Single nucleotide polymorphisms in MDR1 gen correlates with outcome in advanced non-small-cell lung cancer patients treated with cisplatin plus vinorelbine.
New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying NSCLC could influence chemosensitivity. In this study, we assessed whether the presence of polymorphisms in ERCC1, XPD, RRM1 and MDR1 genes can affect the efficacy and the tolerability of cisplatin and vinorelbine in NSCLC patients.


METHODS
Eligible patients had histological confirmed stage IV or IIIB (with malignant pleural effusion) non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy; World Health Organization performance status (PS) 0-1. Patients received intravenous doses of vinorelbine 25 mg/m² on day 1 and 8 and cisplatin 75 mg/m² on day 1, every 21 days, for a maximum of eight cycles.


RESULTS
94 patients were included. Median age was 61 years; 84% were male; WHO performance status (PS) was 0 in 24%; and 88% of patients had stage IV disease. The median number of cycles was 6. Overall median survival was 10.92 months (95% CI 9.0-12.9). Overall median time to progression was 5.89 months (95% CI 5.2-6.6). Results of the multivariate analysis for time to progression showed that ECOG 0 (hazard ratio [HR] ECOG 1 vs. ECOG 0, 1.74; p=0.036), MDR13435CC (HR CT vs. CC, 2.01; p=0.017; HR TT vs. CC, 1.54; p=0.22), and decreasing age (HR of age, 0.97; p=0.016) were the most powerful prognostic factors significantly related to lower risk of progression. Whereas ECOG 0 was the only prognostic factor for survival (HR ECOG 1 vs. ECOG 0, 3.02; p=0.001). There was no significant association between any of the SNPs analysed and the occurrence of vinorelbine and cisplatin-related toxicity.


CONCLUSIONS
In our results, the most important prognostic factors associated with lower risk of progression were MDR1 3435 CC genotype, PS 0 and younger age.
Viñolas
N
N
Hospital Clinic de Barcelona, IDIBAPS, Barcelona, Spain. nvinolas@clinic.ub.es
Provencio
M
M
Reguart
N
N
Cardenal
F
F
Alberola
V
V
Sánchez-Torres
J M
JM
Barón
F J
FJ
Cobo
M
M
Maestu
I
I
Moreno
I
I
Mesía
C
C
Izquierdo
A
A
Felip
E
E
López-Brea
M
M
Márquez
A
A
Sánchez-Ronco
M
M
Tarón
M
M
Santarpia
M C
MC
Rosell
R
R
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077235:Vinorelbine
D000970:Antineoplastic Agents; D014747:Vinblastine; D002945:Cisplatin; D000077235:Vinorelbine