ABSTRACT
BACKGROUND: Platinum-based doublets (PBDs) remain the cornerstone of treatment in non-small-cell lung cancer (NSCLC) and may include gemcitabine. A biomarker predicting sensitivity to this antimetabolite would represent a major step forward. Accordingly, we explored the predictive role of ribonucleotide reductase subunit M (RRM1) in advanced NSCLC. PATIENTS AND METHODS: A total of 443 patients were randomly assigned to regimen A [paclitaxel (Taxol) and cisplatin with gemcitabine] or regimen B (cisplatin and vinorelbine). Immunohistochemical evaluation of RRM1 was correlated to clinical end-points. RESULTS: A total of 261 (58.9%) patients had representative tissue samples for RRM1 evaluation. Disease control rate, progression-free survival (PFS) and overall survival (OS) were substantially improved in patients with RRM-negative (neg) tumors receiving regimen B when compared with patients with RRM-positive (pos) tumors (68.8% versus 31.2%, P = 0.046, 6.90 months versus 3.93 months, P = 0.000 and 11.57 months versus 7.4 months, P = 0.002, respectively). Interaction analysis between RRM1-neg status and adenocarcinomas yielded a hazard ratio (HR) of 0.36 for death (P = 0.000). CONCLUSIONS: RRM1 protein expression was without any predictive impact in patients treated with cisplatin, paclitaxel and gemcitabine. Surprisingly, the predictive power was demonstrated in the cisplatin and vinorelbine arm and may suggest that RRM1 is involved in vinorelbine sensitivity warranting further research.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Radiation-Sensitizing Agents/therapeutic use , Tumor Suppressor Proteins/metabolism , Adult , Aged , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Cisplatin/therapeutic use , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Disease-Free Survival , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Male , Middle Aged , Paclitaxel/therapeutic use , Prognosis , Ribonucleoside Diphosphate Reductase , Survival Rate , Tumor Suppressor Proteins/biosynthesis , Vinblastine/analogs & derivatives , Vinblastine/therapeutic use , Vinorelbine , Young Adult , GemcitabineABSTRACT
Treating patients with advanced nonsmall cell lung cancer (NSCLC) is a daunting task but during recent years new options have emerged. By tailoring treatment using either information on histological subtypes of NSCLC or biomarkers it is now possible to improve outcome and maintain stable quality of life. We conducted a literature search of tailored treatment already implemented in advanced NSCLC in order to highlight the information required to decide on the optimal oncological treatment for individual patients. 16 studies were identified by literature review. Significantly improved outcome was demonstrated in patients with nonsquamous NSCLC treated with cisplatin/pemetrexed in pre-planned, exploratory and retrospective analysis from large-scale, randomised trials. Level 1 evidence showed significantly better progression-free survival when patients carrying an epidermal growth factor receptor (EGFR) mutation were treated with gefitinib compared to standard chemotherapy. Retrospective, unplanned analysis of excision repair cross complementation group 1 (ERCC1) and betatubulin III upregulation demonstrated poorer outcome in NSCLC patients treated with platinum-doublets and vinorelbine-based chemotherapy, respectively. In conclusion, tailoring treatment according to either histological subtype or EGFR mutation status in advanced NSCLC should today be part of daily practice based on current evidence. Future biomarkers need optimisation of methodology and prospective validation before clinical implementation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Molecular Targeted Therapy , Patient Selection , Precision Medicine , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/chemistry , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Humans , Lung Neoplasms/chemistry , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Neoplasm Staging , Odds Ratio , Protein Kinase Inhibitors/therapeutic use , Risk Assessment , Risk Factors , Survival Analysis , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Customized chemotherapy is likely to improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). Excision repair cross-complementation group 1 (ERCC1) is a promising biomarker; however, current evidence is inadequate. Impact of ERCC1 status was evaluated among patients participating in a large randomized chemotherapy trial. PATIENTS AND METHODS: Four hundred and forty-three patients with advanced NSCLC were enrolled in a phase III trial and were randomly allocated to triplet chemotherapy or standard doublet regimen. Immunohistochemical evaluation for ERCC1 status was mainly carried out on bioptic material. RESULTS: Two hundred and sixty-four (59.5%) patients had representative tissue samples for ERCC1 evaluation. Median overall survival (OS) in the ERCC1-negative and ERCC1-positive population was 11.8 and 9.8 months, respectively (P = 0.028). The median OS among patients with adenocarcinomas (n = 122) was 15.2 and 8.3 months, respectively (P = 0.007). Interaction analysis between ERCC1-negative status and adenocarcinomas yielded a hazard ratio of 0.64 for death (P = 0.002). CONCLUSIONS: Clinically applicable evaluation of ERCC1 status predicted cisplatin sensitivity in the largest randomized patient population with advanced NSCLC reported to date. The predictive value can be ascribed to the adenocarcinomas emphasizing the relevance of ERCC1 expression in this subgroup.
