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Early liver metastasis (Early-LiM) is the most significant prognostic factor in pancreatic ductal adenocarcinoma (PDAC) and is thought to originate from occult micrometastases present at the time of surgery. Reliable preoperative detection of such lesions remains an unmet clinical need.
The EXELiM study aims to develop and validate a circulating exosomal microRNA (exo-miRNA)-based liquid biopsy assay to accurately identify PDAC patients at high risk of occult liver metastasis before surgery. By integrating machine learning with multi-institutional plasma exosome profiling, this study seeks to enable biology-driven patient stratification and guide treatment sequencing toward precision oncology.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human malignancies, with a 5-year overall survival rate below 10%. Even after curative-intent pancreatectomy, over 70% of patients experience disease recurrence, with early liver metastasis (within six months postoperatively) representing the most aggressive and fatal pattern.
Emerging evidence indicates that pancreatic tumors release exosomes that modulate the liver microenvironment, establishing a premetastatic niche that facilitates early colonization. We hypothesize that circulating exosomal microRNAs reflect these biological processes and can serve as non-invasive biomarkers for detecting occult liver metastasis.
In this multi-center observational study, preoperative plasma-derived exosomes from PDAC patients are analyzed using next-generation small RNA sequencing and validated by RT-qPCR. A machine learning model is employed to integrate exo-miRNA expression profiles and clinical variables, yielding a predictive score for early liver metastasis risk.
The study evaluates the diagnostic accuracy, prognostic utility, and clinical benefit of the exo-miRNA panel compared to conventional biomarkers such as CA19-9.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Training Cohort - PDAC with Occult Liver Metastasis | Patients with PDAC who were found to have occult liver metastases at the time of or shortly after curative-intent pancreatectomy (within 6 months post-surgery), in the first cohort (training set). |
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| Training Cohort - PDAC without Occult Liver Metastasis | Patients with PDAC who did not develop liver metastasis for at least 6 months after curative-intent surgery in the first cohort (training set). |
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| Validation Cohort - PDAC with Occult Liver Metastasis | Patients with PDAC who were found to have occult liver metastases (early postoperative hepatic recurrence within 6 months) in the second cohort (validation set). |
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| Validation Cohort - PDAC without Occult Liver Metastasis | Patients with PDAC who did not develop liver metastasis for at least 6 months after curative-intent surgery in the second cohort (validation set). |
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| Discovery Cohort - PDAC with Occult Liver Metastasis | Patients with PDAC who were found to have occult liver metastases at the time of or shortly after curative-intent pancreatectomy (within 6 months post-surgery), in the discovery cohort. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| EXELiM assay (qRT-PCR validation) | Diagnostic Test | Quantitative reverse-transcription PCR (qRT-PCR)-based validation assay performed on preoperative plasma samples from PDAC patients in the training and validation cohorts. Candidate microRNAs identified by small RNA sequencing were tested using the EXELiM assay to validate their predictive accuracy for occult liver metastasis detection prior to surgery. |
| Measure | Description | Time Frame |
|---|---|---|
| Specificity | True Negative Rate: probability of a negative test result conditioned on absence of early liver metastasis | Through study completion, an average of 3 year |
| Measure | Description | Time Frame |
|---|---|---|
| Sensitivity | True Positive Rate: probability of a positive test result conditioned on the presence of early liver metastasis | Through study completion, an average of 3 year |
| Area Under the Receiver Operating Characteristic Curve (AUC) |
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Inclusion Criteria:
Exclusion Criteria:
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Patients with histologically confirmed pancreatic ductal adenocarcinoma (PDAC) who have undergone curative-intent pancreatectomy with available preoperative plasma samples.
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| Name | Affiliation | Role |
|---|---|---|
| Ajay Goel, PhD | City of Hope Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| City of Hope Medical Center | Duarte | California | 91016 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25985394 | Background | Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, Becker A, Hoshino A, Mark MT, Molina H, Xiang J, Zhang T, Theilen TM, Garcia-Santos G, Williams C, Ararso Y, Huang Y, Rodrigues G, Shen TL, Labori KJ, Lothe IM, Kure EH, Hernandez J, Doussot A, Ebbesen SH, Grandgenett PM, Hollingsworth MA, Jain M, Mallya K, Batra SK, Jarnagin WR, Schwartz RE, Matei I, Peinado H, Stanger BZ, Bromberg J, Lyden D. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015 Jun;17(6):816-26. doi: 10.1038/ncb3169. Epub 2015 May 18. | |
| 26524530 |
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Data collected for the study will be made available to others, including de-identified participant data, at publication, via a signed data access agreement and at the discretion of the investigators' approval of the proposed use of such data.
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|
| Discovery Cohort - PDAC without Occult Liver Metastasis | Patients with PDAC who did not develop liver metastasis for at least 6 months after curative-intent surgery in the discovery cohort. |
|
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| EXELiM small RNA sequencing | Diagnostic Test | High-throughput small RNA sequencing performed on preoperative plasma samples from PDAC patients in the discovery cohort to identify exosome-derived microRNAs associated with occult liver metastasis or early postoperative hepatic recurrence. |
|
Description: AUC representing the overall discriminative ability of the circRNA-based model.
| Through study completion, an average of 3 year |
| Background |
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| 30842658 | Background | Lee JW, Stone ML, Porrett PM, Thomas SK, Komar CA, Li JH, Delman D, Graham K, Gladney WL, Hua X, Black TA, Chien AL, Majmundar KS, Thompson JC, Yee SS, O'Hara MH, Aggarwal C, Xin D, Shaked A, Gao M, Liu D, Borad MJ, Ramanathan RK, Carpenter EL, Ji A, de Beer MC, de Beer FC, Webb NR, Beatty GL. Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature. 2019 Mar;567(7747):249-252. doi: 10.1038/s41586-019-1004-y. Epub 2019 Mar 6. |
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