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. - 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)