NEW YORK – A liquid biopsy test based on exosomal and cell-free microRNA accurately detected 97 percent of stage 1 and stage 2 pancreatic ductal carcinoma (PDAC) when combined with the CA 19-9 blood test in results from a large, prospective study presented at the annual meeting of the American Association for Cancer Research on Monday.
The five-year survival rate for patients diagnosed with metastatic pancreatic cancer is just 3.2 percent. Survival increases to 44.3 percent for those diagnosed early, but early detection of pancreatic cancer is difficult. For example, the CA 19-9 blood test alone has a sensitivity of 79 percent to 81 percent, and specificity of 82 percent to 90 percent, but is not useful as a screening test because it has a low positive predictive value. Moreover, the disease tends to have few symptoms in the early stages and is not readily detected during physical examinations.
Ajay Goel, a professor in the department of molecular diagnostics and experimental therapeutics at City of Hope and lead investigator on the study, noted in a webcast press conference at AACR that pancreatic cancer evolves slowly, progressing through a series of precancerous lesions. "It takes about 15 to 20 years for pancreatic cancer to evolve," Goel said. "As long as we have a test which can detect this disease early, this is a window of opportunity for early detection."
In addition to the CA19-9 test, several other blood-based tests are used for early detection of PDAC, but with generally inadequate sensitivity and specificity. For example, 20/20's OneTest has 89 percent sensitivity for detection of regional or metastatic pancreatic cancer, but 0 percent sensitivity for localized disease, when there is the greatest likelihood of long-term survival with treatment. Similarly, Exact Sciences' CancerGuard test has 71 percent to 72 percent sensitivity for detection of localized, regional, and metastatic pancreatic cancer, and Grail's Galleri assay has 84.7 percent sensitivity for regional or metastatic pancreatic cancer, but unknown sensitivity for early disease.
"If the goal is early detection, we shouldn't be looking at numbers in advanced cancers, because the [question] is, 'What is the earliest we can find these cancers?'," Goel said.
With the help of funding from the National Cancer Institute's Cancer Detection Consortium, Geol and his team at City of Hope focused on microRNAs, which are short, non-coding RNAs whose expression levels are frequently altered in cancers. "They're quite stable," Goel said. "You can capture them in any kind of bodily fluid very easily."
MicroRNAs can be found in cell-free form and encapsulated in tumor-derived exosomes that are isolated based on cell surface markers specific to the pancreas. Goel's team hypothesized that cell-free microRNAs would be highly sensitive for cancer detection, while microRNAs found in tumor-derived exosomes would have high specificity, and combining the two would result in a test that is both sensitive and specific.
In a previous pilot study published in Gastroenterology in 2022, conducted in 95 patients from the US and Japan, the test had a 98 percent detection rate for early pancreatic cancer.
In order to validate those results in a larger cohort of patients, Goel and his collaborators collected plasma samples from a total of about 900 patients from Japan, the US, South Korea, and China, including patients with pancreatic cancer and healthy donors, and conducted a real-time, quantitative PCR assay on the samples. They used the Japanese cohort to train their algorithm, and the US, China, and South Korean cohorts for validation.
The resulting exosomal and cell-free microRNA signature was highly accurate in the Japanese training cohort. In the validation cohorts, the detected between 88 percent and 93 percent of pancreatic cancers. In the US cohort, the test detected 93 percent of cases; in the China cohort, 88 percent of cases; and in the South Korea cohort, 91 percent of cases.
When the researchers broke the results down according to whether the cancer was early-stage or late-stage, the test was 91 percent accurate on its own for early-stage cancer, a number that rose to 97 percent when combined with CA 19-9 testing. For late-stage pancreatic cancer, the test was 93 percent accurate.
Goel and his team are continuing to validate the test in larger populations. They are also working on a long-term study to identify the earliest possible signs of pancreatic cancer through the NCI-sponsored Prostate, Lung, Colorectal, Ovarian Cancer (PLCO) Screening Trial. For that, investigators collected over 2.9 million specimens from more than 155,000 patients over more than two decades to study whether screening exams reduce mortality from those four cancers. Goel and his team will be analyzing samples from the study to pinpoint the earliest detectable signs of pancreatic cancer in patients who were ultimately diagnosed with the disease. They would also like to study whether their microRNA liquid biopsy test can identify pancreatic cysts in the preoperative setting that are likely to develop into cancer.