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

Insights into the metastatic cascade through research autopsies

Metastasis is a complex process and the leading cause of cancer-related death globally. Recent studies have demonstrated that genomic sequencing data from paired primary and metastatic tumours can be used to trace the evolutionary origins of cells responsible for metastasis. This approach has yielded new insights into the genomic alterations that engender metastatic potential, and the mechanisms by which cancer spreads. Given that the reliability of these approaches is contingent upon how representative the samples are of primary and metastatic tumour heterogeneity, we review insights from studies that have reconstructed the evolution of metastasis within the context of their cohorts and designs. We discuss the role of research autopsies in achieving the comprehensive sampling necessary to advance the current understanding of metastasis

The translational challenges of precision oncology

The translational challenges in the field of precision oncology are in part related to the biological complexity and diversity of this disease. Technological advances in genomics have facilitated large sequencing efforts and discoveries that have further supported this notion. In this review, we reflect on the impact of these discoveries on our understanding of several concepts: cancer initiation, cancer prevention, early detection, adjuvant therapy and minimal residual disease monitoring, cancer drug resistance, and cancer evolution in metastasis. We discuss key areas of focus for improving cancer outcomes, from biological insights to clinical application, and suggest where the development of these technologies will lead us. Finally, we discuss practical challenges to the wider adoption of molecular profiling in the clinic and the need for robust translational infrastructure

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

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