Advanced Pancreatic Cancer: Flourishing Novel Approaches in the Era of Biological Therapy

Abstract

The progress in the development of systemic treatment for advanced pancreatic cancer (APC) has been slow. The mainstream treatment remains using chemotherapy including gemcitabine, FOLFIRINOX, and nab-paclitaxel. Erlotinib is the only approved biological therapy with marginal benefit. Studies of agents targeting epidermal growth factor receptor, angiogenesis, and RAS signaling have not been satisfying, and the usefulness of targeted therapy in APC is uncertain. Understanding in molecular processes and tumor biology has opened the door for new treatment strategies such as targeting insulin-like growth factor 1 receptor, transforming growth factor b, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Notch pathway. New directions also include the upcoming immunotherapy and many novel agents that act on the microenvironment. The practice of personalized medicine using predictive biomarkers and pharmacogenomics signatures may also enhance the effectiveness of existing treatment. Future treatment approaches may involve comprehensive genomic assessment of tumor and integrated combinations of multiple agents to overcome treatment resistance. The Oncologist 2014;19:937-950 Implications for Practice: Pancreatic cancer is a dismal disease with an unmet need for novel treatment approaches. This paper provides a comprehensive review in the current development of new treatment strategies, supported with concise scientific background and brief descriptions of ongoing phase II/III clinical trials. It provides both nonspecialists and specialists in pancreatic cancer care an overview of the topic that they can easily reference in their clinical practice or research.

Genome-scale analysis identifies GJB2 and ERO1LB as prognosis markers in patients with pancreatic cancer

“…The top 3 up-regulated DEGs were all involved in these processes. Cell adhesion dysfunction contributes to, at least in part, the inclination to metastasis of pancreatic cancer, and this propensity is a result of multiple activated signaling pathways in the malignancy [ 6 ]. It has been recognized that a dense stroma, with enormous quantities of extracellular matrix in the surrounding area, is a defining characteristic of pancreatic adenocarcinoma [ 4 , 25 ].…”

“…Relapse of the disease after treatment for those 10-20% of patients with resectable tumor also contributes to a poor prognosis [ 4 , 5 ]. What makes the situation worse is the existence of a subgroup of cancer stem cells (CSCs) within the tumor in that they harbor resistance to chemotherapy and radiation therapy [ 6 – 8 ].…”

Allelic Ratio of KRAS Mutations in Pancreatic Cancer

“…The Oncologist 2015;20:e8-e9 www.TheOncologist.com ©AlphaMed Press 2015 that prior data should not simply be disregarded in light of newer, more sensitive technologies. Moreover, these considerations demonstrate that the same mutated gene in the same type of cancer may have different biological, prognostic, and-with ongoing trials assessing the efficacy of novel KRAS inhibitors [1,2] -possibly therapeutic implications [1]. The mutation status is only one element of a more difficult equation revealed by new sequencing technologies.…”

“…Computational methods for precise determination of tumor content can overcome limitations of histology-based approaches and take at least purity, clonality, and ploidy into account [9]. With these tools readily available for implementation in routine molecular diagnostics, we propose that the tumor-specific allelic ratio of somatically mutated genes should be an integral component of a comprehensive molecular diagnostic report for personalized cancer care [1,10]. Inconclusion, KRASisnot simplymutatedorwildtypeinPDAC; actually, it has never been.More than 90%of PDACs carry mutated KRAS alleles; however,the impact on PDAC biology may vary with the tumor-specific allelic ratio and dosage of mutated KRAS.…”

Molecular Profiling-Selected Therapy for Treatment of Advanced Pancreaticobiliary Cancer: A Retrospective Multicenter Study

“…Other technologies like NGS which has become increasingly used in translational oncology may not be therapeutically relevant in pancreatic cancer. In this disease, KRAS mutations, which currently are not successfully targeted, are very common, occurring in the majority of patients (reviewed by Chiu et al [ 38 ]). In a recent analysis of 2,400 pancreatic cancer patients of whom 82% were found to have mutated KRAS, mutations in BRAF, EGFR, HER2, FLT3, HRAS, PDGFRA, and PTEN were identified exclusively in KRAS wild-type patients, and even there, only rarely (8%) [ 39 ].…”