Blood-based CHRNA3 single nucleotide polymorphism and outcome in advanced non-small-cell lung cancer patients.
Nicotine acetylcholine receptors (nAChRs) are associated with resistance to gemcitabine, cisplatin and paclitaxel in non-small-cell lung cancer (NSCLC) cell lines. Three single nucleotide polymorphisms (SNPs) of CHRNA3, CHRNA5 and LOC123688 increase lung cancer risk. These SNPs may have influenced outcome in patients treated in our phase III trial. Stage IV NSCLC patients were treated with customized chemotherapy based on ERCC1 (excision repair cross-complementing 1) mRNA expression. Patients in the control arm received docetaxel/cisplatin; patients in the genotypic arm with low levels of ERCC1 received docetaxel/cisplatin; patients in the genotypic arm with high levels of ERCC1 received docetaxel/gemcitabine. DNA was extracted from lymphocytes, and CHRNA3 (rs1051730), CHRNA5 (rs16969968) and LOC123688 (rs8034191) SNPs were genotyped with the Taqman allele discrimination assay. A significant interaction was found for CHRNA3 and PS (P=0.02). In patients with PS 0, CT patients had a better response than both CC (P=0.01) and TT (P=0.02) patients, and patients in the low genotypic group also had a better response (P=0.01). When the CHRNA3 genotype was added in the multivariate analysis for progression-free survival, an improvement was observed in the low genotypic group in PS 0 patients (P=0.02). PS 0 patients in the low genotypic group with the CT genotype attained an 84% response rate, 12.1-month progression-free survival, and 19-month median survival. CHRNA3 (rs1051730) genotyping can improve customized chemotherapy based on tumor assessment of ERCC1 mRNA in stage IV NSCLC with PS 0.
Carcereny
Enric
E
Catalan Institute of Oncology, Badalona, Spain.
Ramirez
Jose Luis
JL
Sanchez-Ronco
Maria
M
Isla
Dolores
D
Cobo
Manuel
M
Moran
Teresa
T
de Aguirre
Itziar
I
Okamoto
Tatsuro
T
Wei
Jia
J
Provencio
Mariano
M
Lopez-Vivanco
Guillermo
G
Camps
Carlos
C
Domine
Manuel
M
Alberola
Vicente
V
Sanchez
Jose Miguel
JM
Massuti
Bartomeu
B
Mendez
Pedro
P
Taron
Miquel
M
Rosell
Rafael
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004359:Drug Therapy, Combination; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine / Q000379:methods; D011978:Receptors, Nicotinic / Q000235:genetics*; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D000093542:Gemcitabine
D002945:Cisplatin; D004268:DNA-Binding Proteins; D003841:Deoxycytidine; D000077143:Docetaxel; D004720:Endonucleases; D011978:Receptors, Nicotinic; D043823:Taxoids; D000093542:Gemcitabine; C071447:ERCC1 protein, human