Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery.
OBJECTIVE
The first suggestions of a relationship between gene mRNA expression and differential sensitivity to gemcitabine/cisplatin are now emerging. ERCC1, RRM1, and XPD are involved in the nucleotide excision repair pathways, and tumor up-regulation of these genes leads to chemotherapy failure. In the present study, we have examined the potential correlation and predictive value of ERCC1, RRM1, and XPD mRNA expression in resected specimens from 67 stage IIB, IIIA, and IIIB non-small cell lung cancer patients treated with neoadjuvant gemcitabine/platinum followed by surgery.


METHODS
ERCC1, RRM1, and XPD expression was quantified using real-time quantitative reverse transcription-PCR.


RESULTS
A good correlation was found between mRNA expression levels of the three genes. For RRM1 levels, patients in the bottom quartile had a decreased risk of death compared with those in the top quartile (risk ratio = 0.30; P = 0.033). Median survival for the 17 patients in the bottom quartile was 52 months, whereas for the 15 in the top quartile, it was 26 months (P = 0.018). When the characteristics of these 17 patients were compared with all of the other 50 patients, no differences in initial staging were observed. However, the 17 patients in the bottom quartile had better outcomes, including more radiographic responses (65% versus 54%; P = 0.24), complete resections (94% versus 72%; P = 0.03), lobectomies (71% versus 34%; P = 0.004), and pathological complete responses (29% versus 0%; P = 0.00001).


CONCLUSIONS
Patients with RRM1 levels in the bottom quartile benefited significantly from gemcitabine/cisplatin neoadjuvant chemotherapy, leading us to conclude that RRM1 mRNA levels should be additionally validated to proceed with tailored chemotherapy.
Rosell
Rafael
R
Institut Catala d'Oncologia, Medical Oncology Service, Hospital Germans Trias i Pujol, Barcelona, Spain. rrosell@ns.hugtip.scs.es
Felip
Enriqueta
E
Taron
Miquel
M
Majo
Joaquim
J
Mendez
Pedro
P
Sanchez-Ronco
Maria
M
Queralt
Cristina
C
Sanchez
Jose Javier
JJ
Maestre
Jose
J
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D004265:DNA Helicases / Q000096:biosynthesis* / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004720:Endonucleases / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012262:Ribonucleoside Diphosphate Reductase; D016019:Survival Analysis; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics*; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein; D000093542:Gemcitabine
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C071447:ERCC1 protein, human; D004720:Endonucleases; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D000093542:Gemcitabine