Circulating tumor DNA analysis in the era of precision oncology

Abstract

The spatial and temporal genomic heterogeneity of various tumor types and advances in technology have stimulated the development of circulating tumor DNA (ctDNA) genotyping. ctDNA was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is associated with significant risk, when tumor tissue is insufficient or inaccessible, and/or when repeated assessment of tumor molecular abnormalities is needed to optimize treatment. The role of ctDNA is now well established in the clinical decision in certain alterations and tumors, such as the epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer and the v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer. The role of ctDNA analysis in other tumor types remains to be validated. Evolving data indicate the association of ctDNA level with tumor burden, and the usefulness of ctDNA analysis in assessing minimal residual disease, in understanding mechanisms of resistance to treatment, and in dynamically guiding therapy. ctDNA analysis is increasingly used to select therapy. Carefully designed clinical trials that use ctDNA analysis will increase the rate of patients who receive targeted therapy, will elucidate our understanding of evolution of tumor biology and will accelerate drug development and implementation of precision medicine. In this article we provide a critical overview of clinical trials and evolving data of ctDNA analysis in specific tumors and across tumor types.

Early plasma circulating tumor DNA (ctDNA) changes predict response to first-line pembrolizumab-based therapy in non-small cell lung cancer (NSCLC)

“…Assessment of ctDNA has had increasing clinical utility in determining certain actionable genetic alterations in NSCLC to guide selection of targeted therapies with kinase inhibitors. 6 More recently, ctDNA detection following resection of early stage lung cancer has also been shown to detect molecular residual disease earlier than standard-of-care radiologic imaging in patients with localized lung cancer. 18 19 However, it is still unclear whether ctDNA can be used to predict and monitor response and resistance to ICI in NSCLC.…”

“…In NSCLC, plasma genotyping of circulating tumor DNA (ctDNA) is currently used in clinical practice for detecting targetable genomic alterations in genes such as the epidermal growth factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ). 6 7 In addition, clearance of ctDNA after treatment initiation, as in the case of EGFR -mutant NSCLC is associated with improved clinical outcomes to EGFR tyrosine kinase inhibitors, while an increase in ctDNA can predict disease progression weeks ahead of imaging modalities. 8 ctDNA dynamics have been explored also as potential biomarker of response to ICIs.…”

A Targeted Gene Panel for Circulating Tumor DNA Sequencing in Neuroblastoma

“…Furthermore, detecting mutations in key cancer genes, that are not actionable per se, could also benefit patient's management by improving diagnosis, prognosis and treatment strategies setting (see (10,12,15,45,46)). In this context, we observed mutations in KMT2C (5/11 cases), in CREBBP (3/11 cases) and in ARID1A/B (3/11 cases).…”

“…However, ctDNA assays designed to target selected genes in customized panels could map tumor heterogeneity and may facilitate the identification of druggable mutations. Several commercially available ctDNA sequencing panels, designed to target specific exons or mutational hotspots, have shown their validity in clinical settings in adult cancers as in lung cancers (12).…”

Biomarkers for precision immunotherapy in the metastatic setting: hope or reality?

“…A promising application of ICPis can also be found in neoadjuvant therapy as recent publications note neoadjuvant immunotherapy may result in better clinical efficacy over an adjuvant application ICPis may also be used in the neoadjuvant setting since recent studies support that neoadjuvant immunotherapy can result in better clinical efficacy compared to the corresponding adjuvant therapy [ 144 ]. Added to all dated advancements, common means of time-consuming and painful tissue biopsies may be replaced by ctDNA in the peripheral blood [ 145 , 146 ]. Most tumours are highly heterogeneous and may change during the progression of the disease.…”