The Current Treatment Paradigm for Pancreatic Ductal Adenocarcinoma and Barriers to Therapeutic Efficacy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a median survival time of 10-12 months. Clinically, these poor outcomes are attributed to several factors, including late stage at the time of diagnosis impeding resectability, as well as multi-drug resistance. Despite the high prevalence of drug-resistant phenotypes, nearly all patients are offered chemotherapy leading to modest improvements in postoperative survival. However, chemotherapy is all too often associated with toxicity, and many patients elect for palliative care. In cases of inoperable disease, cytotoxic therapies are less efficacious but still carry the same risk of serious adverse effects, and clinical outcomes remain particularly poor. Here we discuss the current state of pancreatic cancer therapy, both surgical and medical, and emerging factors limiting the efficacy of both. Combined, this review highlights an unmet clinical need to improve our understanding of the mechanisms underlying the poor therapeutic responses seen in patients with PDAC, in hopes of increasing drug efficacy, extending patient survival, and improving quality of life.

Precision Medicine for BRCA/PALB2-Mutated Pancreatic Cancer and Emerging Strategies to Improve Therapeutic Responses to PARP Inhibition

“…Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the United States, with an overall survival rate of 10% [ 1 ]. At the present time, nearly all pancreatic cancers are treated similarly with a combination of surgery, if eligible, and broad-spectrum chemotherapy [ 2 ]. Though this approach offers a survival benefit to most patients, mounting evidence suggests that there are several genomically distinct PDAC subtypes, many of which may ultimately dictate therapeutic responses [ 3 , 4 ].…”

“…Additionally, these mutations are associated with differences in chemo-sensitivity, particularly regarding platinum-based alkylating agents (discussed in detail below). Thus, for PDAC tumors with loss-of-function mutations in HR genes BRCA1 , BRCA2 , and PALB2 , both first-line and maintenance therapy differ significantly [ 2 ]. Here, we discuss the known roles of HRD in PDAC, with a particular focus on the mechanisms of altered drug responses and the current guidelines for treatment.…”

Undifferentiated Sarcomatoid Carcinoma of the Pancreas: From Histology and Molecular Pathology to Precision Oncology

“…The standard of care for patients with PC remains surgery and chemotherapy/radiotherapy. However, most patients due to late diagnosis are not eligible for surgery, while they also rapidly develop resistance to chemotherapeutic regimens [5]. Interestingly, immune-checkpoint inhibitors for cancers with microsatellite instability, as well as targeted therapies such as those based on PARP inhibitors for BRCA-mutated tumors, are gradually entering into clinical practice, but these opportunities regard only a small proportion of PDAC patients [6][7][8][9][10].…”

TGFβ Signaling in the Pancreatic Tumor Microenvironment

“…Despite significant progress for several difficult-to-treat malignancies in recent years, there is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC). While broad-spectrum chemotherapy can modestly extend survival for most patients, nearly all will eventually progress during treatment [1], and overall five-year survival remains at a dismal 10% [2]. The poor clinical outcomes associated with PDAC largely stem from a late stage of diagnosis, the lack of an effective screening modality, and widespread drug resistance [1,3,4].…”

“…While broad-spectrum chemotherapy can modestly extend survival for most patients, nearly all will eventually progress during treatment [1], and overall five-year survival remains at a dismal 10% [2]. The poor clinical outcomes associated with PDAC largely stem from a late stage of diagnosis, the lack of an effective screening modality, and widespread drug resistance [1,3,4]. This highlights an urgent need for new therapeutic approaches in order to improve outcomes for what is largely considered an incurable disease.…”