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Perspectives in the treatment of pancreatic adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an incurable lethal disease whose incidence rate is growing. There is no effective screening for detection of early stage tumors and, in most cases, PDAC is diagnosed at advanced disease stages, when radical pancreatic resection is not possible. The aggressive nature of pancreatic tumor cells lies in the complex genetic mechanisms behind their uncontrolled capability to grow and metastasize, which involve essential adaptive changes in cellular metabolism, signaling, adhesion and immunoediting. In addition, PDAC cells promote a dense functional stroma that facilitates tumor resistance to chemotherapy and radiation. During the last two decades, gemcitabine has been the reference for the systemic treatment of PDAC. However, recently, a regimen combining fluorouracil, irinotecan, oxaliplatin, and leucovorin (FOLFIRINOX) and another combining albumin-bound paclitaxel with gemcitabine have shown clear therapeutic advantage in advanced PDAC, with survival outcomes of 11.3 and 8.5 mo on phase III trials, respectively, over single-agent gemcitabine. With the pending issue of their higher toxicities, these regimens set the reference for ongoing and future clinical studies in advanced PDAC. In addition, the efficacy of oral fluoropyrimidine (S-1) has been well documented in Asiatic PDAC patients. The development of therapeutic approaches other than cytotoxic drugs has proven difficult in the past, with only one drug (erlotinib) approved to date. Besides, a number of agents targeting signaling pathways in tumor or stroma cells are being investigated. Likewise, immunotherapies that target PDAC in various ways are the subject of a number of clinical trials. The search for reliable biomarkers with diagnostic and prognostic value using genomics and mass spectrometry methods may facilitate monitoring and refinement of therapies. This review focuses on current understanding of the pathogenesis of PDAC and the latest developments in the treatment of advanced PDAC.

SUBMITTER: Cid-Arregui A

PROVIDER: S-EPMC4541382 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Perspectives in the treatment of pancreatic adenocarcinoma.

Cid-Arregui Angel A Juarez Victoria V

World journal of gastroenterology 20150801 31

Pancreatic ductal adenocarcinoma (PDAC) is an incurable lethal disease whose incidence rate is growing. There is no effective screening for detection of early stage tumors and, in most cases, PDAC is diagnosed at advanced disease stages, when radical pancreatic resection is not possible. The aggressive nature of pancreatic tumor cells lies in the complex genetic mechanisms behind their uncontrolled capability to grow and metastasize, which involve essential adaptive changes in cellular metabolis ...[more]

PMID: 26309356

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, with systemic therapy being the mainstay of treatment. Survival continues to be limited, typically less than 1 year. The PDAC microenvironment is characterized by a paucity of malignant epithelial cells, abundant stroma with predominantly immunosuppressive T cells and myelosuppressive-type macrophages (M2), and hypovascularity. The current treatment options for metastatic PDAC are modified (m)FOLFIRINOX /FOLFIRINOX or nab-paclitaxel and gemcitabine in patients with good performance status (PS) (ECOG 0-1/KPS 70-100%) and gemcitabine with or without a second agent for those with ECOG PS 2-3. New therapies are emerging, and the current guidelines endorse both germline and somatic testing in PDAC to evaluate actionable findings. Important themes related to new therapeutic approaches include DNA damage repair strategies, immunotherapy, targeting the stroma, and cancer-cell metabolism. Targeted therapy alone (outside small genomically defined subsets) or in combination with standard cytotoxic therapy, thus far, has proven disappointing in PDAC; however, novel therapies are evolving with increased integration of genomic profiling along with a better understanding of the tumor microenvironment and immunology. A small but important sub-group of patients have some of these agents available in the clinics for use. Olaparib was recently approved by the US Food and Drug Administration for maintenance therapy in germline BRCA1/2 mutated PDAC following demonstration of survival benefit in a phase 3 trial. Pembrolizumab is approved for patients with defects in mismatch repair/microsatellite instability. PDAC with wild-type KRAS represents a unique subgroup who have enrichment of potentially targetable oncogenic drivers. Small-molecule inhibitors including ERBB inhibitors (e.g., afatinib, MCLA-128), TRK inhibitors (e.g., larotrectinib, entrectinib), ALK/ROS inhibitor (e.g., crizotinib), and BRAF/MEK inhibitors are in development. In a small subset of patients with the KRASG12C mutation, a KRASG12C inhibitor, AMG510, and other agents are being investigated. Major efforts are underway to effectively target the tumor microenvironment and to integrate immunotherapy into the treatment of PDAC, and although thus far the impact has been modest to ineffective, nonetheless, there is optimism that some of the challenges will be overcome.

Dataset Information

Perspectives in the treatment of pancreatic adenocarcinoma.

Publications

Perspectives in the treatment of pancreatic adenocarcinoma.

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