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Lung cancer is the leading cause of cancer-related death worldwide,1,2 with non–small-cell lung cancer (NSCLC) being the most common type. Large-scale sequencing studies have revealed the complex genomic landscape of NSCLC3–6 and genomic differences between lung adenocarcinomas and lung squamous-cell carcinomas.7 However, in-depth exploration of NSCLC intratumor heterogeneity (which provides the fuel for tumor evolution and drug resistance) and cancer genome evolution has been limited to small retrospective cohorts.8,9 Therefore, the clinical significance of intratumor heterogeneity and the potential for clonality of driver events to guide therapeutic strategies have not yet been defined.
Tracking Non–Small-Cell Lung Cancer Evolution through Therapy (TRACERx)10 is a multicenter, prospective cohort study, which began recruitment in April 2014 with funding from Cancer Research UK. The target enrollment is 842 patients from whom samples will be obtained for high-depth, multiregion whole-exome sequencing of surgically resected NSCLC tumors in stages IA through IIIA. One primary objective of TRACERx is to investigate the hypothesis that intratumor heterogeneity — in terms of mutations (single or dinucleotide base substitutions or small insertions and deletions) or somatic copy-number alterations (reflecting gains or losses of chromosome segments) — is associated with clinical outcome. Here, we report on the first 100 patients who were prospectively recruited in the study.
Methods
Patients and Tumor Samples
We collected tumor samples from 100 patients with NSCLC who had not received previous systemic therapy (Figure 1A; and Fig. S1 in Supplementary Appendix 1, available with the full text of this article at NEJM.org). Identifiers of patients were reassigned to protect anonymity and were ordered according to intratumor heterogeneity and histologic subtype. Eligible patients were at least 18 years of age and had received a diagnosis of NSCLC in stages IA through IIIA (except Patient CRUK0035, whose tumor was classified as stage IIIB on the basis of postoperative histologic analysis). The cohort was representative of a population of patients with NSCLC who were eligible for curative resection. Histologic data were confirmed on central review by a lung pathologist. (Details regarding the study design are provided in the protocol, available at NEJM.org.)
To assess intratumor heterogeneity, samples of at least two tumor regions that were separated by a margin of 0.3 cm to...