Novel miRNA signature reliably detects lethal pancreatic cancer in the early stages

An exosome-based liquid biopsy showed favourable signals for noninvasive, early detection of pancreatic ductal adenocarcinoma (PDAC) in a prospective study.

“PDAC is one of the most aggressive and lethal diseases … Most patients with early PDAC do not experience any specific symptom at all, which makes early detection challenging,” said Dr Caiming Xu from The City of Hope, Monrovia, California, US, who presented the findings at AACR 2024. Only 10–15 percent of patients are diagnosed at an early stage (I–II). [CA Cancer J Clin 2024;74:12-49]

Xu stressed that the stage at diagnosis is a very important determinant of survival in PDAC, highlighting that an early diagnosis would equate to a chance at potentially curable surgery and treatment. PDAC patients diagnosed at the early stages have a 44-percent 5-year survival rate. But once the disease metastasizes and reaches stage III, this survival rate drops significantly to 16 percent, and plummets to 3 percent when diagnosed at stage IV, he explained.

Therefore, PDAC should be detected as early as possible before it becomes incurable, he stressed. “We need to find a way to improve the current tests [available].”

Micro-RNAs (miRNAs) are promising liquid biopsy biomarkers that are highly stable and abundant in cells and are easily detectable in body fluids, Xu said. It exists in blood primarily in two forms: cell-free (cf-miRNAs) and exosomal (exo-miRNAs).

Since an ideal diagnostic assay must offer the highest possible sensitivity and specificity, a combination of cf-miRNA and exo-miRNA biomarkers may offer a superior approach for early pancreatic cancer detection, Xu pointed out.

In a pilot study, 13 miRNAs (five cf-miRNA, eight exo-miRNA) had an area under the curve (AUC) of 93 percent. [Gastroenterology 2022;163:1252-1266.e2] Xu said that this result was ‘extremely exciting’, hence their drive to further assess the performance of these biomarkers in larger, multinational, multicentre prospective cohorts.

Xu and colleagues used a Japan population as a training cohort (n=150 PDAC/102 non-cancer controls). The validation cohorts were from the US (n=139/193), China (n=50/80), and South Korea (n=184/86). The total study population was 984. [AACR 2024, abstract 3899]

In the training cohort, the team successfully established the cf-miRNA end exo-miRNA panels, with respective AUC values of 95 percent and 97 percent. “We established the miRNA signature by combining [the two panels, yielding] an AUC of 98 percent,” said Xu. The cf-miRNA was more sensitive than the exo-miRNA (94 percent vs 92 percent), while the latter was more specific than the former (97 percent vs 83 percent).

“Our final miRNA signature leveraged the advantage from both to maximize its accuracy in PDAC detection,” he continued.

In the US cohort, the miRNA signature could identify PDAC with an AUC of 93 percent, specificity of 91 percent, and sensitivity of 87 percent. “These numbers mean that we could identify 87 percent of true cases, with only a 9-percent false positive rate, which is good,” Xu explained.

Similar patterns were seen in the China (88, 90, and 86 percent for AUC, specificity, and sensitivity, respectively) and South Korea cohorts (91, 90, and 81 percent, respectively).

“Collectively, we successfully validated our miRNA signature in three independent prospective cohorts [with diverse ethnicities and geographical backgrounds, which boost] the capability of our miRNA signature,” Xu said.

Looking at the signature scores in the US cohort, there was no difference between the early (AUC 91 percent) and late stages (AUC 93 percent). This means that the miRNA signature was able to identify early-stage PDAC, thus holding very promising capabilities in early PDAC detection, he said.

Moreover, the diagnostic accuracy of the miRNA signature significantly improved when combined with CA19-9, a tumour marker in pancreatic cancer. In the US cohort, the AUC, sensitivity, and specificity values with the miRNA signature jumped from 93, 87, and 91 percent to 97, 95, and 96 percent, respectively (for all PDAC stages) and from 91, 85, and 91 percent to 97, 91, and 96 percent (for stage I/II).

“Given the capability of our blood test to reliably detect even stage I/II PDAC with an AUC of 97 percent, we have successfully validated an exosome-based miRNA signature that could robustly identify patients with PDAC, even those with an early-stage disease with very high sensitivity and specificity,” Xu concluded.