Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer

Abstract

Purpose: 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.

Patients and 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.

Conclusion: 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.

Fig 1.

Disease-specific survival outcome based on the 15-gene signature in the JBR.10 training set. (A) Observation all; (B) observation stage IB; (C) observation stage II. HR, hazard ratio; ACT, adjuvant chemotherapy arm.

Fig 2.

In silico and quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) validation of the signature in stage IB to II patients who received no adjuvant therapy. (A) Director's Challenge Consortium adenocarcinoma data set; (B) Duke University data set; (C) University of Michigan squamous cancer data set; (D) Netherlands Cancer Institute data set; (E) observation with RT-qPCR; (F) observation with RT-qPCR with additional samples. HR, unadjusted hazard ratio.

Fig 3.

Predictive effect of the signature to adjuvant chemotherapy. Only high-risk group benefits from adjuvant chemotherapy. (A) High risk (microarray); (B) low risk (microarray); (C) high risk quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR); (D) low risk RT-qPCR.