Advanced pancreatic cancer: a meta-analysis of clinical trials over thirty years

Hall, Brendan; Cannon, Andrew; Atri, Pranita; Wichman, Christopher; Smith, Lynette M.; Ganti, Apar Kishor; Are, Chandrakanth; Sasson, Aaron R.; Kumar, Sushil; Batra, Surinder K.

doi:10.18632/oncotarget.25036

Cited by 40 publications

(33 citation statements)

References 29 publications

(29 reference statements)

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“…2 Moreover, current chemotherapeutic agents have low efficacy; median OS in patients with inoperable PDAC is only 14 mo. 3 One of the pathological characteristics of PDAC is a profuse desmoplastic tumor stromal component, which represent up to 90% of the tumor volume. [4][5][6] Tumor stroma is known to have a heterogeneous microenvironment, 7,8 consisting of cancer-associated fibroblasts (CAFs), 9,10 pancreatic stellate cells, 11,12 immune cells, 13 endothelial cells, and extracellular matrices, 14 and has been shown to promote cell growth and invasion and to contribute to reduced delivery of chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Cancer‐associated adipocytes promote pancreatic cancer progression through SAA1 expression

et al. 2020

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Although pancreatic cancer often invades peripancreatic adipose tissue, little information is known about cancer‐adipocyte interaction. We first investigated the ability of adipocytes to de‐differentiate to cancer‐associated adipocytes (CAAs) by co‐culturing with pancreatic cancer cells. We then examined the effects of CAA‐conditioned medium (CAA‐CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3‐L1 adipocytes were co‐cultured with pancreatic cancer cells (PANC‐1) using the Transwell system, adipocytes lost their lipid droplets and changed morphologically to fibroblast‐like cells (CAA). Adipocyte‐specific marker mRNA levels significantly decreased but those of fibroblast‐specific markers appeared, characteristic findings of CAA, as revealed by real‐time PCR. When PANC‐1 cells were cultured with CAA‐CM, significantly higher migration/invasion capability, chemoresistance, and epithelial‐mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC‐1 cells cultured with CAA‐CM and found a 78.5‐fold higher expression of SAA1 compared with control cells. When the SAA1 gene in PANC‐1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1‐positive group was significantly shorter than in the SAA1‐negative group (P = .013). In conclusion, we demonstrated that pancreatic cancer cells induced de‐differentiation in adipocytes toward CAA, and that CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

Cancer‐associated adipocytes promote pancreatic cancer progression through SAA1 expression

et al. 2020

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“…As a result, few patients are eligible for curative surgical resection and the majority must be treated with systemic chemotherapy. Despite substantial progress in recent years, chemotherapy remains largely ineffectual in producing meaningful clinical responses or improving PDAC patient survival [ 2 ]. Several factors contribute to the failure of chemotherapy in PDAC including, the prevalence of desmoplasia in the PDAC tumor microenvironment (TME).…”

Section: Introductionmentioning

confidence: 99%

Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential

et al. 2018

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Extensive desmoplasia is a prominent feature of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Initially, studies demonstrated that desmoplasia promotes proliferation, invasion and chemoresistance in PDAC cells. While these findings suggested the therapeutic potential of targeting desmoplasia in PDAC, more recent studies utilizing genetically-engineered mouse models of PDAC, which lack key components of desmoplasia, demonstrated accelerated progression of PDAC. This contrast calls into question the paradigm that desmoplasia unilaterally promotes PDAC progression and the premise of desmoplasia-targeted therapy. This review briefly examines the major reports of the tumor-promoting and -restraining roles of desmoplasia in PDAC with commentary on the gaps in our current understanding of desmoplasia in PDAC. Additionally, we discuss the studies demonstrating the heterogeneous and multifaceted nature of desmoplasia in PDAC and advocate for future areas of research to thoroughly address the various facets of desmoplasia in PDAC, reconcile seemingly contradictory reports of the role of desmoplasia in PDAC progression, and discover aspects of desmoplasia that are therapeutically actionable.

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“…PDAC is a disease of older people, with median age of 70 years at diagnosis in the U.S. [1]. Despite recent advances in the management of PDAC with the use of combination chemotherapy, patients with advanced PDAC still have poor prognosis [2]. In addition, poor performance status and other medical comorbidities in older patients bring more difficulties and complexities to their management [3].…”

Section: Introductionmentioning

confidence: 99%

Role of Surgery and Perioperative Therapy in Older Patients with Resectable Pancreatic Ductal Adenocarcinoma

et al. 2020

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Background It is unclear whether results from recent trials of resectable pancreatic ductal adenocarcinoma (PDAC) are generalizable to older patients, who are underrepresented. We aimed to evaluate outcomes of surgery and of neoadjuvant and adjuvant therapy in older patients with resectable PDAC. Patients and Methods We included patients aged ≥65 years with upfront resectable PDAC from a prospectively maintained pancreatic cancer registry from 2007 to 2016. Patients were stratified into ages 65–75 and 75+ years. Overall survival (OS) was assessed in treatment comparisons: (A) surgery (n = 636) versus nonsurgical (n = 178), (B) neoadjuvant therapy (n = 139) versus upfront surgery (n = 497), and (C) adjuvant therapy (n = 379) versus surgery alone (n = 118). We compared neoadjuvant (n = 139) versus adjuvant therapy (n = 379) in an exploratory analysis. Results Nine hundred and three patients had a median age of 73.7 (range, 65–96.6) years. Median OS was 26.6 versus 11.9 months (adjusted hazard ratio [HRadj], 0.4; 95% confidence interval [CI], 0.31–0.52; p < .001) in Comparison A groups, 30.7 versus 25.8 months (HRadj, 0.69; 95% CI, 0.49–0.96; p = .03) in Comparison B groups, and 26.9 versus 17.4 months (HRadj, 0.62; 95% CI, 0.44–0.88; p = .008) in Comparison C groups, respectively. OS benefit in these treatment comparisons was present in age group 75+ with HRadj 0.24 (95% CI, 0.16–0.36; p < .001) in Comparison A and HRadj 0.52 (95% CI, 0.27–1; p = .049) in Comparison B, but not in Comparison C with HRadj 0.68 (95% CI, 0.43–1.08; p = .1). Statistically comparable median OS of patients who received neoadjuvant or adjuvant therapy stratified by age groups was observed. Conclusion Older patients with resectable PDAC who received surgery, neoadjuvant therapy, or adjuvant therapy appeared to have improved survival outcomes compared with those who did not receive such treatment. Implications for Practice Older patients with resectable pancreatic ductal adenocarcinoma (PDAC) in general are underrepresented in large clinical trials and less well studied in terms of the role of surgery, neoadjuvant therapy, and adjuvant therapy. This study collected data on older patients with resectable PDAC from a prospectively maintained single‐institutional pancreatic cancer registry of a tertiary referral center from 2007 to 2016. It was found that, with multidisciplinary evaluation, older patients with resectable PDAC who received surgery, neoadjuvant therapy, or adjuvant therapy appeared to have improved survival outcomes compared with those who did not receive such treatment. These results are of substantial importance to practitioners who treat older patients, who are traditionally underrepresented in most clinical trials.

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Advanced pancreatic cancer: a meta-analysis of clinical trials over thirty years

Cited by 40 publications

References 29 publications

Cancer‐associated adipocytes promote pancreatic cancer progression through SAA1 expression

Cancer‐associated adipocytes promote pancreatic cancer progression through SAA1 expression

Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential

Role of Surgery and Perioperative Therapy in Older Patients with Resectable Pancreatic Ductal Adenocarcinoma

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