Predictive value of BRCA1, ERCC1, ATP7B, PKM2, TOPOI, TOPΟ-IIA, TOPOIIB and C-MYC genes in patients with small cell lung cancer (SCLC) who received first line therapy with cisplatin and etoposide.
BACKGROUND
The aim of the study was to evaluate the predictive value of genes involved in the action of cisplatin-etoposide in Small Cell Lung Cancer (SCLC).


METHODS
184 SCLC patients' primary tumour samples were analyzed for ERCCI, BRCA1, ATP7B, PKM2 TOPOI, TOPOIIA, TOPOIIB and C-MYC mRNA expression. All patients were treated with cisplatin-etoposide.


RESULTS
The patients' median age was 63 years and 120 (65%) had extended stage, 75 (41%) had increased LDH serum levels and 131 (71%) an ECOG performance status was 0-1. Patients with limited stage, whose tumours expressed high ERCC1 (p=0.028), PKM2 (p=0.046), TOPOI (p=0.008), TOPOIIA (p=0.002) and TOPOIIB (p<0.001) mRNA had a shorter Progression Free Survival (PFS). In limited stage patients, high expression of ERCC1 (p=0.014), PKM2 (p=0.026), TOPOIIA (p=0.021) and TOPOIIB (p=0.019) was correlated with decreased median overall survival (mOS) while in patients with extended stage, only high TOPOIIB expression had a negative impact on Os (p=0.035). The favorable expression signature expression signature (low expression of ERCC1, PKM2, TOPOIIA and TOPOIIB) was correlated with significantly better PFS and Os in both LS-SCLC (p<0.001 and p=0.007, respectively) and ES-SCLC (p=0.007 and (p=0.011, respectively) group. The unfavorable expression signature was an independent predictor for poor PFS (HR: 3.18; p=0.002 and HR: 3.14; p=0.021) and Os (HR: 4.35; p=0.001and HR: 3.32; p=0.019) in both limited and extended stage, respectively.


CONCLUSIONS
Single gene's expression analysis as well as the integrated analysis of ERCC1, PKM2, TOPOIIA and TOPOIIB may predict treatment outcome in patients with SCLC. These findings should be further validated in a prospective study.
Laboratory of Tumour Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece ; Department of Medical Oncology, University General Hospital of Heraklion, Crete, Greece.
Niki
N
Karachaliou
Chara
C
Papadaki
Eleni
E
Lagoudaki
Maria
M
Trypaki
Maria
M
Sfakianaki
Anastasios
A
Koutsopoulos
Dimitris
D
Mavroudis
Efstathios
E
Stathopoulos
Vassilis
V
Georgoulias
John
J
Souglakos
D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D000073840:Copper-Transporting ATPases; D004264:DNA Topoisomerases, Type I / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D004720:Endonucleases / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000235:genetics*; D016259:Genes, myc; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D013963:Thyroid Hormones / Q000235:genetics; D016896:Treatment Outcome; D000097810:Thyroid Hormone-Binding Proteins
D000251:Adenosine Triphosphatases; D000951:Antigens, Neoplasm; D019313:BRCA1 Protein; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D002945:Cisplatin; D000073840:Copper-Transporting ATPases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005047:Etoposide; D008565:Membrane Proteins; D012333:RNA, Messenger; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C071447:ERCC1 protein, human; C528909:TOP1 protein, human; C000612464:ATP7B protein, human