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Cell Apr 2023Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant disease.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Tumor Microenvironment; Early Diagnosis; Prognosis
PubMed: 37059070
DOI: 10.1016/j.cell.2023.02.014 -
JAMA Sep 2021Pancreatic ductal adenocarcinoma (PDAC) is a relatively uncommon cancer, with approximately 60 430 new diagnoses expected in 2021 in the US. The incidence of PDAC is... (Review)
Review
IMPORTANCE
Pancreatic ductal adenocarcinoma (PDAC) is a relatively uncommon cancer, with approximately 60 430 new diagnoses expected in 2021 in the US. The incidence of PDAC is increasing by 0.5% to 1.0% per year, and it is projected to become the second-leading cause of cancer-related mortality by 2030.
OBSERVATIONS
Effective screening is not available for PDAC, and most patients present with locally advanced (30%-35%) or metastatic (50%-55%) disease at diagnosis. A multidisciplinary management approach is recommended. Localized pancreas cancer includes resectable, borderline resectable (localized and involving major vascular structures), and locally advanced (unresectable) disease based on the degree of arterial and venous involvement by tumor, typically of the superior mesenteric vessels. For patients with resectable disease at presentation (10%-15%), surgery followed by adjuvant chemotherapy with FOLFIRINOX (fluorouracil, irinotecan, leucovorin, oxaliplatin) represents a standard therapeutic approach with an anticipated median overall survival of 54.4 months, compared with 35 months for single-agent gemcitabine (stratified hazard ratio for death, 0.64 [95% CI, 0.48-0.86]; P = .003). Neoadjuvant systemic therapy with or without radiation followed by evaluation for surgery is an accepted treatment approach for resectable and borderline resectable disease. For patients with locally advanced and unresectable disease due to extensive vascular involvement, systemic therapy followed by radiation is an option for definitive locoregional disease control. For patients with advanced (locally advanced and metastatic) PDAC, multiagent chemotherapy regimens, including FOLFIRINOX, gemcitabine/nab-paclitaxel, and nanoliposomal irinotecan/fluorouracil, all have a survival benefit of 2 to 6 months compared with a single-agent gemcitabine. For the 5% to 7% of patients with a BRCA pathogenic germline variant and metastatic PDAC, olaparib, a poly (adenosine diphosphate [ADB]-ribose) polymerase inhibitor, is a maintenance option that improves progression-free survival following initial platinum-based therapy.
CONCLUSIONS AND RELEVANCE
Approximately 60 000 new cases of PDAC are diagnosed per year, and approximately 50% of patients have advanced disease at diagnosis. The incidence of PDAC is increasing. Currently available cytotoxic therapies for advanced disease are modestly effective. For all patients, multidisciplinary management, comprehensive germline testing, and integrated supportive care are recommended.
Topics: Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Early Detection of Cancer; Humans; Incidence; Neoadjuvant Therapy; Pancreatectomy; Pancreatic Neoplasms
PubMed: 34547082
DOI: 10.1001/jama.2021.13027 -
Nature Reviews. Gastroenterology &... Jan 2024Pancreatic ductal adenocarcinoma (PDAC) has a rising incidence and is one of the most lethal human malignancies. Much is known regarding the biology and pathophysiology... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) has a rising incidence and is one of the most lethal human malignancies. Much is known regarding the biology and pathophysiology of PDAC, but translating this knowledge to the clinic to improve patient outcomes has been challenging. In this Review, we discuss advances and practice-changing trials for PDAC. We briefly review therapeutic failures as well as ongoing research to refine the standard of care, including novel biomarkers and clinical trial designs. In addition, we highlight contemporary areas of research, including poly(ADP-ribose) polymerase inhibitors, KRAS-targeted therapies and immunotherapies. Finally, we discuss the future of pancreatic cancer research and areas for improvement in the next decade.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Immunotherapy; Forecasting
PubMed: 37798442
DOI: 10.1038/s41575-023-00840-w -
Annual Review of Pathology Jan 2023Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. Recent advances in tissue imaging capabilities, single-cell analytics, and disease modeling have shed light on organizing principles that shape the stromal complexity of PDAC tumors. These insights into the functional and spatial dependencies that coordinate cancer cell biology and the relationships that exist between cells and extracellular matrix components present in tumors are expected to unveil therapeutic vulnerabilities. We review recent advances in the field and discuss current understandings of mechanisms by which the tumor microenvironment shapes PDAC pathogenesis and therapy resistance.
Topics: Humans; Drug Resistance, Neoplasm; Tumor Microenvironment; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal
PubMed: 36130070
DOI: 10.1146/annurev-pathmechdis-031621-024600 -
Best Practice & Research. Clinical... 2022Pancreatic cancer is one of the deadliest malignancies. Therefore, there is an urgent need to detect pancreatic cancer in an earlier stage to improve outcomes. A variety... (Review)
Review
Pancreatic cancer is one of the deadliest malignancies. Therefore, there is an urgent need to detect pancreatic cancer in an earlier stage to improve outcomes. A variety of hereditary cancer syndromes have been associated with an increased risk of developing pancreatic cancer, and these individuals may benefit from surveillance programs. Surveillance programs have shown potential to improve outcomes, but have important risks such as overtreatment. In this review we will discuss the definitions and epidemiology of hereditary pancreatic cancer, recommendations for genetic testing and participation in surveillance. Important aspects are differences in surveillance strategies, target lesions, and potential benefits and harms of surveillance. Lastly we will highlight future directions for research and improvement of care for individuals at high-risk of pancreatic cancer.
Topics: Carcinoma; Genetic Predisposition to Disease; Humans; Neoplastic Syndromes, Hereditary; Pancreatic Neoplasms; Risk Factors
PubMed: 35988957
DOI: 10.1016/j.bpg.2021.101783 -
Updates in Surgery Feb 2022Multimodal treatment including surgery and chemotherapy is considered the gold standard treatment of pancreatic cancer by most guidelines. Neoadjuvant therapy (NAT) has... (Review)
Review
Multimodal treatment including surgery and chemotherapy is considered the gold standard treatment of pancreatic cancer by most guidelines. Neoadjuvant therapy (NAT) has been seen as a possible treatment option for resectable, borderline resectable and locally advanced PaC. The aim of this paper is to offer a state-of-the-art review on neoadjuvant treatments in the setting of pancreatic ductal adenocarcinoma. A systematic literature search was performed using PubMed, Cochrane, Web of Science and Embase databases, in order to identify relevant studies published up to and including July 2021 that reported and analyzed the role of neoadjuvant therapy in the setting of pancreatic carcinoma. Most authors are concordant on the strong role of neoadjuvant therapy in the setting of borderline resectable pancreatic cancers. Recent randomized trials demonstrated improvement of R0 rate and survival after NAT in this setting. Patients with locally advanced cancers may become resectable after NAT, with better results than those obtained with palliative therapies. Even in the setting of resectable cancers, NAT is being evaluated by ongoing randomized trials. Chemotherapy regimens in the setting of NAT and response to NAT are discussed. NAT has an important role in the multimodal treatment of patients with borderline resectable pancreatic cancer. It has a role in patients with locally advanced tumors as it can allow surgical resection in a relevant proportion of patients. For resectable pancreatic cancers, the role of NAT is under evaluation by several randomized trials.
Topics: Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Humans; Neoadjuvant Therapy; Pancreatic Neoplasms
PubMed: 34628591
DOI: 10.1007/s13304-021-01186-1 -
Nature Cancer Apr 2023Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer entity characterized by a heterogeneous genetic landscape and an immunosuppressive tumor... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer entity characterized by a heterogeneous genetic landscape and an immunosuppressive tumor microenvironment. Recent advances in high-resolution single-cell sequencing and spatial transcriptomics technologies have enabled an in-depth characterization of both malignant and host cell types and increased our understanding of the heterogeneity and plasticity of PDAC in the steady state and under therapeutic perturbation. In this Review we outline single-cell analyses in PDAC, discuss their implications on our understanding of the disease and present future perspectives of multimodal approaches to elucidate its biology and response to therapy at the single-cell level.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Gene Expression Profiling; Tumor Microenvironment
PubMed: 36959420
DOI: 10.1038/s43018-023-00526-x -
Australian Journal of General Practice Dec 2019Pancreatic cancer has the highest mortality rate among all main cancer types and is the fourth leading cause of cancer death in Australia. (Review)
Review
BACKGROUND
Pancreatic cancer has the highest mortality rate among all main cancer types and is the fourth leading cause of cancer death in Australia.
OBJECTIVE
This review focuses on the 95% of pancreatic cancers that arise as pancreatic ductal adenocarcinoma, with the aim to summarise current recommendations for diagnosis and treatment.
DISCUSSION
No cardinal symptoms for pancreatic cancer exist. Weight loss combined with abdominal symptoms or back pain in individuals aged ≥60 years prompts urgent computed tomography of the abdomen, while individuals aged ≥40 years with jaundice require direct specialist referral. Pancreatic cancer is categorised as resectable, borderline resectable, locally advanced or metastatic. Resectable disease is treated with surgical resection and adjuvant chemotherapy. Borderline resectable and locally advanced disease are treated with neoadjuvant therapy, followed by surgical exploration if the disease is non-progressive. Metastatic and unresectable disease is treated with chemotherapy or best supportive care. Nutritional support is required for most patients.
Topics: Age Factors; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Genetic Predisposition to Disease; Humans; Neoadjuvant Therapy; Neoplasm Staging; Pancreatectomy; Pancreatic Neoplasms; Referral and Consultation; Risk Factors
PubMed: 31774983
DOI: 10.31128/AJGP-06-19-4957 -
Cancer Treatment Reviews Jun 2020Pancreatic adenocarcinoma (PAC) is associated with extremely poor prognosis and remains a lethal malignancy. The main cure for PAC is surgical resection. Further... (Review)
Review
Pancreatic adenocarcinoma (PAC) is associated with extremely poor prognosis and remains a lethal malignancy. The main cure for PAC is surgical resection. Further treatment modalities, such as surgery, chemotherapy, radiotherapy and other locoregional therapies provide low survival rates. Currently, many clinical trials seek to assess the efficacy of immunotherapeutic strategies in PAC, including immune checkpoint inhibitors, cancer vaccines, adoptive cell transfer, combinations with other immunotherapeutic agents, chemoradiotherapy or other molecularly targeted agents; however, none of these studies have shown practice changing results. There seems to be a synergistic effect with increased response rates when a combinatorial approach of immunotherapy in conjunction with other modalities is being exploited. In this review, we illustrate the current role of immunotherapy in PAC.
Topics: Animals; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Humans; Immunotherapy; Pancreatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 32247999
DOI: 10.1016/j.ctrv.2020.102016 -
Gastroenterology Clinics of North... Sep 2022Individuals at increased risk of developing pancreatic cancer, including those with a significant family history of the disease and those with pancreatic cancer... (Review)
Review
Individuals at increased risk of developing pancreatic cancer, including those with a significant family history of the disease and those with pancreatic cancer susceptibility gene variants, can benefit from pancreas surveillance. Most pancreatic cancers diagnosed during surveillance are early-stage and such patients can achieve long-term survival. Determining who should undergo pancreas surveillance is still a work-in-progress, but the main tools clinicians use to estimate an individual's risk of pancreatic cancer are patient's age, the extent of their family history of pancreatic cancer, and whether or not they have a pancreatic cancer susceptibility gene mutation.
Topics: Carcinoma; Early Detection of Cancer; Genetic Predisposition to Disease; Humans; Pancreatic Neoplasms; Risk Factors
PubMed: 36153110
DOI: 10.1016/j.gtc.2022.06.006