The molecular landscape of pancreatic ductal adenocarcinoma.

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. Surgical resection of early, localised disease provides the only chance for potentially curative treatment; however, most patients with PDAC present with advanced disease and are not suitable for surgery. Genomic analyses of PDAC tumour lesions have identified a small number of recurrent alterations that are detected across most tumours, and beyond that a large number that either occur at a low (<5%) prevalence or are patient-specific in nature. This molecular heterogeneity has presented a significant challenge for the characterisation of tumour subtypes and effective molecular biomarkers, which have not yet manifested clinical benefits for diagnosis, treatment or prognosis in PDAC. These challenges are compounded by the overall lack of tumour biopsies for sequencing, the invasive nature of tissue sampling and the confounding effects of low tumour cellularity in many PDAC biopsy specimens, which have limited the applications of molecular profiling in unresectable patients and for longitudinal tumour monitoring. Further investigation into alternative sources of tumour analytes that can be sampled using minimally invasive methods and used to complement molecular analyses from tissue sequencing are required.

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

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.