Applied precision medicine in metastatic pancreatic ductal adenocarcinoma

Hossein Taghizadeh; Leonhard Müllauer; Robert M Mader; Martin Schindl; Gerald W Prager

doi:10.1177/1758835920938611

Applied precision medicine in metastatic pancreatic ductal adenocarcinoma

Ther Adv Med Oncol. 2020 Jul 10:12:1758835920938611. doi: 10.1177/1758835920938611. eCollection 2020.

Authors

Hossein Taghizadeh¹, Leonhard Müllauer², Robert M Mader¹, Martin Schindl², Gerald W Prager³

Affiliations

¹ Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Austria.
² Comprehensive Cancer Center Vienna, Austria.
³ Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Center Vienna, Precision Cancer Medicine Unit, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.

Abstract

Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) bears a dismal prognosis due to the limited activity of systemic chemotherapy. In our platform for precision medicine, we aim to offer molecular-guided treatments to patients without further standard therapy options.

Methods: In this single center, real-world retrospective analysis of our platform, we describe the molecular-based therapy approaches used in all 50 patients diagnosed with therapy-refractory mPDAC. A molecular portrait of the tumor specimens was created by next-generation sequencing, immunohistochemistry (IHC), microsatellite instability (MSI) testing, and fluorescence in situ hybridization.

Results: In total, we detected 123 mutations in 50 patients. The five most frequent mutations were KRAS (n = 40; 80%), TP53 (n = 29; 58%), CDKN2A (n = 8; 16%), SMAD4 (n = 4; 8%), and NOTCH1 (n = 4; 8%), which together accounted for 40.2% of all mutations. Two patients had gene fusions, namely, TBL1XR1-PIK3CA and EIF3E-RSPO2. IHC detected expression of EGFR, phosphorylated mTOR, and PTEN in 36 (72%), 33 (66%), and 17 patients (34%), respectively. For 14 (28%) of the 50 patients, a targeted therapy was suggested based on the identified molecular targets. The recommended treatments included the mTOR inhibitor everolimus (n = 3), pembrolizumab (n = 3), palbociclib (n = 2), nintedanib (n = 2), and cetuximab, crizotinib, tamoxifen, and the combination of lapatinib and trastuzumab, in one patient each.Finally, five patients received the recommended therapy. Four patients died due to disease progression before radiological assessment. One patient was treated with nintedanib and achieved stable disease for 6 months.

Conclusion: Based on our observations, precision medicine approaches are feasible and implementable in clinical routine and may provide molecular-based therapy recommendations for mPDAC.

Keywords: immunohistochemistry; metastatic pancreatic ductal adenocarcinoma; molecular aberrations; molecular profiling; precision medicine; targeted agents.