Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer.
OBJECTIVE
The treatment of patients with advanced non-small-cell lung cancer (NSCLC) is based on clinical trials experience. Molecular characteristics that impact metabolism and efficacy of chemotherapeutic agents are not used for decision making. Ribonucleotide reductase subunit 1 (RRM1) is crucial for nucleotide metabolism, and it is the dominant molecular determinant of gemcitabine efficacy. Excision repair cross-complementing group 1 gene (ERCC1), a component of the nucleotide excision repair complex, is important for platinum-induced DNA adduct repair. We hypothesized that selection of double-agent chemotherapy based on tumoral RRM1 and ERCC1 expression would be feasible and beneficial for patients with advanced NSCLC.


METHODS
We conducted a prospective phase II clinical trial in patients with advanced NSCLC. Patients were required to have a dedicated tumor biopsy for determination of RRM1 and ERCC1 gene expression by real-time quantitative reverse transcriptase polymerase chain reaction. Double-agent chemotherapy consisting of carboplatin, gemcitabine, docetaxel, and vinorelbine was selected based on gene expression. Disease response and patient survival were monitored.


RESULTS
Eighty-five patients were registered, 75 had the required biopsy without significant complications, 60 fulfilled all eligibility criteria, and gene expression analysis was not feasible in five patients. RRM1 expression ranged from 0 to 1,637, ERCC1 expression ranged from 1 to 8,103, and their expression was correlated (Spearman's rho = 0.46; P < .01). Disease response was 44%. Overall survival was 59% and progression-free survival was 14% at 12 months, with a median of 13.3 and 6.6 months, respectively.


CONCLUSIONS
Therapeutic decision making based on RRM1 and ERCC1 gene expression for patients with advanced NSCLC is feasible and promising for improvement in patient outcome
Simon
George
G
Program and Division of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612-9497, USA.
Sharma
Anupama
A
Li
Xueli
X
Hazelton
Todd
T
Walsh
Frank
F
Williams
Charles
C
Chiappori
Alberto
A
Haura
Eric
E
Tanvetyanon
Tawee
T
Antonia
Scott
S
Cantor
Alan
A
Bepler
Gerold
G
D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D018736:DNA Adducts; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D018572:Disease-Free Survival; D004720:Endonucleases / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D009711:Nucleotides / Q000737:chemistry; D011446:Prospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D009711:Nucleotides; D014157:Transcription Factors; C071447:ERCC1 protein, human; D004720:Endonucleases