title: Resistance to first line platinum paclitaxel chemotherapy in serous epithelial ovarian cancer: the prediction value of ERCC1 and Tau expression.
abstract: In oncology, a rational approach to identify patients who are likely to benefit from therapy, already before initiation of treatment, is urgently required. Excision repair cross-complementation group 1 enzyme (ERCC1) has been proposed as a molecular predictor of clinical resistance to platinum-based chemotherapy. Other data suggest Tau protein expression as a predictor of clinical outcome in cancer patients treated with paclitaxel-based chemotherapy as low tau expression may render microtubules more vulnerable to paclitaxel. Therefore, the combination of ERCC1 and Tau may be a valuable predictor of sensitivity to platinum/paclitaxel treatment. The primary aim of the study was to investigate whether ERCC1 and Tau protein expression correlates with patient outcome in newly diagnosed epithelial ovarian cancer (EOC) patients. Formalin-fixed, paraffin-embedded tissue sections from 227 newly diagnosed EOC patients were used for immunohistochemical staining for ERCC1 and Tau proteins. All patients received standard first-line combination platinum and paclitaxel chemotherapy. The patients were divided in a training set of 84 patients and an independent validation cohort of 143 patients. Neither ERCC1 nor Tau expression was associated with clinical response or platinum resistance in both the training and validation sets. Patients with ERCC1-positive tumors had significantly shortened progression-free and overall survival compared to patients with ERCC1-negative tumors, p<0.00001 and p=0.0006. In multivariate analysis ERCC1 also proved as an independent predictor of PFS and OS with HR of 3.86 and 1.98, respectively but the data could not be confirmed in the validation set. Tau expression was not associated with PFS or OS in this study. ERCC1 and Tau might serve as biomarkers of DNA repair and for paclitaxel sensitivity but the present study could not validate ERCC1 or Tau protein expression in tumors as pre-treatment tools to predict sensitivity to first-line platinum/paclitaxel chemotherapy.
authors.affiliation: Department of Oncology, Vejle Hospital, DK-7100 Vejle, Denmark.
authors.forename: Karina Dahl
authors.initials: KD
authors.lastname: Steffensen
authors.affiliation: Department of Oncology, Military Institute of Health Services, 00-909 Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Smoter
authors.affiliation: Department of Pathology, Vejle Hospital, DK-7100 Vejle, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Waldstrøm
authors.affiliation: Department of Pathology, Military Institute of Health Services, 00-909 Warsaw, Poland.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Grala
authors.affiliation: Department of Oncology, Military Institute of Health Services, 00-909 Warsaw, Poland.
authors.forename: Lubomir
authors.initials: L
authors.lastname: Bodnar
authors.affiliation: Department of Oncology, Military Institute of Health Services, 00-909 Warsaw, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Stec
authors.affiliation: Department of Oncology, Military Institute of Health Services, 00-909 Warsaw, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Szczylik
authors.affiliation: Department of Oncology, Vejle Hospital, DK-7100 Vejle, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Jakobsen
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000627:therapeutic use; D000077216:Carcinoma, Ovarian Epithelial; D002945:Cisplatin / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004720:Endonucleases / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use; D016896:Treatment Outcome; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016875:tau Proteins; D016190:Carboplatin; C071447:ERCC1 protein, human; D004720:Endonucleases; D017239:Paclitaxel; D002945:Cisplatin