BACKGROUNDAmong patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.METHODSIn this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival.RESULTSWe observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4x10(-4)), which remained significant in multivariate analysis.CONCLUSIONSIntratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601.)

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

: The importance of in-tratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multire-gion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types.

The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types.

This chapter describes the radiological appearances of benign and malignant asbestos-related chest diseases and the utility of the various imaging modalities for the assessment of each manifestation. Topics covered include ILO classification of radiographs of the pneumoconioses, pleural effusion, diffuse pleural thickening, rounded atelectasis, malignant mesothelioma, asbestosis, and lung cancer.

Asbestos-related neoplastic and nonneoplastic diseases of the lungs and pleura range from pleural effusion and pleural plaques to lung cancer and malignant mesothelioma. Pleural effusions are typically hemorrhagic exudates of mixed cellularity but do not typically contain asbestos bodies. The classic distribution of pleural plaques seen on chest radiographs is the posterolateral chest wall between the seventh and tenth ribs, lateral chest wall between the sixth and ninth ribs, the dome of the diaphragm, and the mediastinal pleura. Computed tomographic (CT) findings support this distribution but also show anterior and paravertebral plaques not well shown at chest radiography. Imaging features of diffuse pleural thickening include a continuous sheet, often involving the costophrenic angles and apices, that rarely calcifies. The typical CT features of round atelectasis are of a round or oval mass that abuts the pleura, a "comet tail" of bronchovascular structures going into the mass, and thickening of the adjacent pleura. Features of asbestosis on chest radiographs include ground-glass opacification, small nodular opacities, "shaggy" cardiac silhouette, and ill-defined diaphragmatic contours. CT, however, is more sensitive in their detection. Chest radiography in patients with malignant mesothelioma may show an effusion, pleural thickening, and as the tumor progresses, a more lobulated outline. CT can help identify the disease in its early stages. Asbestos-related cancers can occur anywhere in the lungs. Recognition of the clinical, radiologic, and pathologic features of these diseases will be important for some years to come. (C) RSNA, 2002.