Tracking Genomic Cancer Evolution for Precision Medicine: The Lung TRACERx Study

Tracking Genomic Cancer Evolution for Precision Medicine: The Lung TRACERx Study Mariam Jamal-Hanjani Alan Hackshaw Yenting Ngai Jacqueline Shaw Caroline Dive Sergio Quezada Gary Middleton Elza de Bruin John Le Quesne Seema Shafi Mary Falzon Stuart Horswell Fiona Blackhall Iftekhar Khan Sam Janes Marianne Nicolson David Lawrence Martin Forster Dean Fennell Siow-Ming Lee Jason Lester Keith Kerr Salli Muller Natasha Iles Sean Smith Nirupa Murugaesu Richard Mitter Max Salm Aengus Stuart Nik Matthews Haydn Adams Tanya Ahmad Richard Attanoos Jonathan Bennett Nicolai Juul Birkbak Richard Booton Ged Brady Keith Buchan Arrigo Capitano Mahendran Chetty Mark Cobbold Philip Crosbie Helen Davies Alan Denison Madhav Djearman Jacki Goldman Tom Haswell Leena Joseph Malgorzata Kornaszewska Matthew Krebs Gerald Langman Mairead MacKenzie Joy Millar Bruno Morgan Babu Naidu Daisuke Nonaka Karl Peggs Catrin Pritchard Hardy Remmen Andrew Rowan Rajesh Shah Elaine Smith Yvonne Summers Magali Taylor Selvaraju Veeriah David Waller Ben Wilcox Maggie Wilcox Ian Woolhouse Nicholas McGranahan Charles Swanton - Abstract: 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 nonsmall 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. Each patients cancer has a unique genomic landscape, often comprised of populations of genetically distinct, separated subclones with the potential to undergo dynamic evolutionary processes throughout the disease course [1,2]. One of the major challenges in achieving the goal of precision medicine lies in obtaining an accurate view of this genomic landscape, in order to choose the appropriate therapeutic regimen [3]. Intratumour heterogeneity poses a challenge in that a single tumour biopsy may not fully capture the current or future tumour landscape and merely represents a snapshot of the disease in space and time. Several studies have demonstrated branched evolution in different tumour types, including breast [4,5], pancreatic [6], kidney [7], colorectal [8], and prostate [9] cancers, as well as haematological malignancies such as chronic lymphoblastic leukaemia [1] and acute lymphoblastic leukaemia [10]. Understanding how tumour clonal heterogeneity impacts upon clinical outcome, and how cancer subclones compete, adapt, and The Community Page is a forum for organizations and societies to highlight their efforts to enhance the dissemination and value of scientific knowledge. evolve through the disease course in relation to therapy, is an area of unmet clinical and scientific need. Lung TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx], ClinicalTrials.gov number, NCT01888601), is a prospective study in primary non-small cell lung cancer (NSCLC), which through multiregion and longitudinal tumour sampling and sequencing, aims to define the genomic landscape of NSCLC and to understand the impact of tumour clonal heterogeneity upon therapeutic and survival outcome. Overview of Lung TRACERx Lung TRACERx incorporates longitudinal sample collection from diagnosis to relapse in order to investigate how each cancer responds to treatment, the potential mutational processes and mechanisms involved in drug resistance, and development of metastatic disease. Although here we discuss TRACERx in NSCLC, the proposed longitudinal sample collection and study template is also relevant to other tumour types. TRACERx, conducted across six sites in the United Kingdom (London, Leicester, Manchester, Aberdeen, Birmingham, and Cardiff), will enrol 842 patients with primary NSCLC stages I-IIIA over an accrual period of four years with a total five-year follow-up per patient. Primary surgically resected NSCLC tumours and associated lymph nodes, surplus to diagnostic requirements, will be subject to multiregion sampling and subsequent whole-exome and/or whole-genome sequencing. In patients suffering disease recurrence, consent will be obtained for a further biopsy to assess how the tumour clonal structure has changed through therapy and disease progression. The primary objectives of TRACERx are to determine the relationship between intratumour heterogeneity and clinical outcome (disease-free survival [DFS] and overall survival [OS]), and to establish the impact of adjuvant platinum-containing regimens on intratumour heterogeneity in relapsed disease. The secondary objectives include developing and validating an intratumour heterogeneity index as a prognostic or predictive biomarker and identifying drivers of genomic instability, metastatic progression, and drug resistance by identifying and tracking the dynamics of somatic mutational heterogeneity. TRACERx also aims to define clonally dominant drivers of disease to address the role of clonal driver dominance in targeted therapeutic response, and to guide lung cancer treatment stratification. The sample collection per patient and overall study schema are summarised in Figure 1 and Figure 2, respectively. Spatial Heterogeneity and Branched Evolution in NSCLC Previous efforts to characterise the cancer genome of NSCLC have involved the analysis of copy number alterations [11,12], targeted sequencing of candidate cancer genes [13,14] and next-generation sequencing of genomes and/or exomes [1518]. By interrogating the mutational spectrum of tumours, these studies have demonstrated its complex and heterogeneous genomic landscape from point mutations to large structural variants, and the high mutational burden of smoking-related NSCLC. However, few studies in NSCLC have investigated the clonal and subclonal architecture of lung cancer tumours and their evolution through disease progression. The TRACERx consortium has developed methods to analyse the dynamics of genetic intratumour heterogeneity within individual tumours over time [7]. Distance-based phylogenetic trees will be inferred from the variants, insertions and deletions (INDELS), and Citation: Jamal-Hanjani M, Hackshaw A, Ngai Y, Shaw J, Dive C, et al. (2014) Tracking Genomic Cancer Evolution for Precision Medicine: The Lung TRACERx Study. PLoS Biol 12(7): e1001906. doi:10.1371/journal.pbio. 1001906 Published July 8, 2014 Copyright: 20 (...truncated)