of the bladder between January
2004 and December 2010 at Samsung Medical Center
(Seoul, Korea). Of these, 93 patients were included in the
analysis after excluding 12 patients who had not been
completely resected, eight who recei (...truncated)