Tumor BRCA1, RRM1 and RRM2 mRNA expression levels and clinical response to first-line gemcitabine plus docetaxel in non-small-cell lung cancer patients.
BACKGROUND
Overexpression of RRM1 and RRM2 has been associated with gemcitabine resistance. BRCA1 overexpression increases sensitivity to paclitaxel and docetaxel. We have retrospectively examined the effect of RRM1, RRM2 and BRCA1 expression on outcome to gemcitabine plus docetaxel in advanced non-small-cell lung cancer (NSCLC) patients.


RESULTS
Tumor samples were collected from 102 chemotherapy-naïve advanced NSCLC patients treated with gemcitabine plus docetaxel as part of a randomized trial. RRM1, RRM2 and BRCA1 mRNA levels were assessed by quantitative PCR and correlated with response, time to progression and survival. As BRCA1 levels increased, the probability of response increased (Odds Ratio [OR], 1.09: p = 0.01) and the risk of progression decreased (hazard ratio [HR], 0.99; p = 0.36). As RRM1 and RRM2 levels increased, the probability of response decreased (RRM1: OR, 0.97; p = 0.82; RRM2: OR, 0.94; p<0.0001) and the risk of progression increased (RRM1: HR, 1.02; p = 0.001; RRM2: HR, 1.005; p = 0.01). An interaction observed between BRCA1 and RRM1 allowed patients to be classified in three risk groups according to combinations of gene expression levels, with times to progression of 10.13, 4.17 and 2.30 months (p = 0.001). Low BRCA1 expression was the only factor significantly associated with longer time to progression in 31 patients receiving cisplatin-based second-line therapy.


CONCLUSIONS
The mRNA expression of BRCA1, RRM1 and RRM2 is potentially a useful tool for selecting NSCLC patients for individualized chemotherapy and warrants further investigation in prospective studies.
Boukovinas
Ioannis
I
Theagenion Cancer Hospital of Thessaloniki, Thessaloniki, Greece.
Papadaki
Chara
C
Mendez
Pedro
P
Taron
Miquel
M
Mavroudis
Dimitris
D
Koutsopoulos
Anastasios
A
Sanchez-Ronco
Maria
M
Sanchez
Jose Javier
JJ
Trypaki
Maria
M
Staphopoulos
Eustathios
E
Georgoulias
Vassilis
V
Rosell
Rafael
R
Souglakos
John
J
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077143:Docetaxel; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics* / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D012333:RNA, Messenger; D043823:Taxoids; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D000077143:Docetaxel; C093713:ribonucleotide reductase M2; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine