Patients with pancreatic ductal adenocarcinoma (PDAC) and preoperative CA19-9 ≥ 1,000 U/mL that does not decrease postresection have the worst prognosis, but the mechanism is unclear. Here, we elucidated the relationship between this signature and driver-gene mutations, and the cavins/caveolin-1 axis. Four major driver-genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4) that are associated with PDAC and five critical molecules (cavin-1/-2/-3/-4 and caveolin-1) in the cavins/caveolin-1 axis were screened by immunohistochemistry in tumor tissue microarrays. Additionally, six pancreatic cancer cell lines and a spleen subcapsular inoculation nude mouse model were also used. Overexpression of mutant p53 was the major mutational event in patients with the CA19-9 signature. Cavin-1 was also overexpressed, and mutant p53 correlated directly with high cavin-1 expression in pancreatic cancer cell lines and tumor specimens (P < 0.01). Furthermore, mutant p53(R172H) upregulated cavin-1 and promoted invasiveness and metastasis of pancreatic cancer cells in vitro and in vivo. Finally, combination of mutant p53 and high cavin-1 density indicated the shortest survival for patients with PDAC after resection (P < 0.001). Mutant p53-driven upregulation of cavin-1 represents the major mechanism of poor outcome for PDAC patients with the CA19-9 signature after resection, indicating that inhibition of cavin-1 may improve the long-term efficacy of pancreatectomy.