A Patient With Locally Advanced Mismatch-Repair-Deficient Pancreatic Ductal Adenocarcinoma Successfully Treated With Neoadjuvant Immunotherapy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a dismal prognosis. Approximately 30% of patients present with locally advanced disease, defined as pancreatic tumor with invasion to adjacent structures, including the vasculatures that preclude an upfront surgical resection. Emerging data suggest that neoadjuvant therapy, typically consisting of systemic chemotherapy followed by concurrent chemoradiation, increases the likelihood of potentially curative R0 resection by downstaging the tumor and improves survival in patients with locally advanced PDAC. PDAC with deficient DNA mismatch repair (dMMR)/microsatellite instability-high molecular signature is exceedingly rare. The role of immunotherapy is emerging in various dMMR gastrointestinal tumors, both in the metastatic and neoadjuvant settings. However, the efficacy of immunotherapy in the neoadjuvant setting in patients with dMMR locally advanced PDAC remains unknown. Herein, we describe a patient who presented with unresectable dMMR locally advanced PDAC and underwent neoadjuvant immunotherapy with pembrolizumab that resulted in a remarkable reduction of the tumor size, rendering the tumor resectable. Furthermore, the presence of dMMR signature in the tumor was detected by circulating tumor DNA analysis. This is the first report, to our knowledge, of the successful use of neoadjuvant immunotherapy in a patient with locally advanced PDAC.

Keywords: ctdna; deficient mismatch repair; immunotherapy; liquid biopsy; pancreatic adenocarcinoma.

Figure 1. Representative CT images of pancreatic mass at diagnosis and after treatment

(A) At diagnosis, the pancreatic body and tail were occupied by a large heterogeneous solid and cystic mass measuring 11.6 x 6.4 cm. Invasion into the surrounding vasculature was noted. (B) About three months into the initial treatment (hyperthermia with low-dose chemotherapy), the pancreatic mass size decreased, measuring 7.9 x 5.9 cm. Pembrolizumab was started at this time. (C) The pancreatic mass demonstrated further shrinkage measuring 5.3 x 3.7 cm, about six months after the first dose of pembrolizumab.  (D) Approximately 12 months after the first dose of pembrolizumab, the pancreatic tumor showed markedly decreased size, measuring 3.1 x 3.0 cm.

Figure 2. Serial CA 19-9 levels demonstrating normalization after the treatment with pembrolizumab