title: Phase II trial of customized first line chemotherapy according to ERCC1 and RRM1 SNPs in patients with advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  Customized chemotherapy has several advantages: patients are more likely to be treated with the most effective agents and can be spared the toxicity of ineffective drugs. Based on the literature, excision repair cross complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) genes represent predictive biomarkers of response to platinum compound and gemcitabine, in NSCLC.
  
  
  METHODS
  We had planned a phase II trial (Simon design) to evaluate combination chemotherapy according to single nucleotide polymorphisms (SNPs) of ERCC1 (118T/C and 8092C/A) and RRM1 (-37C/A and -524T/C) in naïve patients affected by advanced NSCLC. ERCC1 and RRM1 SNPs assessment was performed in peripheral blood lymphocytes (PBLs). Combination chemotherapy was selected based on ERCC1 and RRM1 SNPs: we assume that patients with one or two C alleles at position 118 and with one or two A alleles at position 8092 in ERCC1 gene would correspond to Cisplatin non-responder and than with two A alleles at -37 and two C alleles at -524 in RRM1 gene to gemcitabine non-responder. Four schedules were provided: cisplatin+gemcitabine, cisplatin+docetaxel, gemcitabine+docetaxel; docetaxel+vinorelbine. Primary endpoint was overall response (ORR) in the intention-to-treat population.
  
  
  RESULTS
  42 patients were enrolled from January 2010 to November 2011; 40 patients received at least 1 cycle of chemotherapy; median age was 66 years (range: 47-72); 36(90%) had stage IV, 4(10%) IIIB; 23(58%) had adenocarcinoma, 14(35%) squamous carcinoma. Twenty-five (62%) patients received treatment A, 3(8%) treatment B, 11(28%) treatment C, 1(23%) treatment D. ORR was 55%, analysis in squamous patients subgroups showed 71.4% ORR. The median follow-up was 19.7 months, PFS was 23 weeks (95% CI = 15-26) and OS was 40.4 weeks (95% CI = 32-55). Treatment was well tolerated.
  
  
  CONCLUSIONS
  We observed an increase of ORR in NSCLC patients when they were treated with chemotherapy according to ERCC1 and RRM1 SNPs status.
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, Firenze, Italy. Electronic address: francescamazzoni@hotmail.com.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mazzoni
authors.forename: Fabiana Letizia
authors.initials: FL
authors.lastname: Cecere
authors.forename: Giulia
authors.initials: G
authors.lastname: Meoni
authors.forename: Costanza
authors.initials: C
authors.lastname: Giuliani
authors.forename: Luca
authors.initials: L
authors.lastname: Boni
authors.forename: Andrea
authors.initials: A
authors.lastname: Camerini
authors.forename: Sara
authors.initials: S
authors.lastname: Lucchesi
authors.forename: Francesca
authors.initials: F
authors.lastname: Martella
authors.forename: Domenico
authors.initials: D
authors.lastname: Amoroso
authors.forename: Elisa
authors.initials: E
authors.lastname: Lucherini
authors.forename: Francesca
authors.initials: F
authors.lastname: Torricelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Costanzo
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D012262:Ribonucleoside Diphosphate Reductase; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin; D000093542:Gemcitabine
keywords: Chemotherapy; ERCC1; Non-small-cell lung cancer; Polymorphisms; RRM1; SNPs