Pancreatic ductal adenocarcinoma: Treatment hurdles,tumor microenvironment and immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with an average 5-year survival rate of less than 10%. Unfortunately, the majority of patients have unresectable, locally advanced, or metastatic disease at the time of diagnosis. Moreover, traditional treatments such as chemotherapy, surgery, and radiation have not been shown to significantly improve survival. Recently, there has been a swift increase in cancer treatments that incorporate immunotherapy-based strategies to target all the stepwise events required for tumor initiation and progression. The results in melanoma, non-small-cell lung cancer and renal cell carcinoma are very encouraging. Unfortunately, the application of checkpoint inhibitors, including anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies, in pancreatic cancer has been disappointing. Many studies have revealed that the PDAC microenvironment supports tumor growth, promotes metastasis and consists of a physical barrier to drug delivery. Combination therapies hold great promise for enhancing immune responses to achieve a better therapeutic effect. In this review, we provide an outline of why pancreatic cancer is so lethal and of the treatment hurdles that exist. Particular emphasis is given to the role of the tumor microenvironment, and some of the latest and most promising studies on immunotherapy in PDAC are also presented.     

Pancreatic ductal adenocarcinoma: State-of-the-art 2017 and new therapeutic strategies

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy with an overall 5-year survival of 8% for all stages combined. The majority of patients present with stage IV disease at diagnosis and these patients have an overall 5-year survival of 3%. Currently, the standard of care for metastatic pancreas adenocarcinoma is combination cytotoxic therapy, namely FOLFIRINOX or gemcitabine plus nab-paclitaxel for good performance status patients. Given the challenges and the rising incidence of PDAC expected to become the second leading cause of cancer-related death by 2030, there is a major unmet need to develop more effective therapies. In this setting, the molecular and genomic characterization of PDAC have underpinned the use of targeted therapies. To date, the results from targeted agent evaluation have been disappointing with some exceptions. Novel promising strategies depend on biomarker identification and patient selection e.g. germline mutations in DNA repair or mismatch repair genes, where the addition of a platinum agent or checkpoint inhibitor can have a positive impact on survival. This article will review the state-of-the-art treatment of metastatic pancreatic cancer with an emphasis on novel promising therapeutic strategies and an overview on emerging biomarkers.     

胰腺导管腺癌免疫治疗研究现状和展望

胰腺导管腺癌(Pancreatic ductal adenocarcinoma,PDAC)是胰腺癌最常见的类型,预后极差。手术切除是目前唯一的根治手段,但多数患者就诊时已失去手术机会。免疫治疗作为一种新兴的治疗手段,在多种实体瘤和血液系统恶性肿瘤治疗中显现出乐观前景。然而,PDAC肿瘤抗原性低以及免疫抑制微环境等特征导致其免疫治疗困难重重。本文通过综述PDAC的肿瘤微环境组成特点和目前开展的新型免疫治疗策略,为PDAC的免疫治疗研究提供新思路。     

Arpin downregulation is associated with poor prognosis in pancreatic ductal adenocarcinoma

IntroductionArpin (Arp2/3 complex inhibitor), a novel protein found in 2013, plays a pivotal role in cell motility and migration. However, the prognostic value of Arpin in pancreatic ductal adenocarcinoma (PDAC) remains unknown.Materials and methodsWe analyzed the gene expression of ARPIN using the GEO dataset (GSE71989) and validated the results by immunohistochemistry (IHC) and Western blot in our clinical database. Tissue microarray specimens from 214 patients who underwent curative pancreatectomy for PDAC were used. The tumors that expressed high and low levels of Arpin were compared with patient outcome using Kaplan-Meier curves and the multivariate Cox proportional hazard regression model. IHC was then used in 43 paired primary tumor tissues and metastasis tissues to detect the expression of Arpin.ResultsArpin had low expression in the tumor tissue compared with the paracancerous tissue in PDAC. Patients with low intratumoral Arpin expression had worse overall survival (OS) and recurrence-free survival (RFS) than patients with high expression in the training set (p < 0.001, p < 0.001) and validation set (p < 0.001, p < 0.001). The multivariate analysis revealed that the 8th edition TNM stage and Arpin expression were independent prognostic factors associated with OS and RFS in the training and validation sets, respectively. Arpin had lower expression in the metastasis tissues than in the primary tumors of patients with PDAC (p = 0.048).ConclusionThe Arpin level is an independent prognostic factor that can be a potential predictor to aid in the management of PDAC.     

Analysis of liver metastasis after resection for pancreatic ductal adenocarcinoma

AIM:To investigate the risk factors affecting the liver metastasis(LM) of pancreatic ductal adenocarcinoma(PDAC) after resection.METHODS:We retrospectively analyzed 101 PDAC patients who underwent surgical resection at the Samsung Medical Center between January 2000 and December 2004.Forty one patients with LM were analyzed for the time of metastasis,prognostic factors affecting LM,and survival.RESULTS:LM was found in 40.6%.The median time of the LM(n = 41) was 6.0 ± 4.6 mo and most LM occurred within 1 year.In univariate analysis,tumor size,preoperative carbohydrate antigen 19-9,and perineural invasion were factors affecting LM after resection.In multivariate analysis,tumor size was the most important factor for LM.In univariate analysis,tumor cell differentiation was significant to LM in low-risk groups.CONCLUSION:LM after resection of PDAC occurs early and shows poor survival.Tumor size is the key indicator for LM after resection.     

Claudin 18.2 is a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed and treated in advanced tumor stages with poor prognosis. More effective screening programs and novel therapeutic means are urgently needed. Recent studies have regarded tight junction protein claudin 18.2 (CLDN18.2) as a candidate target for cancer treatment, and zolbetuximab (formerly known as IMAB362) has been developed against CLDN18.2. However, there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.AIMTo investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.METHODSThe Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue. Second, we analyzed the expression of CLDN18.2 in 93 primary PDACs, 86 para-cancer tissues, and 13 normal pancreatic tissues by immunohistochemistry. Immunostained tissues were assessed applying the histoscore. subsequently, they fell into two groups according to the expression state of CLDN18.2. Furthermore, the correlations between CLDN18.2 expression and diverse clinicopathological characteristics, including survival, were investigated.RESULTSThe gene expression of CLDN18 was statistically higher (P < 0.01) in pancreatic tumors than in normal tissues. However, there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients. CLDN18.2 was expressed in 88 (94.6%) of the reported PDACs. Among these tumors, 50 (56.8%) cases showed strong immunostaining. The para-cancer tissues were positive in 81 (94.2%) cases, among which 32 (39.5%) of cases were characterized for strong staining intensities. Normal pancreatic tissue was identified solely via weak immunostaining. Finally, CLDN18.2 expression significantly correlated with lymph node metastasis, distant metastasis, nerve invasion, stage, and survival of PDAC patients, while there was no correlation between CLDN18.2 expression and localization, tumor size, patient age and sex, nor any other clinicopathological characteristic. CONCLUSIONCLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in PDAC.     

Metastatic lymph node ratio as an important prognostic factor in pancreatic ductal adenocarcinoma

Background

Overall five year survival following pancreaticoduodenectomy for ductal adenocarcinoma is poor with typical reported rates in the literature of 8–27%. The aim of this study was to identify the histological variables best able to predict long-term survival in these patients.

Methods

A prospective database of patients undergoing pancreaticoduodenectomy between April 2002 and June 2009 was analysed to identify patients with histologically proven pancreatic ductal adenocarcinoma. Patients with ampullary tumours, cholangiocarcinoma, duodenal adenocarcinoma and neuroendocrine tumours were excluded. The histology reports for these patients were reviewed. Uni-variate and multi-variate survival analysis was performed to identify variables useful in predicting long-term outcome.

Results

134 patients underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma during this period. 5 year survival in this series was 18.6%. Uni-variate analysis identified nodal status and the metastatic to resected lymph node ratio as predictors of survival. Using multi-variate Cox Regression analysis a metastatic to lymph node ratio of >15% (p < 0.01) and the presence of perineural invasion (p < 0.05) were identified as independent predictors of patient survival. Metastatic to resected lymph node ratio is better able to stratify prognosis than nodal status alone with 5 year survival of those with N0 disease being 55.6% and 12.9% for N1 disease. However for those with <15% of resected nodes positive, 5 year survival was 21.7% and in those with >15% nodes positive it was 5.2% (p = 0.0017).

Conclusion

The metastatic to resected lymph node ratio can provide significant prognostic information in those patients with node positive disease after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.     

High expression of DDR1 is associated with the poor prognosis in Chinese patients with pancreatic ductal adenocarcinoma

Background

Discoidin domain receptors 1 (DDR1), a subtype of DDRs, has been reported as a critical modulator of cellular morphogenesis, differentiation, migration and invasion.

Methods and results

In this study, we investigated the expression of DDR1 and its clinical association in Chinese patients with pancreatic ductal adenocarcinoma (PDAC). Across a cohort of 30 patients, we examined DDR1 expression in paired PDAC and corresponding adjacent non-tumor tissues by real-time quantitative PCR (RT-qPCR), or western blotting. DDR1 expression is significantly higher in PDAC, as compared to normal adjacent tissue, confirming results from the Oncomine databases. We validated DDR1 expression by immunohistochemistry across a non-overlapping cohort of 205 PDAC specimens. Kaplan-Meier survival curves indicate that increased expression of DDR1 is associated with a poor prognosis in PDAC patients (P = 0.013). Multivariate Cox regression analysis identified DDR1 expression, age, N classification and liver metastasis as independent prognostic factors in PDAC.

Conclusions

This study demonstrated that DDR1 can well serve as a novel prognostic biomarker in PDAC.     

Serum biomarkers for the differentiation of autoimmune pancreatitis from pancreatic ductal adenocarcinoma

Autoimmune pancreatitis(AIP), a chronic inflammation caused by the immune system attacking the pancreas, usually presents imaging and clinical features that overlap with those of pancreatic ductal adenocarcinoma(PDAC). Serum biomarkers, substances that quantitatively change in sera during disease development, are a promising non-invasive tool with high utility for differentiating between these diseases. In this way, the presence of AIP is currently suspected when serum concentrations of immunogl...     

pT but not pN stage of the 8th TNM classification significantly improves prognostication in pancreatic ductal adenocarcinoma

The UICC TNM (tumour-node-metastasis) staging system for pancreatic ductal adenocarcinoma (PDAC) has been a matter of debate over decades because survival prediction based on T stages was weak and unreliable. To improve staging, the recently published 8th TNM edition (2016) introduced a conceptually completely changed strictly size-based T staging system and a refined N stage for PDAC. To investigate the clinical value of the novel TNM classification, we compared the prognostic impact of pT and pN stage between the 7th and 8th edition in two well-characterised independent German PDAC cohorts from different decades, including a total number of 523 patients. Former UICC T staging (7th edition 2009) resulted in a clustering of pT3 cases (72% and 85% of cases per cohort, respectively) and failed to show significant prognostic differences between the four stages in one of the investigated cohorts (p = 0.074). Application of the novel size-based T stage system resulted in a more equal distribution of cases between the four T categories with a predominance of pT2 tumours (65% and 60% of cases). The novel pT staging algorithm showed greatly improved discriminative power with highly significant overall differences between the four pT stages in both investigated cohorts in univariate and multivariate analyses (p < 0.001, each). In contrast, no prognostic differences were observed between the recently introduced pN1 and pN2 categories in both cohorts (p = 0.970 and p = 0.061).pT stage of resected PDAC patients according to the novel UICC staging protocol (8th edition) significantly improves patient stratification, whereas introduction of an extended N stage protocol does not demonstrate high clinical relevance in our cohorts.     

A novel preoperative MRI-based radiomics nomogram outperforms traditional models for prognostic prediction in pancreatic ductal adenocarcinoma

To develop an efficient prognostic model based on preoperative magnetic resonance imaging (MRI) radiomics for patients with pancreatic ductal adenocarcinoma (PDAC), the preoperative MRI data of PDAC patients in two independent centers (defined as development cohort and validation cohort, respectively) were collected retrospectively, and the radiomics features of tumors were then extracted. Based on the optimal radiomics features which were significantly related to overall survival (OS) and progression-free survival (PFS), the score of radiomics signature (Rad-score) was calculated, and its predictive efficiency was evaluated according to the area under receiver operator characteristic curve (AUC). Subsequently, the clinical-radiomics nomogram which incorporated the Rad-score and clinical parameters was developed, and its discrimination, consistency and application value were tested by calibration curve, concordance index (C-index) and decision curve analysis (DCA). Moreover, the predictive value of the clinical-radiomics nomogram was compared with traditional prognostic models. A total of 196 eligible PDAC patients were enrolled in this study. The AUC value of Rad-score for OS and PFS in development cohort was 0.724 and 0.781, respectively, and the value of Rad-score was negatively correlated with PDAC’s prognosis. Moreover, the developed clinical-radiomics nomogram showed great consistency with the C-index for OS and PFS in development cohort was 0.814 and 0.767, respectively. In addition, the DCA demonstrated that the developed nomogram displayed better clinical predictive usefulness than traditional prognostic models. We concluded that the preoperative MRI-based radiomics signature was significantly related to the poor prognosis of PDAC patients, and the developed clinical-radiomics nomogram showed better predictive ability, it might be used for individualized prognostic assessment of preoperative patients with PDAC.     

Severe postoperative complications decrease overall and disease free survival in pancreatic ductal adenocarcinoma after pancreaticoduodenectomy

Background

Postoperative complications influence overall and disease free survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma is still a matter of debate and controversy.

Oncologic outcomes of minimally invasive versus open distal pancreatectomy for pancreatic ductal adenocarcinoma: A systematic review and meta-analysis

In the absence of randomized trials, uncertainty regarding the oncologic efficacy of minimally invasive distal pancreatectomy (MIDP) remains. This systematic review aimed to compare oncologic outcomes after MIDP (laparoscopic or robot-assisted) and open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). Matched and non-matched studies were included. Pooled analyses were performed for pathology (e.g., microscopically radical (R0) resection and lymph node retrieval) and oncologic outcomes (e.g., overall survival). After screening 1760 studies, 21 studies with 11,246 patients were included. Overall survival (hazard ratio 0.86; 95% confidence interval (CI) 0.73 to 1.01; p = 0.06), R0 resection rate (odds ratio (OR) 1.24; 95%CI 0.97 to 1.58; p = 0.09) and use of adjuvant chemotherapy (OR 1.07; 95%CI 0.89 to 1.30; p = 0.46) were comparable for MIDP and ODP. The lymph node yield (weighted mean difference (WMD) −1.3 lymph nodes; 95%CI -2.46 to −0.15; p = 0.03) was lower after MIDP. Patients undergoing MIDP were more likely to have smaller tumors (WMD -0.46 cm; 95%CI -0.67 to −0.24; p < 0.001), less perineural (OR 0.48; 95%CI 0.33 to 0.70; p < 0.001) and less lymphovascular invasion (OR 0.53; 95%CI 0.38 to 0.74; p < 0.001) reflecting earlier staged disease as a result of treatment allocation bias. Based on these results we can conclude that in patients with PDAC, MIDP is associated with comparable survival, R0 resection, and use of adjuvant chemotherapy, but a lower lymph node yield, as compared to ODP. Due to treatment allocation bias and lower lymph node yield the oncologic efficacy of MIDP remains uncertain.     

A systematic review of economic evaluation in pancreatic ductal adenocarcinoma

ObjectivesThe economic evaluation (EE) of healthcare interventions has become a necessity. However, high quality needs to be ensured in order to achieve validated results and help making informed decisions. Thus, the objective of the present study was to systematically identify and review published pancreatic ductal adenocarcinoma-related EEs and to assess their quality.MethodsSystematic literature research was conducted in PubMed and Cochrane to identify published EEs between 2000 and 2015. The quality of each selected EE was assessed by two independent reviewers, using the Drummond's checklist.ResultsOur systematic review was based on 32 EEs and showed a wide variety of methodological approaches, including different perspectives, time horizon, and cost effectiveness analyses. Nearly two-thirds of EEs are full EEs (n = 21), and about one-third of EEs had a Drummond score ≥7, synonymous with ‘high quality’. Close to 50% of full EEs had a Drummond score ≥7, whereas all of partial EEs had a Drummond score <7 (n = 11).ConclusionsOver the past 15 years, a lot of interest has been evinced over the EE of pancreatic ductal adenocarcinoma (PDAC) and its direct impact on therapeutic advances in PDAC. To provide a framework for health care decision-making, to facilitate transferability and to lend credibility to health EEs, their quality must be improved. For the last 4 years, a tendency towards a quality improvement of these studies has been observed, probably coupled with a context of rational decision-making in health care, a better and wider spread of recommendations and thus, medical practitioners' full endorsement.     

The update of prostatic ductal adenocarcinoma

Since initially described in 1967, prostatic ductal adenocarcinoma (PDA) has engendered a series of controversies on its origin, histological features, and biological behavior. Owing to the improvement of molecular biological technique, there are some updated findings on the characteristics of PDA. In the current review, we will mainly analyze its origin, clinical manifestations, morphological features, differential diagnosis, immunophenotype and molecular genetics, with the purpose of enhancing recognition of this tumor and making a correct diagnosis and treatment choice.     

系统免疫炎症指数与接受新辅助化疗胰腺导管腺癌患者预后的关系

目的 探讨新辅助化疗后系统免疫炎症指数（systemic immune-inflammation index,SII）对胰腺导管腺癌（pancreatic ductal adenocarcinoma,PDAC）预后评估的价值。方法 回顾性分析2013年1月至2016年12月在盘锦辽油宝石花医院行胰腺切除术的PDAC患者的临床资料。新辅助化疗后检测SII,依据ROC曲线确定SII最佳临界值（885）分为SII＞885组（n=37）和SII≤885组（n=58）,采用Cox回归评估SII与PDAC患者术后生存的关系。结果 SII与肿瘤大小、胆道引流、术前CA19-9水平有关（P<0.05）。SII≤885组的3年生存率高于SII＞885（43.1% vs 18.9%,P=0.015）。多因素Cox回归显示,肿瘤大小>3 cm（HR=1.367,95%CI：1.227～2.215,P=0.031）、CA19-9>37 IU/mL（HR=1.292,95%CI：1.132～1.931,P=0.011）及SII＞885（HR=1.451,95%CI：1.327～2.431,P=0.021）是影响PDAC患者术后生存的独立危险因素。结论 新辅助化疗后SII高的PDAC患者预后较差且SII＞885提示PDAC患者预后不良。     

Histo-molecular oncogenesis of pancreatic cancer: From precancerous lesions to invasive ductal adenocarcinoma

Pancreatic cancer is a lethal malignancy, whose precursor lesions are pancreatic intraepithelial neoplasm, intraductal papillary mucinous neoplasm, intraductal tubulopapillary neoplasm, and mucinous cystic neoplasm. To better understand the biology of pancreatic cancer, it is fundamental to know its precursors and to study the mechanisms of carcinogenesis. Each of these precursors displays peculiar histological features, as well as specific molecular alterations. Starting from such pre-invasive lesions, this review aims at summarizing the most important aspects of carcinogenesis of pancreatic cancer, with a specific focus on the recent advances and the future perspectives of the research on this lethal tumor type.