Measuring ctDNA With ddPCR May Help Drive Precision Medicine in Pancreatic Cancer

Circulating tumor DNA (ctDNA) has emerged as a promising biomarker in several cancers and a viable alternative to traditional blood-based protein biomarkers, including in pancreatic ductal adenocarcinoma (PDAC), one of the deadliest forms of cancer.

A recent review took a look at the promise of measuring the novel biomarker with digital-droplet PCR (ddPCR) in PDAC as the cancer landscape continues to push toward personalized, precision treatment. In this setting, ctDNA allows for a unique approach to exploring genetic mutations that may be translated into the clinical setting, explained the authors of the review.

“Liquid biopsy is of great importance in PDAC as adequate tumor tissue is scarce. The trouble of obtaining enough tumor sample to carry out molecular studies in PDAC makes it difficult to advance the field of personalized therapy in this tumor type,” wrote the authors. “For this reason, the possibility of performing genetic studies in peripheral blood takes on special relevance in PDAC and would probably stimulate the advancement in precision medicine in these patients.”

The ddPCR approach hinges on nanoliter-sized water-in-oil emulsion droplet technology and allows for accurate quantification of a small amount of circulating nucleic acids in plasma. The sensitive, accurate approach has suggested the possibility of alternative, unestablished biomarkers in PDAC that have traditionally eluded alternative, more traditional methods.

In one study, ddPCR identified plasma KRAS mutant ctDNA in 8 of 31 patients (26%) that were at various stages of disease. The researchers of the study also found that KRAS mutant detection has significant associations with inferior overall survival (OS). Similar results were shown in several other studies that showed an approximately 30% ctDNA KRAS detection rate with ddPCR and determined associations between KRAS mutations and OS.

“NGS approaches have the potential to detect a broad range of molecular targets. Therefore, most studies have focused on the presence of ctDNA mutations in a comprehensive set of genes to highlight tumor heterogeneity and demonstrate clonal evolution over the course of disease progression,” wrote the researchers. “In these types of studies, ddPCR technology has been performed in order to validate NGS results and to follow-up the disease. Thus, [next-generation sequencing] has been combined with ddPCR for liquid biopsy analysis.”

The researchers highlighted one study of 51 patients that used somatic mutations in ctDNA to identify patients who would likely relapse following surgical intervention, tumor tissue whole-exome sequencing revealed different somatic mutations that would likely be detected in ctDNA. Using ddPCR, they focused on alterations in KRAS, BRAF, and PIK3CA both prior to and after tumor resection in localized PDAC. There were alterations found in 43% of patients, and analyses revealed that patients with ctDNA in their plasma after resection were at a higher risk of relapse.

Reference

Huerta M, Roselló S, Sabater L, et al. Circulating tumor DNA detection by digital-droplet PCR in pancreatic ductal adenocarcinoma: a systematic review. Cancers. 2021:13(5):994. doi: 10.3390/cancers13050994