ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine.
BACKGROUND
Pivotal studies indicate a role of excision repair cross-complementation 1 (ERCC1) gene and ribonucleotide reductase M1 (RRM1) gene in conferring a differential sensitivity to cytotoxic chemotherapy and epidermal growth factor receptor (EGFR) gene has been recently extensively investigated in non-small-cell lung cancer (NSCLC).


METHODS
Formalin-fixed, paraffin-embedded bronchoscopic/fine needle aspiration biopsies obtained from 70 patients with advanced NSCLC were retrospectively collected to investigate the expression level of ERCC1, RRM1 and EGFR by real-time PCR. Sufficient amounts of messenger RNA (mRNA) were successfully extracted from 61 (87%) specimens, reverse transcribed and amplified with intron-spanning primers. Forty-one patients had stage IV disease and 43 received cisplatin/gemcitabine chemotherapy.


RESULTS
A strong correlation between ERCC1 and RRM1 mRNA levels (r(s) = 0.624, P < 0.0001) was found. Median survival time in patients with low ERCC1 was significantly longer (17.3 versus 10.9, P = 0.0032 log-rank test) as well as in patients with low RRM1 (13.9 versus 10.9, P = 0.0390 log-rank test). Concomitant low expression levels of ERCC1 and RRM1 (n = 33) were predictive of a better outcome (14.9 versus 10.0, P = 0.0345 log-rank test). Among cisplatin-treated patients, a low ERCC1 level was highly predictive of a longer survival (23.0 versus 12.4, P = 0.0001 log-rank test). No correlation between gene expression levels and histology was reported. No significant correlation between EGFR expression level and survival was found. At multivariate analysis, performance status, response to chemotherapy, presence of weight loss and ERCC1 were independent prognostic factors for survival.


CONCLUSIONS
This retrospective study further validates ERCC1 and RRM1 genes as reliable candidates for customized chemotherapy and shows a higher impact on the survival of NSCLC patients treated with cisplatin/gemcitabine for ERCC1. Prospective pharmacogenomic studies represent a research priority in early and advanced NSCLC.
Ceppi
P
P
Thoracic Oncology Unit, Orbassano, Torino, Italy.
Volante
M
M
Novello
S
S
Rapa
I
I
Danenberg
K D
KD
Danenberg
P V
PV
Cambieri
A
A
Selvaggi
G
G
Saviozzi
S
S
Calogero
R
R
Papotti
M
M
Scagliotti
G V
GV
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004720:Endonucleases / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012189:Retrospective Studies; D012262:Ribonucleoside Diphosphate Reductase; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000093542:Gemcitabine
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D066246:ErbB Receptors; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin; D000093542:Gemcitabine