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Therapeutic advances in metastatic pancreatic cancer: a focus on targeted therapies
Anthony Turpin1, Cindy Neuzillet2, Elise Colle3
1Department of Medical Oncology, CNRS UMR9020, Inserm UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University Lille, CHU Lille, Lille, France.
Abstract:
Mortality from pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide and effective new treatments are urgently needed. The current treatment of metastatic PDAC in fit patients is based on two chemotherapy combinations (FOLFIRINOX and gemcitabine plus nab-paclitaxel) which were validated more than 8 years ago. Although almost all treatments targeting specific molecular alterations have failed so far when administered to unselected patients, encouraging results were observed in the small subpopulations of patients with germline BRCA 1/2 mutations, and somatic gene fusions (neurotrophic tyrosine receptor kinase, Neuregulin 1, which are enriched in KRAS wild-type PDAC), KRAS G12C mutations, or microsatellite instability. While targeted tumor metabolism therapies and immunotherapy have been disappointing, they are still under investigation in combination with other drugs. Optimizing pharmacokinetics and adapting available chemotherapies based on molecular signatures are other promising avenues of research. This review evaluates the current expectations and limits of available treatments and analyses the existing trials. A permanent search for actionable vulnerabilities in PDAC tumor cells and microenvironments will probably result in a more personalized therapeutic approach, keeping in mind that supportive care must also play a major role if real clinical efficacy is to be achieved in these patients.
Insights
Effective treatments for pancreatic ductal adenocarcinoma (PDAC) are urgently needed as mortality rises. Research is exploring targeted therapies for specific mutations and optimizing existing chemotherapy for better patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Translational Medicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) mortality is increasing globally, necessitating novel therapeutic strategies.
- Current metastatic PDAC treatments, primarily chemotherapy combinations like FOLFIRINOX and gemcitabine plus nab-paclitaxel, were established over eight years ago.
- Limited success of molecularly targeted therapies in unselected PDAC patients highlights the need for personalized approaches.
Purpose of the Study:
- To review the current landscape of PDAC treatments, evaluating their efficacy and limitations.
- To analyze ongoing clinical trials and emerging therapeutic avenues for PDAC.
- To discuss the potential of personalized medicine and supportive care in improving clinical outcomes for PDAC patients.
Main Methods:
- Literature review of current and investigational treatments for pancreatic ductal adenocarcinoma.
- Analysis of clinical trial data for targeted therapies, chemotherapy, and immunotherapy in PDAC.
- Evaluation of molecular alterations and their potential as therapeutic targets in PDAC.
Main Results:
- Encouraging results observed in specific patient subpopulations with germline BRCA 1/2 mutations, NTRK gene fusions, KRAS G12C mutations, or microsatellite instability.
- Targeted tumor metabolism therapies and immunotherapy have shown disappointing results as monotherapies but are under investigation in combination regimens.
- Optimizing pharmacokinetics and adapting chemotherapy based on molecular signatures represent promising research directions.
Conclusions:
- A continuous search for actionable vulnerabilities in PDAC cells and the tumor microenvironment is crucial for developing personalized therapeutic strategies.
- While targeted therapies show promise in select patient groups, optimizing existing treatments and exploring novel combinations are essential.
- Integrating comprehensive supportive care alongside effective treatments is vital for achieving significant clinical efficacy in PDAC patients.
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Assessment: