The Clonal Trajectory of Liver and Lung Metastases in Pancreatic Ductal Adenocarcinoma

Background: Metastatic spread can follow either the linear route-dissemination of fully malignant cells from the primary tumor, or the parallel route-dissemination of immature tumor cells and independent maturation to metastases in target organs. The linear/parallel ratio (LPR) is a model that uses metastases diameter comparisons to decipher dissemination route. LPR of +1 suggests pure linear and −1 pure parallel spread. Aims: To examine the metastases trajectory in pancreatic duct adenocarcinoma (PDAC). Methods and Results: A total of 133 patients with PDAC, including 97 patients (72.9%) with synchronous and 36 (27.1%) with metachronous metastases with a total of 1054 lung and 2898 liver metastases, were evaluated. We found that metastatic spread to both liver and lungs is almost exclusively via the linear route (lungs median LPR + 1, interquartile range [IQR] 0.97,1. Liver median LPR + 0.98, IQR 0.83,1). Calculated from the primary diagnosis, overall survival (OS) of patients with metachronous metastases was significantly better compared to patients with synchronous disease (14 months, IQR 10,26, vs. 7 months, IQR 6,9, p < 0.0001). However, calculated from the time of metastases diagnosis, OS of both groups was similar (4 months, IQR 3,8, vs. 7 months, IQR 6,9, p = 0.235). Conclusion: These two observations suggest that metastatic spread of PDAC is almost exclusively via the linear route, that is, directly from the primary tumor. Therefore, liver or lung metastases are already present in most patients with PDAC at the time of initial diagnosis. This suggests that local treatment in patients with seemingly localized disease does not decrease their risk of developing metastases and that systemic treatment must follow.