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Applied precision medicine in metastatic pancreatic ductal adenocarcinoma
Hossein Taghizadeh1, Leonhard Müllauer2, Robert M Mader1
1Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Austria.
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.
Insights
Precision medicine offers feasible molecular-guided treatments for metastatic pancreatic ductal adenocarcinoma (mPDAC). This approach identified actionable targets and recommended therapies for patients with limited standard options.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a poor prognosis due to limited chemotherapy efficacy.
- Precision medicine platforms aim to provide molecular-guided treatments for patients lacking standard therapy options.
Purpose of the Study:
- To evaluate the feasibility and outcomes of molecular-based therapy approaches in patients with therapy-refractory mPDAC.
- To identify actionable molecular targets through comprehensive tumor profiling.
Main Methods:
- Retrospective analysis of 50 patients with therapy-refractory mPDAC.
- Tumor molecular profiling using next-generation sequencing, immunohistochemistry (IHC), microsatellite instability (MSI) testing, and fluorescence in situ hybridization.
Main Results:
- 123 mutations were detected across 50 patients, with KRAS, TP53, and CDKN2A being the most frequent.
- Targeted therapy was recommended for 28% of patients based on identified molecular alterations.
- One patient treated with nintedanib achieved stable disease for 6 months; others either died or were awaiting assessment.
Conclusions:
- Precision medicine approaches are feasible and implementable in clinical practice for mPDAC.
- Molecular profiling can guide therapy recommendations for patients with limited treatment options.
