Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer.
OBJECTIVE
The JBR.10 trial demonstrated benefit from adjuvant cisplatin/vinorelbine (ACT) in early-stage non-small-cell lung cancer (NSCLC). We hypothesized that expression profiling may identify stage-independent subgroups who might benefit from ACT.


METHODS
Gene expression profiling was conducted on mRNA from 133 frozen JBR.10 tumor samples (62 observation [OBS], 71 ACT). The minimum gene set that was selected for the greatest separation of good and poor prognosis patient subgroups in OBS patients was identified. The prognostic value of this gene signature was tested in four independent published microarray data sets and by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR).


RESULTS
A 15-gene signature separated OBS patients into high-risk and low-risk subgroups with significantly different survival (hazard ratio [HR], 15.02; 95% CI, 5.12 to 44.04; P < .001; stage I HR, 13.31; P < .001; stage II HR, 13.47; P < .001). The prognostic effect was verified in the same 62 OBS patients where gene expression was assessed by qPCR. Furthermore, it was validated consistently in four separate microarray data sets (total 356 stage IB to II patients without adjuvant treatment) and additional JBR.10 OBS patients by qPCR (n = 19). The signature was also predictive of improved survival after ACT in JBR.10 high-risk patients (HR, 0.33; 95% CI, 0.17 to 0.63; P = .0005), but not in low-risk patients (HR, 3.67; 95% CI, 1.22 to 11.06; P = .0133; interaction P < .001). Significant interaction between risk groups and ACT was verified by qPCR.


CONCLUSIONS
This 15-gene expression signature is an independent prognostic marker in early-stage, completely resected NSCLC, and to our knowledge, is the first signature that has demonstrated the potential to select patients with stage IB to II NSCLC most likely to benefit from adjuvant chemotherapy with cisplatin/vinorelbine.
Zhu
Chang-Qi
CQ
University Health Network, Ontario Cancer Institute and Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.
Ding
Keyue
K
Strumpf
Dan
D
Weir
Barbara A
BA
Meyerson
Matthew
M
Pennell
Nathan
N
Thomas
Roman K
RK
Naoki
Katsuhiko
K
Ladd-Acosta
Christine
C
Liu
Ni
N
Pintilie
Melania
M
Der
Sandy
S
Seymour
Lesley
L
Jurisica
Igor
I
Shepherd
Frances A
FA
Tsao
Ming-Sound
MS
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
D014747:Vinblastine; D002945:Cisplatin; D000077235:Vinorelbine
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