Outcome In Pancreatic Ductal Adenocarcinoma Research Articles

Blood-based and Imaging-Based Biomarker Outcomes for Patients with Pancreatic Ductal Adenocarcinoma Treated with Different Radiotherapy Techniques

Different prognostic markers have been identified in pancreatic cancer, including blood-based and imaging-based biomarkers. For example, lymphopenia can occur in patients receiving radiation therapy (RT) and is associated with decreased survival in several malignancies, including pancreatic ductal adenocarcinoma (PDAC) (Venkatesulu B, et al. Crit Rev Oncol Hematol 2018). Notably, prior work showed that 5 fractions of pancreas stereotactic radiation therapy (SBRT) resulted in less lymphopenia and an improved overall survival (OS) than chemoradiation (CRT) given over 5-6 weeks (Wild A, et al. Int J Radiat Oncol Biol Phys 2016). Quantitative computed tomography (CT) based biomarkers, such as tumor interface response, have also been correlated with clinical outcomes in PDAC (Amer A, et al. Cancer 2018). Specifically, patients with tumors exhibiting a type II interface response were shown to have a worse prognosis than those with a type I interface response. We investigated if the imaging phenotype of a tumor and RT characteristics were associated with lymphopenia in patients with PDAC. We utilized an IRB approved prospective registry to analyze 54 patients (29 male, 25 female, median age of 69 [range 47 - 84]) with locally advanced (n = 40) or borderline resectable (n = 14) PDAC who underwent chemotherapy followed by RT. RT regimens included SBRT (n = 13), hypofractionated RT over 10-15 days (n = 17), or CRT over 25-28 days (n = 24). All patients received pancreatic protocol CT scans and had absolute lymphocyte counts (ALC) measured pre-therapy, post-chemotherapy, and post-radiotherapy. The tumor interface response was graded as previously described (Amer A, et al. Cancer 2018). Lymphopenia grade was assigned according to CTCAE 4.0 criteria. Associations between interface response after chemotherapy (type I vs type II), RT technique (SBRT vs. other), and degree of lymphopenia (less than grade 3 vs. grade 3+) were tested using the likelihood-ratio test. Log rank and Cox proportional hazards tests were used for survival analyses. OS was measured from the start of chemotherapy. Median follow up time was 9.7 months and median overall survival was 15.4 months. On multivariate analysis, interface response post-chemo and pre-RT ALC independently associated with OS (Type II vs. Type I: HR 4.451, p = 0.0075; per increase of 1000 cells/μL: HR 0.3933, p = 0.0073). There was no correlation between interface response and degree of lymphopenia (p = 0.3829) nor RT technique and interface response (p = 0.2140). Patients treated with SBRT were less likely to develop grade 3-4 lymphopenia toxicity (7.7%) than patients treated with other RT regimens (60%) (p = 0.001). Interface response after chemotherapy and ALC prior to RT independently associated with OS in this prospective cohort. Ongoing work will expand analysis to an additional 49 patients. This information may help to personalize RT decisions for patients with PDAC.

Pancreatic Cancer Malnutrition and Pancreatic Exocrine Insufficiency in the Course of Chemotherapy in Unresectable Pancreatic Cancer

Background: Malnutrition and cachexia are common in patients with advanced pancreatic ductal adenocarcinoma (PDAC) and have a significant influence on the tolerance and response to treatments. If timely identified, malnourished PDAC patients could be treated to increase their capacity to complete the planned treatments and, therefore, possibly, improve their efficacy.Aims: The aim of this study is to assess the impact of nutritional status, pancreatic exocrine insufficiency (PEI), and other clinical factors on patient outcomes in patients with advanced PDAC.Methods: PAncreatic Cancer MAlnutrition and Pancreatic Exocrine INsufficiency in the Course of Chemotherapy in Unresectable Pancreatic Cancer (PAC-MAIN) is an international multicenter prospective observational cohort study. The nutritional status will be determined by means of Mini-Nutritional Assessment score and laboratory blood tests. PEI will be defined by reduced fecal elastase levels. Main outcome: adherence to planned chemotherapy in the first 12 weeks following the diagnosis, according to patients' baseline nutritional status and quantified and reported as “percent of standard chemotherapy dose delivered.” Secondary outcomes: rate of chemotherapy-related toxicity, progression-free survival, survival at 6 months, overall survival, quality of life, and the number of hospitalizations. Analysis: chemotherapy dosing over the first 12 weeks of therapy (i.e., percent of chemotherapy received in the first 12 weeks, as defined above) will be compared between well-nourished and malnourished patients. Sample size: based on an expected percentage of chemotherapy delivered of 70% in well-nourished patients, with a type I error of 0.05 and a type II error of 0.20, a sample size of 93 patients per group will be required in case of a percentage difference of chemotherapy delivered of 20% between well-nourished and malnourished patients, 163 patients per group in case of a difference of 15% between the groups, and 356 patients per group in case of a 10% difference. Centers from Russia, Romania, Turkey, Spain, Serbia, and Italy will participate in the study upon Local Ethics Committee approval.Discussion: PAC-MAIN will provide insights into the role of malnutrition and PEI in the outcomes of PDAC. The study protocol was registered at clinicaltrials.gov as NCT04112836.

Abstract 2644: Oncostatin M in pancreatic cancer tumor microenvironment

Abstract The Pancreatic Ductal Adenocarcinoma (PDAC) tumor microenvironment (TME) is comprised of numerous cell types. Among those, cancer associated fibroblasts (CAFs) play roles in tumor development, drug resistance, fibrosis and inflammation. GP130 cytokines, including Interleukin-6 (IL-6) and Leukemia Inhibitory Factor in the TME are implicated in pancreatic cancer progression and drug resistance, but less is known of the other cytokines in this family. Oncostatin M (OSM) enhances tumorigenicity, regulates tissue remodeling, and activates epithelial-to-mesenchymal transition in cancer; however, the functions of OSM in the pancreatic cancer TME and relevant phenotypes in PDAC patients have not been fully elucidated. Staining of murine tumor tissue revealed staining of OSM in tumor cells, and its receptor, OSMR, in tumor cells and fibroblasts. To model the effects of OSM in the TME, we used a spheroid culture system with patient-derived tumor cells (Pa03C cells) and patient-derived pancreatic cancer associated fibroblasts (CAF3 and CAF19) treated with rhOSM. In vitro, OSM promoted activation and proliferation of CAF monocultures, but had no effect on tumor cells. In co-cultures, OSM caused clustering of CAFs, resulting in a denser and more fibrotic spheroid with a network of CAFs clustered tightly around tumor cells. There was no effect of OSM on tumor cells in monoculture, suggesting the effects of OSM are mediated on and through fibroblasts. To study OSM in human PDAC, we used TCGA for expression and correlative gene analysis. OSM expression in tumors did not correlate with survival. In contrast, high expression of OSMR correlated with decreased patient survival (p=0.051). This effect was sex-specific–the top quartile of OSMR expressing tumors associated with median overall survival (OS) of 600 days, while the bottom three quartiles showed OS of 1100 days (p=0.0047). There was no correlation with OSMR expression and survival in female patients. Tumor OSM and OSMR expression were not different between the sexes, however. For OSM, 504 genes correlated positively with r>0.03. For OSMR, 5962 genes correlated with |r|0.3, with OSM identified as an upstream regulator (Z-score 5.770). The top upstream regulators identified in common between the OSM and OSMR correlated genes were lipopolysaccharide (Z-scores 8.408 and 8.556 for OSM and OSMR respectively), TGFB1 (7.562 and 8.799), and TNF (7.397 and 6.813), linking inflammation to fibrosis in the TME. Taken together with data from our functional studies, these data suggest that OSM and OSMR modulate the PDAC tumor microenvironment and disease outcomes in PDAC. More functional investigation is warranted for this important pathway. Citation Format: Daenique H. Jengelley, Melissa L. Fishel, Michael Ostrowski, Teresa A. Zimmers. Oncostatin M in pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2644.

Complete loss of ATM function augments replication catastrophe induced by ATR inhibition and gemcitabine in pancreatic cancer models

BackgroundPersonalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, in combination with gemcitabine (ATRi/gem), we investigated ATM loss as a predictive biomarker of response to ATRi/gem in PDAC.MethodsThrough kinase inhibition, siRNA depletion and CRISPR knockout of ATM, we assessed how ATM targeting affected the sensitivity of PDAC cells to ATRi/gem. Using flow cytometry, immunofluorescence and immunoblotting, we investigated how ATRi/gem synergise in ATM-proficient and ATM-deficient cells, before assessing the impact of ATM loss on ATRi/gem sensitivity in vivo.ResultsComplete loss of ATM function (through pharmacological inhibition or CRISPR knockout), but not siRNA depletion, sensitised to ATRi/gem. In ATM-deficient cells, ATRi/gem-induced replication catastrophe was augmented, while phospho-Chk2-T68 and phospho-KAP1-S824 persisted via DNA-PK activity. ATRi/gem caused growth delay in ATM-WT xenografts in NSG mice and induced regression in ATM-KO xenografts.ConclusionsATM loss augments replication catastrophe-mediated cell death induced by ATRi/gem and may predict clinical responsiveness to this combination. ATM status should be carefully assessed in tumours from patients with PDAC, since distinction between ATM-low and ATM-null could be critical in maximising the success of clinical trials using ATM expression as a predictive biomarker.

CORRELATION BETWEEN BODY COMPOSITION, INFLAMMATION AND SURVIVAL IN PANCREATIC CANCER TREATED WITH NEOADJUVANT THERAPY

To evaluate the association between body composition (BC) and systemic inflammatory response (SIR) following neoadjuvant treatment (NAD), and to explore their impact on long-term outcome in pancreatic ductal adenocarcinoma (PDAC) pts. Non-consecutive PDAC pts undergoing surgical exploration after NAD with available CT-scans (both at diagnosis and preoperatively) at two academic medical institutions from 2013 to 2015 were evaluated. BC was assessed by analyzing L3 CT-scan images before and after NAD. Neutrophil-lymphocyte ratio (NLR) was as a marker for SIR. Data were correlated with OS using Cox model. Kaplan-Meier curves were compared with Log-Rank test. The study population consisted of 108 pts (males: 56.5%), with a median follow-up of 16 months. 91 pts (89.8%) received FOLFIRINOX. BC changed significantly during NAD: total and visceral adipose tissue decreased (p<0.001), whereas the lean mass was increased (p<0.001). Sarcopenia was found in 45 pts (41.7%). Moreover, an NLR ≥ 3 was common (58.3%) and significantly related to total adipose and muscle tissue (p=0.032, p=0.002, respectively). Univariate analyses showed that age (HR 1.02, p=0.016), resection (HR 3.77, p=0.001), baseline skeletal mass normalized for height (TAMA) (HR 1.02, p=0.004) and increase in TAMA during NAD (HR 0.98, p=0.035) significantly affected OS. At MVA, age (HR 2.52, p=0.12) and baseline TAMA (HR 4.36, p=0.001) were significant independent predictors for OS. Our data provide evidence that BC impacts on long-term outcome in PDAC pts submitted to NAD. In addition, our results suggest a strict correlation between host SIR and changes in BC during and after NAD.

Abstract D113: Socioeconomic disparities underlie outcomes in patients with pancreatic neuroendocrine tumors

Abstract Background Disparities are known to underlie outcomes in pancreatic ductal adenocarcinoma (PDAC). Pancreatic neuroendocrine tumors (PNET) represent a rare yet deadly form of pancreatic cancer. Health disparities have not been well described in this patient population. We hypothesize that given the significant health disparities in PDAC, cancer health disparities exist in patients with PNETs. Methods Patients treated for PNETs were identified in a National Cancer Database (NCDB) Patient User File for the years 2004-2015. Kaplan-Meier analysis was performed to assess survival. Cox proportional hazards models were used to assess the effect of clinical and socioeconomic factors on survival. Results Review of the NCDB found 19,752 reported cases of PNETs. Of those, 15,589 (78.9%) were non-Hispanic white (NHW), 2,462 (12.5%) were black (B), and 1,710 (8.6%) were Hispanic, white (H). On univariate analysis, greater age, male sex, higher Charlson comorbidity score, higher disease stage, lack of insurance, decreased median household income in area of residence, and no surgery were associated with worse survival (p&amp;lt; 0.05). While not statistically significant and unlike pancreatic adenocarcinoma, black patients had greater median survival (89.6 months; 95% CI 77.9-101.196) compared to NHW (76.4 months; 95% CI 72.9-79.8) and H (80.1 months; 95%CI 70.7-89.5) patients. On multivariate analysis, the same factors from the univariate analysis were associated with worsened survival (p&amp;lt; 0.05). Sub-analyses of patients who received surgery and those who did not again showed no significant difference in survival based on race. Conclusion While insurance status, median income in area of residence, and sex were associated with clinical outcomes in PNETs, race was not a contributing factor. This is in contrast to literature in PDAC which has demonstrated that black patients have worse survival. The reasons for this difference are unclear, but may biologically driven. It is important to understand disparities from different types of pancreatic tumors. Further work to understand biologic contributions to health inequities are needed. Citation Format: Patrick W Underwood, Andrea N Riner, Michael U Maduka, Sushanth Reddy, J. Bart Rose, Jose G Trevino. Socioeconomic disparities underlie outcomes in patients with pancreatic neuroendocrine tumors [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D113.

Pterostilbene Enhances Cytotoxicity and Chemosensitivity in Human Pancreatic Cancer Cells.

Gemcitabine (GEM) drug resistance causes high mortality rates and poor outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. Receptor for advanced glycation end products (RAGE) involvement in the GEM resistance process has been demonstrated. Therefore, finding a safe and effective way to inhibit receptors for RAGE-initiated GEM resistance is urgent. Pterostilbene (PTE), a natural methoxylated analogue derived from resveratrol and found in grapes and blueberries, has diverse bioactivities, such as antioxidative, anti-inflammatory, and anticancer qualities. The overall research objective was to determine the potential of PTE to enhance tumor cytotoxicity and chemosensitivity in PDAC cells. Our results have demonstrated that PTE induced S-phase cell cycle arrest, apoptosis, and autophagic cell death and inhibited multidrug resistance protein 1 (MDR1) expression by downregulating RAGE/PI3K/Akt signaling in both MIA PaCa-2 and MIA PaCa-2 GEMR cells (GEM-resistant cells). Remarkably, convincing evidence was established by RAGE small interfering RNA transfection. Taken together, our study demonstrated that PTE promoted chemosensitivity by inhibiting cell proliferation and MDR1 expression via the RAGE/PI3K/Akt axis in PDAC cells. The observations in these experiments indicate that PTE may play a crucial role in MDR1 modulation for PDAC treatment.

Arachidonate 12-lipoxygenase and 12-hydroxyeicosatetraenoic acid contribute to stromal aging-induced progression of pancreatic cancer

The incidence of pancreatic cancer increases with age, suggesting that chronological aging is a significant risk factor for this disease. Fibroblasts are the major nonmalignant cell type in the stroma of human pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated whether the chronological aging of normal human fibroblasts (NHFs), a previously underappreciated area in pancreatic cancer research, influences the progression and therapeutic outcomes of PDAC. Results from experiments with murine xenografts and 2D and 3D co-cultures of NHFs and PDAC cells revealed that older NHFs stimulate proliferation of and confer resistance to radiation therapy of PDAC. MS-based metabolite analysis indicated that older NHFs have significantly increased arachidonic acid 12-lipoxygenase (ALOX12) expression and elevated levels of its mitogenic metabolite, 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-(S)-HETE) compared with their younger counterparts. In co-cultures with older rather than with younger NHFs, PDAC cells exhibited increases in mitogen-activated protein kinase signaling and cellular metabolism, as well as a lower oxidation state that correlated with their enhanced proliferation and resistance to radiation therapy. Expression of ALOX12 was found to be significantly lower in PDAC cell lines and tumor biopsies, suggesting that PDAC cells rely on a stromal supply of mitogens for their proliferative needs. Pharmacological (hydroxytyrosol) and molecular (siRNA) interventions of ALOX12 in older NHFs suppressed their ability to stimulate proliferation of PDAC cells. We conclude that chronological aging of NHFs contributes to PDAC progression and that ALOX12 and 12-(S)-HETE may be potential stromal targets for interventions that seek to halt progression and improve therapy outcomes.

Impact of Neoadjuvant Systemic Therapy on Pancreatic Fistula Rates Following Pancreatectomy: a Population-Based Propensity-Matched Analysis

IntroductionPostoperative pancreatic fistula (POPF) drives morbidity and mortality following pancreatectomy. Use of neoadjuvant chemotherapy (NAC) has recently increased in the treatment of potentially resectable pancreatic ductal adenocarcinoma (PDAC). This study examined the effect of NAC on POPF rates and postoperative outcomes in PDAC. MethodsThe American College of Surgeons-National Surgical Quality Improvement Program (NSQIP) Targeted Pancreatectomy dataset was queried to identify PDAC patients who underwent curative-intent pancreatectomies. Propensity score matching was used to stratify patients by receipt of NAC. Postoperative outcomes were compared and logistic regression applied to identify POPF predictors. ResultsSix thousand eight hundred sixty-three patients met the inclusion criteria; of those, 1908 (27.8%) received NAC and 4955 (72.2%) did not (NNAC). Two thousand sixty-two patients were matched 1:1 from each group. NAC patients had significantly lower POPF rates (9.0% vs. 14.5%; P < 0.001); the majority were categorized as grade A (5.1% vs. 9.5%). Overall 30-day morbidity was lower with NAC (40.4% vs. 49.5%; P < 0.001). Specifically, pneumonia (2.3% vs. 4.1%), organ space infections (7.9% vs. 13.2%), sepsis (5.2% vs. 8.0%), and delayed gastric emptying (10.1% vs. 14.8%) occurred less frequently in the NAC group. Postoperative mortality and unplanned reoperations were similar. On multivariate analysis, receipt of NAC was an independent predictor of decreased POPF rates (HR, 0.73 [0.56–0.94]; P = 0.016). Other factors included gland texture, duct size, male gender, and lower BMI. ConclusionsIn this propensity-matched, population-based cohort study of PDAC patients, NAC was associated with lower POPF rates and overall major complications. Those findings suggest a modest protective effect of NAC from POPF.

Glycolysis-Based Genes Associated with the Clinical Outcome of Pancreatic Ductal Adenocarcinoma Identified by The Cancer Genome Atlas Data Analysis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadly tumors in digestive tract tumors. Although there has been advancement in PDAC treatment, its prognosis still remains unsatisfactory, mainly because of dismal diagnosis. This article aims to develop new prognostic factors related to energy metabolism in PDAC and to use these genes for novel risk stratification. Hundred fifty messenger RNA (mRNA) expression profiles and clinicopathological data of PDAC were downloaded from The Cancer Genome Atlas dataset. The glycolysis pathway was the significant pathway based on the gene set enrichment analysis. We chose the glycolysis pathway-related 176 genes for further analysis. Multivariate Cox regression analysis and forward stepwise Cox regression model established a novel three-gene glycolytic signature (including MET, B3GNT3, and SPAG4) for PDAC patients' prognosis prediction. All 150 patients were classified into two groups by the median risk score. High-risk group had a worse outcome compared to the low-risk group. The risk score was also significantly correlated with age and radiotherapy. A nomogram, including the glycolytic gene signature, has shown some clinical net benefit for overall survival prediction. We also validated the validity and reliability in the Puleo dataset. This novel gene expression signature may be involved in the pathophysiology and used for risk stratification and prognosis prediction in PDAC.

M6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling

BackgroundPancreatic cancer is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and chemo-resistance remains a major challenge. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has emerged as a new layer of epigenetic gene regulation.MethodsqRT-PCR and IHC were applied to examine ALKBH5 levels in normal and pancreatic cancer tissues. Cancer cell proliferation and chemo-resistance were evaluated by clonogenic formation, chemosensitivity detection, and Western blotting assays. m6A-seq was performed to identify target genes. We evaluated the inhibitory effect of ALKBH5 in both in vivo and in vitro models.ResultsHere, we show that m6A demethylase ALKBH5 is downregulated in gemcitabine-treated patient-derived xenograft (PDX) model and its overexpression sensitized pancreatic ductal adenocarcinoma (PDAC) cells to chemotherapy. Decreased ALKBH5 levels predicts poor clinical outcome in PDAC and multiple other cancers. Furthermore, silencing ALKBH5 remarkably increases PDAC cell proliferation, migration, and invasion both in vitro and in vivo, whereas its overexpression causes the opposite effects. Global m6A profile revealed altered expression of certain ALKBH5 target genes, including Wnt inhibitory factor 1 (WIF-1), which is correlated with WIF-1 transactivation and mediation of the Wnt pathway.ConclusionsOur work uncovers the tumor suppressive and chemo-sensitizing function for ALKBH5, which provides insight into critical roles of m6A methylation in PDAC.

Prognostic Impact of Coagulation Activity in Patients Undergoing Curative Resection for Pancreatic Ductal Adenocarcinoma.

The aim of this study was to elucidate the clinical impact of coagulation disorders on outcomes after curative resection of pancreatic ductal adenocarcinoma. Preoperative coagulation activity in 135 patients, who had undergone curative resections for pancreatic ductal adenocarcinoma was retrospectively evaluated and the impact on survival outcomes analyzed. A prolonged prothrombin time-international normalized ratio (PT-INR) (≥1.1) was detected in 23/135 patients (17%). Univariate analysis that showed prolonged PT-INR was associated with worse relapse-free (hazard ratio=1.79, p=0.044) and overall (hazard ratio=2.18, p=0.004) survival. Multivariate analyses showed prolonged PT-INR, large tumor (>30 mm), and lymph node metastasis were independent predictors of poor overall survival. Prolonged PT-INR may be a predictor of poor prognosis in patients with pancreatic ductal adenocarcinoma who have undergone curative resection. Coagulation disorders may be a therapeutic target for improving outcomes of pancreatic ductal adenocarcinoma.

Altered Gene Expression along the Glycolysis-Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer.

Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG). On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test P = 0.018) and metastatic settings (log-rank test P = 0.027). Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC-amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test P = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes. Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles.See related commentary by Mehla and Singh, p. 6.

Is Surgery-first Still a Reasonable Option in the Era of Neoadjuvant Chemotherapy for Resectable Pancreatic Cancer?

The incidence of pancreatic ductal adenocarcinoma has risen rapidly. By 2030, it is likely to be the second most prevalent cause of death by cancer, following cancer of the lung. Unfortunately, most patients present with advanced disease. In fact, only 20% of patients are candidates for surgery. More research is needed to find dependable treatment options for this disease. Although we wait for more effective treatments to be developed, we continue using chemotherapy, radiation, and surgery-all with less than optimal outcomes. There is a debate about using chemotherapy in the neoadjuvant setting and counter-debate about better outcomes in the adjuvant settings. In the neoadjuvant setting, not everyone is able to make it to surgery; conversely, in the adjuvant setting, not everyone is able to make it to chemotherapy. Drop-out data after surgery are widely available, but similar drop-out rates after neoadjuvant treatment are not widely published. Here, we will analyze the literature to better understand the treatment strategies and outcomes of pancreatic ductal adenocarcinoma. We argue in favor of an upfront surgery and adjuvant therapy strategy for better outcomes and patient quality of life.

The GALNT14 Genotype Predicts Postoperative Outcome of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is notorious for its poor prognosis. The current mainstay of treatment for PDA is surgical resection followed by adjuvant chemotherapy. However, it is difficult to predict the post-operative outcome because of the lack of reliable markers. The single-nucleotide polymorphism (SNP) of N-acetylgalactosaminyltransferase14 (GALNT14) has been proven to predict the progression-free survival (PFS), overall survival (OS) and response to chemotherapy in various types of gastrointestinal (GI) cancers. However, its role in PDA has not been studied. This study aims to investigate whether the GALNT14 SNP genotype can be a prognostic marker for PDA. A cohort of one hundred and three PDA patients having received surgical resection were retrospectively enrolled. GALNT14 genotypes and the clinicopathological parameters were correlated with postoperative prognosis. The genotype analysis revealed that 19.4%, 60.2% and 20.4% of patients had the GALNT14 “TT”, “TG” and “GG” genotypes, respectively. The patients with the “GG” genotype had a mean OS time of 37.1 months (95% confidence interval [CI]: 18.2–56.1) and those with the “non-GG” genotype had a mean OS time of 16.1 months (95% CI: 13.1–19.2). Kaplan–Meier analysis showed that the “GG” genotype had a significantly better OS compared to the “non-GG” genotype (p = 0.005). However, there was no significant difference between the “GG” and “non-GG” genotypes in PFS (p = 0.172). The baseline characteristics between patients with the “GG” and “non-GG” genotypes were compared, and no significant difference was found. Univariate followed by multivariate Cox proportional hazard models demonstrated the GALNT14 “GG” genotype, negative resection margin, and locoregional disease as independent predictors for favorable OS (p = 0.003, p = 0.037, p = 0.021, respectively). Sensitivity analysis was performed in each subgroup to examine the relationship of GALNT14 with different clinicopathological variables and no heterogeneity was found. The GALNT14 “GG” genotype is associated with favorable survival outcome, especially OS, in patients with resected PDA and could serve as a prognostic marker.

Extracellular volume fraction determined by equilibrium contrast-enhanced dual-energy CT as a prognostic factor in patients with stage IV pancreatic ductal adenocarcinoma.

To evaluate the feasibility of equilibrium contrast-enhanced dual-energy CT (DECT), as compared with single-energy CT (SECT) and to calculate extracellular volume (ECV) fraction to predict the survival outcomes of pancreatic ductal adenocarcinoma (PDAC) patients with distant metastases (stage IV) treated with chemotherapy. The study cohort included a total of 66 patients with stage IV PDAC who underwent DECT before systemic chemotherapy between July 2014 and March 2017. Unenhanced and 120-kVp equivalent images during the equilibrium phase were used to calculate tumor SECT-derived ECV fractions, and iodine density images were obtained from equilibrium-phase DECT for DECT-derived ECV fractions. Correlations between SECT- and DECT-derived ECV fractions were identified using the Pearson correlation coefficient and Bland-Altman analysis. The effects of clinical prognostic factors and tumor SECT- and DECT-derived ECV fractions on progression-free survival (PFS) and overall survival (OS) were assessed by univariate and multivariate analyses using Cox proportional hazards models. The correlation between SECT- and DECT-derived ECV fractions was strong (r = 0.965; p < 0.001). The Bland-Altman plot between SECT- and DECT-derived ECV fractions showed a small bias (- 3.4%). Increasing tumor SECT- and DECT-derived ECV fractions were associated with a positive effect on PFS (SECT, p = 0.002; DECT, p = 0.007) and OS (DECT, p = 0.014; DECT, p = 0.015). Only tumor DECT-derived ECV fraction was an independent predictor of PFS (p = 0.018) and OS (p = 0.022) in patients with stage IV PDAC treated with chemotherapy on multivariate analysis. The ECV fraction determined by equilibrium contrast-enhanced DECT can potentially predict the survival of patients with stage IV PDAC treated with chemotherapy. • Extracellular volume fraction of stage IV pancreatic ductal adenocarcinoma determined by dual-energy CT was strongly correlated to that with single-energy CT (r = 0.965, p < 0.001). • Tumor extracellular volume fraction was an independent predictor of progression-free survival (p = 0.018) and overall survival (p = 0.022). • Extracellular volume fraction determined by dual-energy CT could be a useful imaging biomarker to predict the survival of patients with stage IV pancreatic ductal adenocarcinoma treated with chemotherapy.

717P - Cell-free tumour-DNA (cfDNA) as a very early predictor of therapeutic outcome in pancreatic ductal adenocarcinoma (PDAC)

BackgroundGenomic instability as characteristic for malignant transformation can be identified by quantitative sequencing. Cell-free tumor DNA (cfDNA) is a minimal invasive biomarker that can be used for tumor and therapeutic monitoring. This study evaluates quantitative cfDNA in patients (pts) with pancreatic cancer (PDAC) as an early therapeutic outcome marker. MethodsIn this prospective study plasma samples of 59 PDAC pts were collected in two centers throughout treatment with either FOLFIRINOX (n=35) or Gemcitabine/nab-paclitaxel (n=24). Additionally in 17 pts with FOLFIRINOX samples were collected during and 8hours after treatment initiation. CNI scoring assays were used to quantify cfDNA. The results were correlated to CT/MRT imaging (RECIST 1.1) after 8-12 weeks, or monthly CA 19-9 and CEA values. ResultsAt base-line in 55 out of 59 samples cfDNA could be detected. The CNI scores in metastasized PDAC were significant higher in comparison to locally advanced tumors (p=0.009), however no differences occurred between the centers, therapy regime or outcome. Results to sensitivity, specificity, PPV and accuracy of CNI scores after 3 month of treatment are given in the table. Especially in sensitivity and accuracy CNI score show an advantage above classical tumor marker. Moreover, a dramatic cytolytic burst with subsequent significant increased CNI score 8hours after treatment initiation with FOLFIRINOX was observed in 3/4 pts with PR, 1/4 pts with SD, compared to 0/9 pts with PD. This makes the CNI sore a very early predictor of treatment failure sensitive during first administration of chemotherapy.Table717P CNI and CA19-9 for prediction of therapy outcomeTableFOLFIRINOX CNIFOLFIRINOX CA19-9Gem/nab CNIGem/nab CA19-9Sens PD (%)73365018Spec PD (%)88889362PPV (%)891008640 ConclusionsDetermination of cfDNA in the serum predicts treatment outcome more precise and earlier compared to classical tumor marker such as imaging or CA19-9 in PDAC patients. Prediction of non responsivness to therapy might even be possible after the first administration of FOLFIRINOX. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Gold Nanoparticles sensitize pancreatic cancer cells to gemcitabine.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid cancers with dismal prognosis. Several mechanisms that are mainly responsible for aggressiveness and therapy resistance of PDAC cells include epithelial to mesenchymal transition (EMT), stemness and Mitogen Activated Protein Kinase (MAPK) signaling. Strategies that inhibit these mechanisms are critically important to improve therapeutic outcome in PDAC. In the current study, we wanted to investigate whether gold nanoparticles (AuNPs) could sensitize pancreatic cancer cells to the chemotherapeutic agent gemcitabine. We demonstrated that treatment with AuNPs of 20 nm diameter inhibited migration and colony forming ability of pancreatic cancer cells. Pre-treatment with AuNPs sensitized pancreatic cancer cells to gemcitabine in both viability and colony forming assays. Mechanistically, pre-treatment of pancreatic cancer cells with AuNPs decreased gemcitabine induced EMT, stemness and MAPK activation. Taken together, these findings suggest that AuNPs could be considered as a potential agent to sensitize pancreatic cancer cells to gemcitabine.

Application of the High-throughput TAB-Array for the Discovery of Novel 5-Hydroxymethylcytosine Biomarkers in Pancreatic Ductal Adenocarcinoma.

The clinical outcomes of pancreatic ductal adenocarcinoma (PDAC) remain dismal, with an estimated five-year survival rate of less than 5%. Early detection and prognostic approaches, including robust biomarkers for PDAC, are critical for improving patient survival. Our goal was to explore the biomarker potential of 5-hydroxymethylcytosines (5hmC), an emerging epigenetic marker with a distinct role in cancer pathobiology, yet under-investigated, due largely to technical constraints relating to PDAC. The TET-assisted bisulfite (TAB)-Array assay represents state-of-the-art technology and was used to directly profile 5hmC at single-base resolution with the Illumina EPIC array (~850,000 cytosine modification sites) in 17 pairs of tumor/adjacent tissue samples from US patients collected at the University of Chicago Medical Center. The TAB-Array data were analyzed to explore the genomic distribution of 5hmC and evaluate whether 5hmC markers were differentially modified between tumors and adjacent tissues. We demonstrated distinctive distribution patterns of 5hmC in tissue samples from PDAC patients relative to cis-regulatory elements (e.g., histone modification marks for enhancers), indicating their potential gene regulatory relevance. Substantial differences in 5hmC-modified CpG sites were detected between tumors and adjacent tissues in genes related to cancer pathobiology. The detected 5hmC-contaning marker genes also showed prognostic value for overall survival in the US patients with PDAC from the Cancer Genome Atlas Project. This study demonstrated the technical feasibility of the TAB-Array approach in cancer biomarker discovery and the biomarker potential of 5hmC for PDAC. Future studies using tissues and/or liquid biopsies may include 5hmC as a potential epigenetic biomarker target for PDAC.

Surveillance for pancreatic cancer in high‐risk individuals

BackgroundSurveillance of individuals at high risk of pancreatic ductal adenocarcinoma (PDAC) and its precursors might lead to better outcomes. The aim of this study was to determine the prevalence and outcomes of PDAC and high‐risk neoplastic precursor lesions among such patients participating in surveillance programmes.MethodsA multicentre study was conducted through the International CAncer of the Pancreas Screening (CAPS) Consortium Registry to identify high‐risk individuals who had undergone pancreatic resection or progressed to advanced PDAC while under surveillance. High‐risk neoplastic precursor lesions were defined as: pancreatic intraepithelial neoplasia (PanIN) 3, intraductal papillary mucinous neoplasia (IPMN) with high‐grade dysplasia, and pancreatic neuroendocrine tumours at least 2 cm in diameter.ResultsOf 76 high‐risk individuals identified in 11 surveillance programmes, 71 had undergone surgery and five had been diagnosed with inoperable PDAC. Of the 71 patients who underwent resection, 32 (45 per cent) had PDAC or a high‐risk precursor (19 PDAC, 4 main‐duct IPMN, 4 branch‐duct IPMN, 5 PanIN‐3); the other 39 patients had lesions thought to be associated with a lower risk of neoplastic progression. Age at least 65 years, female sex, carriage of a gene mutation and location of a lesion in the head/uncinate region were associated with high‐risk precursor lesions or PDAC. The survival of high‐risk individuals with low‐risk neoplastic lesions did not differ from that in those with high‐risk precursor lesions. Survival was worse among patients with PDAC. There was no surgery‐related mortality.ConclusionA high proportion of high‐risk individuals who had surgical resection for screening‐ or surveillance‐detected pancreatic lesions had a high‐risk neoplastic precursor lesion or PDAC at the time of surgery. Survival was better in high‐risk individuals who had either low‐ or high‐risk neoplastic precursor lesions compared with that in patients who developed PDAC.