Molecular profiling of ctDNA in pancreatic cancer: Opportunities and challenges for clinical application

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality within the next decade, with limited effective treatment options and a dismal long-term prognosis for patients. Genomic profiling has not yet manifested clinical benefits for diagnosis, treatment or prognosis in PDAC, due to the lack of available tissues for sequencing and the confounding effects of low tumour cellularity in many biopsy specimens. Increasing focus is now turning to the use of minimally invasive liquid biopsies to enhance the characterisation of actionable PDAC tumour genomes. Circulating tumour DNA (ctDNA) is the most comprehensively studied liquid biopsy analyte in blood and can provide insight into the molecular profile and biological characteristics of individual PDAC tumours, in real-time and in advance of traditional imaging modalities. This can pave the way for identification of new therapeutic targets, novel risk variants and markers of tumour response, to supplement diagnostic screening and provide enhanced scrutiny in treatment stratification. In the roadmap towards the application of precision medicine for clinical management in PDAC, ctDNA analyses may serve a leading role in streamlining candidate biomarkers for clinical integration. In this review, we highlight recent developments in the use of ctDNA-based liquid biopsies for PDAC and provide new insights into the technical, analytical and biological challenges that must be overcome for this potential to be realised.

T cells in pancreatic cancer stroma

“…The PDAC tumour microenvironment is characterised by complex fibrotic stroma with substantial infiltration of tumour-promoting immunosuppressive cells and pronounced T cell exhaustion, favouring immune evasion that results in immunotherapeutic failures and poor clinical outcome. Therefore, understanding the complexity of PDAC immune landscape and the mechanisms involved in T cell dysfunction may contribute to identifying new immunotherapeutic strategies for treating PDAC and monitoring such response with novel technologies such as ctDNA to assess tumour lysis[ 77 ]. As such, unsuccessful immunotherapies could be reversed using combined approaches targeting multiple pathways that obstruct T cell anti-tumour immunity along with other strategies to target stroma[ 78 , 79 ].…”

Exploring the Clinical Utility of Pancreatic Cancer Circulating Tumor Cells

“…Marked variations in the amount of cfDNA has been detected in healthy individuals and is associated with a range of conditions such as inflammation and tissue damage during intense physical activity [28,29]. ctDNA has a short half-life which can result in low yield and susceptibility to degradation during processing or inappropriate sample handling [17,30]. Sensitivity for KRAS-specific ctDNA has been reported in 27% to 81% of PDAC patients and the identification of targetable mutations is generally limited to patients with high ctDNA levels [30,31].…”

“…ctDNA has a short half-life which can result in low yield and susceptibility to degradation during processing or inappropriate sample handling [17,30]. Sensitivity for KRAS-specific ctDNA has been reported in 27% to 81% of PDAC patients and the identification of targetable mutations is generally limited to patients with high ctDNA levels [30,31]. Thus far, ctDNA detection has been shown to predict PDAC recurrence, presence of minimal residual disease, and correlates with patient survival [32][33][34].…”

Natural killer cells in pancreatic cancer stroma

“…Additional research is needed to fully elucidate the role of NK cells in pancreatic cancer and deconvolute the intricate relationships between NK and stromal cells within the TME, facilitating co-targeting of tumour stroma[ 73 , 88 ]. Through defining these relationships, novel functional and mechanistic insights into this devastating disease can be achieved[ 89 ] and the full therapeutic potential of NK cells can be harnessed.…”