The role of intratumour heterogeneity and chromosomal instability in cancer

Increasing evidence supports the existence of intratumour heterogeneity in many solid and haematological tumour types, with potential clinical implications for both cancer diagnosis and treatment. Multi-region whole-exome sequencing of surgically resected non-small cell lung cancer (NSCLC) tumours demonstrated intratumour spatial and temporal heterogeneity in the mutational burden, copy number aberrations, and mutational signatures identified in these tumours. Furthermore, heterogeneity of mutations, including driver mutations, was also demonstrated in pre-invasive lung adenocarcinoma in situ lesions, suggesting that clonal evolution may be a feature of the early stages of cancer development. Whilst deciphering the clonal landscape of tumours may rely on multi-region and repeated tissue sampling, this remains challenging outside the context of clinical studies, and is not routine clinical practice. A non-invasive alternative may be the use of circulating biomarkers, such as circulating cell-free tumour DNA (cfDNA). Truncal and branch mutations were identified in cfDNA from patients with early stage NSCLC using different approaches. The detection of low frequency branch mutations, which are predicted to be subclonal in origin and may be potentially involved in the emergence of therapeutic resistance and tumour progression, were difficult to identify in cfDNA. Further studies are required to develop effective strategies for clonal and subclonal mutation detection in cfDNA, and to determine the utility of such biomarkers in representing the tumour genomic landscape, and in tracking tumour evolution in time. Chromosomal instability (CIN), describes an increased rate of numerical and structural chromosome aberrations, and is a known driver of intercellular genetic tumour heterogeneity. CIN has been shown to be associated with drug resistance and poor clinical outcome in several cancer types. However, in oestrogen receptor (ER)-negative breast cancer it has previously been shown that extreme CIN is associated with improved clinical outcome, consistent with a negative impact of CIN on cellular fitness and growth. This paradoxical relationship was further validated in a large breast cancer cohort study, in which extreme CIN was associated with improved outcome in patients with ER-negative cancer (p trend = 0.03). A similar relationship was seen in ERnegative/ human epidermal growth factor receptor (HER2)-negative cancers (p trend = 0.007). Identifying such patients may help distinguish good from poor prognostic groups, and therefore support treatment and risk stratification. We are yet to uncover the true extent of intratumour heterogeneity and CIN in different cancer types, their relevance to clinical outcome, and how we may be able to overcome or exploit these features for the therapeutic gain and benefit of patients with cancer. Longitudinal studies employing serial tissue and circulating biomarker sampling have the potential to address these questions, and to truly define the breadth of genetic diversity in different tumour types and its relevance to patient outcome

Cancer cachexia in thoracic malignancy: a narrative review

PURPOSE OF REVIEW Thoracic malignancies are amongst the most lethal of all cancers. Cancer cachexia lacks unanimously accepted diagnostic criteria, and therefore is referenced to as a conceptual framework whereby cancer cachexia is ‘an ongoing loss of skeletal muscle mass (termed sarcopenia), with or without loss of fat mass that cannot be reversed by conventional nutritional support and leads to progressive functional impairment’. This review summarises the current evidence base in this field, including imaging techniques currently used to define sarcopenia, inflammatory and metabolic changes associated with the syndrome and ongoing research into potential treatment strategies. RECENT FINDINGS Sarcopenia is a key component of the cancer cachexia syndrome. It is common in patients with both early-stage and advanced NSCLC. Patients with sarcopenia have more treatment-related side effects and poorer overall survival compared with nonsarcopenic patients. SUMMARY Early identification of cancer cachexia may facilitate stratification of patients most-at-risk and initiation of emerging anticachexia treatments. If these are proven to be effective, this strategy has the potential to improve tolerance to anti-cancer therapies, improving the quality of life, and perhaps the survival, of patients with thoracic malignancies

Tumour heterogeneity and immune-modulation.

Recent advances in sequencing technologies have revealed extensive intratumour heterogeneity (ITH) both within individual tumours and between primary and metastatic tumours for different cancer types. Such genetic diversity may have clinical implications for both cancer diagnosis and treatment with increasing evidence linking ITH and therapeutic resistance. Nonetheless, whilst limiting the activity of targeted agents, tumour genetic heterogeneity may provide a new therapeutic opportunity through generation of neo-antigens that could be recognised and targeted by the patient's own immune system in response to immune-modulatory therapies. Longitudinal genomic studies assessing tumour clonal architecture and its correlation with the underlying immune response to cancer in each particular patient are needed to follow tumour evolutionary dynamics over time and through therapy, in order to further understand the mechanisms behind drug resistance and to inform the development of new combinatorial therapeutic strategies

Predicting lung cancer recurrence from circulating tumour DNA. Commentary on 'Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution'

No abstract available

Tracking Cancer Evolution through the Disease Course.

During cancer evolution, constituent tumor cells compete under dynamic selection pressures. Phenotypic variation can be observed as intratumor heterogeneity, which is propagated by genome instability leading to mutations, somatic copy-number alterations, and epigenomic changes. TRACERx was set up in 2014 to observe the relationship between intratumor heterogeneity and patient outcome. By integrating multiregion sequencing of primary tumors with longitudinal sampling of a prospectively recruited patient cohort, cancer evolution can be tracked from early- to late-stage disease and through therapy. Here we review some of the key features of the studies and look to the future of the field. SIGNIFICANCE: Cancers evolve and adapt to environmental challenges such as immune surveillance and treatment pressures. The TRACERx studies track cancer evolution in a clinical setting, through primary disease to recurrence. Through multiregion and longitudinal sampling, evolutionary processes have been detailed in the tumor and the immune microenvironment in non-small cell lung cancer and clear-cell renal cell carcinoma. TRACERx has revealed the potential therapeutic utility of targeting clonal neoantigens and ctDNA detection in the adjuvant setting as a minimal residual disease detection tool primed for translation into clinical trials

Optimising fusion detection through sequential DNA and RNA molecular profiling of non-small cell lung cancer

OBJECTIVES: There is an increasing number of driver fusions in NSCLC which are amenable to targeted therapy. Panel testing for fusions is increasingly appropriate but can be costly and requires adequate good quality biopsy material. In light of the typical mutual exclusivity of driver events in NSCLC, the objective of this study was to trial a novel testing pathway, supported by industrial collaboration, in which only patients negative for driver mutations on DNA-NGS were submitted for fusion panel analysis. MATERIALS AND METHODS: Over 18 months, all patients from a single centre with non-squamous NSCLC were submitted for DNA-NGS, plus ALK and ROS1 immunohistochemistry +/− FISH. Those which were negative for a driver mutation were then recalled for RNA panel testing. RESULTS: 307 samples were referred for DNA-NGS mutation analysis, of which, 10% of cases were unsuitable for or failed DNA-NGS analysis. Driver mutations were detected in 61% (167/275) of all those successfully tested. Of those without a driver mutation and with some remaining tissue available, 28% had insufficient tissue/extracted RNA or failed RNA-NGS. Of those successfully tested, 24% (17/72) had a fusion gene detected involving either ALK, ROS, MET, RET, FGFR or EGFR. Overall, 66% (184/277) of patients had a driver event detected through the combination of DNA and RNA panels. CONCLUSION: Sequential DNA and RNA based molecular profiling increased the efficacy of detecting fusion driven NSCLCs. Continued optimisation of tissue procurement, handling and the diagnostic pathways for gene fusion analysis is necessary to reduce analysis failure rates and improve detection rate for treatment with the next generation of small molecule inhibitors

Copy number architectures define treatment-mediated selection of lethal prostate cancer clones

Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10-8 and 6.4 × 10-4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories