Early-stage Pancreatic Cancer Research Articles

Circulating tumor DNA (ctDNA) and disease recurrence in early stage pancreatic cancer.

e16313 Background: Surgical resection with neoadjuvant and/or adjuvant chemotherapy remains to be the cornerstone in treatment for early-stage pancreatic adenocarcinoma. Disease recurrence after curative intent treatment remains to be very common, and early detection of disease recurrence remains challenging. Recent studies explored the role of ctDNA in guiding adjuvant treatment in colon cancer, but its role in pancreatic cancer remains unknown. Methods: Through comprehensive chart review, we identified patients who: 1. Diagnosed with early-stage pancreatic adenocarcinoma; 2. Underwent curative intent surgery at our institution from 2019 to 2021; 3. Have postoperative tissue informed ctDNA results with commercially available assay (Signatera, by Natera Inc). Results: A total of 14 patients, including 7 males and 7 females, were included in the study. Depending on location of tumor, types of surgery included Whipple procedure (N = 13) and distal pancreatectomy (N = 1). The median age at time of surgery was 62 years (Range: 41-83 years). Two patients received neoadjuvant chemotherapy, and 13 patients received adjuvant chemotherapy. Two patients also received adjuvant radiation. A total of 41 ctDNA readings were obtained. The median time from surgery to first ctDNA assay was 2.4 months. First post-op ctDNA was positive in 6 patients, all of whom received adjuvant chemotherapy but still experienced clinical recurrence after a median of 3.7 months. The median overall survival of those ctDNA+ patients was 11.4 months. In the remaining 8 patients, the median progression free survival was 14 months, with clinical recurrence being observed in 4 patients. Median overall survival was not reached at median follow up of 30.5 months (one patient died at 6 months without disease recurrence, and another died at 14 months with progressive disease). In the 4 patients who had clinical recurrence despite initially negative ctDNA, ctDNA turned positive 1 month before clinical recurrence in 1 patient. However, in the other 3 patients, recurrence occurred 3.1, 1.9 and 3.5 months after the most recent negative ctDNA result. Conclusions: Our study demonstrated that positive ctDNA reliably predicts clinical recurrence in early-stage pancreatic cancer after surgery, with a positive predictive value of 100%. Negative result appears to be less reliable. This may be explained by different shedding pattern and test sensitivity. Larger scale study is underway to further evaluate its role in determining prognosis and guiding adjuvant treatment.

Mutation-site localized non-B DNA burden and survival heterogeneity in early-stage pancreatic cancer.

4166 Background: Pancreatic cancer is a highly aggressive disease with a poor prognosis, and one in which most measure of genomic instability (e.g., tumor mutation burden (TMB), fraction of genome altered (FGA)) have thus far, not proven informative in differentiating survival. Non-B DNA are alternative DNA forms that deviate from the canonical B-DNA structure with potential to increase susceptibility to mutations, leading to the development of cancer. The role of non-B in pancreatic cancer has not been fully explored. Herein, we investigate the relationship between gene mutation sites co-localized with non-B DNA motifs in terms of survival and B-DNA features. Methods: Using TCGA data, we derived a genome-wide mutation signature on 104 early-stage pancreatic patients. We introduced a metric, mutation-localized non-B burden (MLNB) by the number of non-b motifs containing mutation sites, normalized to the number of mutations and motif library size. We applied MLNB to patient-specific mutation signatures to derive an MLNB burden for non-B DNA structure motifs: G-quadruplexes (G4), Z-DNA, inverted repeats (IR), mirror repeats (MR), direct repeats (DR), and short tandem repeats (STR). We performed a cluster analysis on MLNB and compared groups based on overall survival (OS) in months (mos) using a log-rank test. Comparisons of B-DNA-derived molecular features among clusters were performed using a Kruskal-Wallis and Fisher Exact test. Results: Among the 104 early-stage pancreatic patients with a mutation signature, MLNB clustering resulted in six patient clusters that differentiated by non-B DNA structure, with DR burden the longest OS cluster (n=23, median OS=30mos), significantly (p < 0.05) differing as compared to IR (n=23, median OS=15 mos), STR (n=20, median OS=16mos), MR with lack of IR (n=14, median OS=13mos) and MR with IR (n=16, median OS=8mos). A mix of Z-DNA and G4 burden defined a cluster with shorter OS (n=22, median OS=14mos) as compared to DR, though not significant. Patients with the longest OS, MLNB-DR burden cluster had mutation signatures enriched in MAPK and Notch signaling pathways, as compared to the other clusters enriched with double-stranded break and mismatch repair (IR), hedgehog and WNT signaling (STR), and interleukin-4 signaling (MR) pathways. Among all clusters, CDKN2A deletion was most prevalent except for MLNB-DR burden cluster. No Significant differences were found between the MLNB clusters with age, race gender, KRAS and TP53 mutations, FGA, TMB, tumor purity, Bailey and Moffit subtypes. Conclusions: Our results point towards the potential use of MLNB as an emerging marker of site-structure genomic instability. Considering that triplex DNA is emerging as a marker genomic instability, and that we distinguish between two MR groups based on IR burden, our results may provide insights into various instability mechanisms associated with poor survival in pancreatic cancer.

Factors associated with failure to operate and its impact on survival in early-stage pancreatic cancer.

Curative intent for localized pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) requires surgery, but despite improved perioperative outcomes, surgery remains underutilized. This study analyzed the Texas Cancer Registry (TCR) to identify resectable PDAC patients who underwent curative-intent surgery in Texas between 2004 and 2018. We then evaluated demographic and clinical factors associated with failure to operate and survival (OS). We identified patients with localized PDAC or regional lymph node spread between 2004 and 2018 in the TCR. Resection rates were determined and multivariable regression and cox proportional hazards were used to identify factors associated with failure to OS. Of 4274 patients, 22% underwent resection, 57% were not offered surgery, 6% had comorbidities precluding surgery, and 3% refused. Resection rates decreased from 31% in 2004 to 22% in 2018. Increasing age was associated with failure to operate (odds ratio [OR] 2.55; 95% confidence interval [CI] 1.80-3.61; p < 0.0001) while treatment at a Commission on Cancer (CoC) center correlated with reduced failure to operate (OR 0.63; 95% CI 0.50-0.78; p < 0.0001). Resection correlated with survival (HR 0.34; 95% CI 0.31-0.38; p < 0.0001) as did treatment at a National Cancer Institute (NCI)-designated center (hazard ratio 0.79; 95% CI 0.70-0.89; p < 0.0001). Surgery is underutilized for the treatment of resectable PDAC in Texas with decreasing utilization, annually. Evaluation at CoC was associated with improved resection rates and NCI was associated with increased survival. Expanding access to multidisciplinary care including trained hepato-pancreatico-biliary surgeons may improve outcomes for PDAC patients.

Novel positron emission tomography imaging targeting cell surface glycans for pancreatic cancer: 18 F-labeled rBC2LCN lectin.

Advancement in early detection modalities will greatly improve the overall prognoses of pancreatic ductal adenocarcinoma (PDAC). For this purpose, we report a novel class of tumor-specific probes for positron emission tomography (PET) based on targeting cell surface glycans. The PDAC-targeting ability of rBC2LCN lectin, combined with fluorine-18 (18 F) ([18 F]FB-rBC2LCN), resulted in reproducible, high-contrast PET imaging of tumors in a PDAC xenograft mouse model. [18 F]N-succinimidyl-4-fluorobenzoate ([18 F]SFB) was conjugated to rBC2LCN, and [18 F]FB-rBC2LCN was successfully prepared with a radiochemical purity >95%. Cell binding and uptake revealed that [18 F]FB-rBC2LCN binds to H-type-3-positive Capan-1 pancreatic cancer cells. As early as 60 min after [18 F]FB-rBC2LCN (0.34 ± 0.15 MBq) injection into the tail vein of nude mice subcutaneously bearing Capan-1 tumors, tumor uptake was high (6.6 ± 1.8 %ID/g), and the uptake increased over time (8.8 ± 1.9 %ID/g and 11 ± 3.2 %ID/g at 150 and 240 min after injection, respectively). Tumor-to-muscle ratios increased over time, up to 19 ± 1.8 at 360 min. High-contrast PET imaging of tumors relative to background muscle was also achieved as early as 60 min after injection of [18 F]FB-rBC2LCN (0.66 ± 0.12 MBq) and continued to increase up to 240 min. Our 18 F-labeled rBC2LCN lectin warrants further clinical development to improve the accuracy and sensitivity of early-stage pancreatic cancer detection.

Gene signature developed for predicting early relapse and survival in early-stage pancreatic cancer.

The aim of this study was to construct a predictive signature integrating tumour-mutation- and copy-number-variation-associated features using machine learning to precisely predict early relapse and survival in patients with resected stage I-II pancreatic ductal adenocarcinoma. Patients with microscopically confirmed stage I-II pancreatic ductal adenocarcinoma undergoing R0 resection at the Chinese PLA General Hospital between March 2015 and December 2016 were enrolled. Whole exosome sequencing was performed, and genes with different mutation or copy number variation statuses between patients with and without relapse within 1 year were identified using bioinformatics analysis. A support vector machine was used to evaluate the importance of the differential gene features and to develop a signature. Signature validation was performed in an independent cohort. The associations of the support vector machine signature and single gene features with disease-free survival and overall survival were assessed. Biological functions of integrated genes were further analysed. Overall, 30 and 40 patients were included in the training and validation cohorts, respectively. Some 11 genes with differential patterns were first identified; using a support vector machine, four features (mutations of DNAH9, TP53, and TUBGCP6, and copy number variation of TMEM132E) were further selected and integrated to construct a predictive signature (the support vector machine classifier). In the training cohort, the 1-year disease-free survival rates were 88 per cent (95 per cent c.i. 73 to 100) and 7 per cent (95 per cent c.i. 1 to 47) in the low-support vector machine subgroup and the high-support vector machine subgroup respectively (P < 0.001). Multivariable analyses showed that high support vector machine was significantly and independently associated with both worse overall survival (HR 29.20 (95 per cent c.i. 4.48 to 190.21); P < 0.001) and disease-free survival (HR 72.04 (95 per cent c.i. 6.74 to 769.96); P < 0.001). The area under the curve of the support vector machine signature for 1-year disease-free survival (0.900) was significantly larger than the area under the curve values of the mutations of DNAH9 (0.733; P = 0.039), TP53 (0.767; P = 0.024), and TUBGCP6 (0.733; P = 0.023), the copy number variation of TMEM132E (0.700; P = 0.014), TNM stage (0.567; P = 0.002), and differentiation grade (0.633; P = 0.005), suggesting higher predictive accuracy for prognosis. The value of the signature was further validated in the validation cohort. The four genes included in the support vector machine signature (DNAH9, TUBGCP6, and TMEM132E were novel in pancreatic ductal adenocarcinoma) were significantly associated with the tumour immune microenvironment, G protein-coupled receptor binding and signalling, cell-cell adhesion, etc. The newly constructed support vector machine signature precisely and powerfully predicted relapse and survival in patients with stage I-II pancreatic ductal adenocarcinoma after R0 resection.

Abstract 1008: A novel biomarker and therapeutic target for early pancreatic cancer

Abstract Purpose: Pancreatic cancer (PC) has a grim prognosis, and an early diagnostic biomarker has been highly desired. The molecular link between diabetes and PC has not been well established. Methods: Bioinformatics screening was performed for a serum PC marker. Experiments in cell lines (5 PC and 1 normal cell lines), mouse models, and human tissue staining (37 PC and 10 normal cases) were performed to test asprosin production from PC. Asprosin’s diagnostic performance was tested with serums from multi-center cohorts (347 PC, 209 normal, and 55 additional diabetic patients) and evaluated according to PC status and stages which was compared with that of CA19-9. Results: Asprosin, a diabetes-related hormone, was found from the bioinformatics screening, and its production from PC was confirmed. Serum asprosin levels from multi-center cohorts yielded an age-adjusted diagnostic area under the curve (AUC) of 0.987 (95% confidence interval [CI] = 0.961 to 0.997), superior to that of CA19-9 (AUC = 0.876, 95% CI = 0.847 to 0.905), and a cut-off of 7.18 ng/mL, at which the validation set exhibited a sensitivity of 0.957 and a specificity of 0.924. Importantly, the performance was maintained in early stage PC, consistent with the tissue staining. A slightly lower performance against additional diabetic patients (n = 55) was restored by combining asprosin and CA19-9 (AUC = 0.985, 95% CI = 0.975 to 0.995). Conclusion: Asprosin is presented as an early-stage PC serum marker that may provide clues for PC-induced diabetes. Larger prospective clinical studies are warranted to solidify its utility. Citation Format: Min Seok Park, Kyung Hee Jung, Sang Eun Kim, Yun Ji Lee, Sunghyouk Park, Soon-Sun Hong. A novel biomarker and therapeutic target for early pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1008.

Abstract 1511: Origin of synchronous or metachronous multiple pancreatic cancers

Abstract Introduction: The majority of patients with pancreatic cancer are inoperable at the time of diagnosis and even those cases with successful tumor resection for early-stage tumors frequently had second tumors within the remaining pancreas shortly after the surgery, contributing to a poor clinical outcome. Moreover, synchronous multiple pancreatic cancers were often reported. One of the long-standing issues about such synchronous and/or metachronous multiple pancreatic cancers is their clonal origins. In this study, we aimed to reveal the origin of multiple pancreatic cancers using an unbiased detection of somatic mutations in primary and metachronous cancers as well as adjacent precursor lesions. Methods: Serially obtained formalin-fixed paraffin-embedded surgical specimens from 18 patients who had undergone curative surgery for an early-stage pancreatic cancer were subjected to laser microdissection for the enrichment of tumor and precancerous lesions, from which DNA was extracted and analyzed for somatic mutations using whole-exome sequencing (WES) with matched normal DNA. Based on shared and private mutations across different samples, we interrogated history of clonal evolution of these lesions. Results: We analyzed 18 patients with multiple pancreatic cancers of 2 metachronous and synchronous, 14 metachronous, and 2 synchronous tumors. In metachronous cases, pathology for primary cancer were margin-negative in all patients, and the median interval between the initial and second surgery was 38.9 months (7 - 85 months). In addition, a total of 20 pancreatic intraepithelial neoplasia (PanIN) from 5 of these cases were analyzed. We identified a median of 66 (range: 31-232) and 20 (14-42) somatic mutations in cancer and PanIN lesions, respectively. None of the patients have known pathogenic germline variants. All samples had one or more driver mutations. In most cases (N=17), sharing many somatic mutations, multiple tumors had a common clonal origin. In another synchronous case, the synchronous tumors shared only one mutation, suggesting that they were clonally independent tumors. By contrast, none of the mutations other than hotspot KRAS mutations were shared between precursor and cancer lesions. While multiple independent clones were observed in precancerous lesions, most of multiple cancers originated from a common ancestor. Moreover, negative pathology of the margins at the initial surgery suggested that those multiple lesions arose from distant dissemination or metastasis, rather than contiguous, intraductal invasion. Conclusions: In conclusion, our study suggests that even early pancreatic cancer might be disseminated within the pancreas and contribute to synchronous and metachronous cancers. Citation Format: Tomonori Hirano, Nobuyuki Kakiuchi, Yasuhide Takeuchi, Tomomi Nishimura, Toshihiko Masui, Kazuyuki Nagai, Takayuki Anazawa, Sachiko Minamigushi, Hironori Haga, Norimitsu Uza, Hiroshi Seno, Yuzo Kodama, Atsuhiro Masuda, Takeshi Tanaka, Seishi Ogawa, Hiroko Tanaka, Satoru Miyano. Origin of synchronous or metachronous multiple pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1511.

Abstract 4193: N-NOSE technology based on C. elegans olfaction. Multi-cancer early detection with high sensitivity using urine. Pancreatic-cancer-specific early detection with high sensitivity using urine

Abstract N-NOSE (Nematode Nose) is a cancer screening test based on the chemotactic characteristics of the nematode C. elegans. C. elegans shows avoidance of the urine of healthy individuals while displaying a chemotactic attraction toward the urine of patients with 15 types of cancer (stomach, colon-rectum, lung, breast, pancreas, liver, prostate, uterus, esophagus, gallbladder, bile duct, kidney, urinary bladder, ovary, oropharynx) rendering N-NOSE a primary multi-cancer screening test. N-NOSE has a high sensitivity of 87.5% and 90.2% specificity, on average, from early stage 0-I. N-NOSE is non-invasive because it relies on a urine sample and is affordable (JPY 13,800, ~USD 100).N-NOSE by Hirotsu Bio Science has been available in Japan since late 2020 and is a commercial hit with over 250,000 screenings performed, rapidly increasing. In this presentation, we outline the N-NOSE technology and business in Japan. We review N-NOSE clinical research and critical findings compared to competitors that highlight its excellent performance as a non-invasive primary cancer screening for early detection. N-NOSE is a multi-cancer early detection test. Next, we introduce an evolution of N-NOSE for identifying the cancer type. Pancreatic cancer is the 12th most common cancer worldwide but remains one the deadliest cancer with a 5-year relative survival rate at only 11%, all stages combined. An affordable, non-invasive, and highly sensitive early-stage pancreatic cancer screening test is sorely needed. As an evolution of N-NOSE we genetically engineered C. elegans by knocking out in AWC olfactory neurons a specific olfactory receptor (GPCR), triggering a chemotactic response particular to the only pancreatic cancer urine specimen at an early stage. In this study, we outline, for the first time, the critical discovery of cr-4 GPCR in AWC, which is crucial for a specific chemotaxis response to the urine of patients with pancreatic cancer. Next, we briefly conclude by outlining the link between N-NOSE primary cancer screening followed by N-NOSE cancer type identification, effectively completing the whole cancer screening and identification process in a non-invasive way. Citation Format: Eric Di Luccio, Takaaki Hirotsu. N-NOSE technology based on C. elegans olfaction. Multi-cancer early detection with high sensitivity using urine. Pancreatic-cancer-specific early detection with high sensitivity using urine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4193.

Diagnostic value of combining preoperative inflammatory markers ratios with CA199 for patients with early-stage pancreatic cancer

BackgroundAn early diagnosis of pancreatic cancer (PC) is extremely difficult because of the lack of sensitive liquid biopsy methods and effective biomarkers. We attempted to evaluate whether circulating inflammatory marker could complement CA199 for the detection of early-stage PC.MethodsWe enrolled 430 patients with early-stage PC, 287 patients with other pancreatic tumors (OPT), and 401 healthy controls (HC). The patients and HC were randomly divided into a training set (n = 872) and two testing sets (n1 = 218, n2 = 28). The receiver operating characteristic (ROC) curves were investigated to evaluate the diagnostic performance of circulating inflammatory markers ratios, CA199, and combinations of the markers ratios in the training set, which would then be validated in the two testing sets.ResultsCirculating fibrinogen, neutrophils, and monocytes in patients with PC were significantly higher while circulating albumin, prealbumin, lymphocytes, and platelets of patients with PC were significantly lower compared to those of HC and OPT (all P < 0.05). The fibrinogen-to-albumin (FAR), fibrinogen-to-prealbumin (FPR), neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), monocyte-to-lymphocyte (MLR), and fibrinogen-to-lymphocyte (FLR) ratios were significantly higher while the prognostic nutrition index values (PNI) were lower in patients with PC than in HC and OPT (all P < 0.05). Combining the FAR, FPR, and FLR with CA199 exhibited the best diagnostic value for distinguishing patients with early-stage PC from HC with an area under the curve (AUC) of 0.964, and for distinguishing patients with early-stage PC from OPT with an AUC of 0.924 in the training sets. In the testing set, compared with HC, the combination markers had powerful efficiency for PC with an AUC 0.947 and AUC 0.942 when comparing PC with OPT. The AUC was 0.915 for the combination of CA199, FAR, FPR, and FLR for differentiating between patients with pancreatic head cancer (PHC) and other pancreatic head tumors (OPHT), and 0.894 for differentiating between patients with pancreatic body and tail cancer (PBTC) and other pancreatic body and tail tumors (OPBTT).ConclusionA combination of FAR, FPR, FLR, and CA199 may serve as a potential non-invasive biomarker for differentiating early-stage PC from HC and OPT, especially early-stage PHC.

Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond.

Pancreatic enzymes assist metabolic digestion, and hormones like insulin and glucagon play a critical role in maintaining our blood sugar levels. A malignant pancreas is incapable of doing its regular functions, which results in a health catastrophe. To date, there is no effective biomarker to detect early-stage pancreatic cancer, which makes pancreatic cancer the cancer with the highest mortality rate of all cancer types. Primarily, mutations of the KRAS, CDKN2A, TP53, and SMAD4 genes are responsible for pancreatic cancer, of which mutations of the KRAS gene are present in more than 80% of pancreatic cancer cases. Accordingly, there is a desperate need to develop effective inhibitors of the proteins that are responsible for the proliferation, propagation, regulation, invasion, angiogenesis, and metastasis of pancreatic cancer. This article discusses the effectiveness and mode of action at the molecular level of a wide range of small molecule inhibitors that include pharmaceutically privileged molecules, compounds under clinical trials, and commercial drugs. Both natural and synthetic small molecule inhibitors have been counted. Anti-pancreatic cancer activity and related benefits of using single and combined therapy have been discussed separately. This article sheds light on the scenario, constraints, and future aspects of various small molecule inhibitors for treating pancreatic cancer-the most dreadful cancer so far.

Hypercapnic Tissue Gene Expression and Survival in Early-Stage Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer. Hypercapnic tumor microenvironments were previously shown to promote cancer chemoresistance. In this study, we aimed to investigate the impact of tissue hypercapnia on PDAC prognosis. PDAC cancer-cell lines were cultured in normocapnic (5% CO 2 ) and hypercapnic conditions (10% CO 2 ). RNA was extracted, and whole-exome transcriptome was sequenced. Differentially expressed genes were identified and used to construct a "hypercapnic gene set." PDAC transcriptomic patient data from the Tumor Cancer Genome Atlas was used to calculate single-sample gene set enrichment scores based on each patient's tissue expression of the hypercapnic gene set. Tissue hypercapnic scores (HSs) in PDAC patients (TMN stages Ia-IIb) were determined and correlated with clinicopathological parameters and overall survival. A cohort of 135 resected stage I-II PDAC patients were assessed in this study. The average age was 65 ± 11.0 years, and the male:female ratio was 74:61. Median overall survival was 19.5 ± 1.4 months. High HSs were associated with increased tumor stage (p < 0.05) and higher lymph-node ratio (p < 0.05). In active smokers, high HS also correlated with smoking pack-years (p < 0.05). Cox regression analysis revealed high HS to be an independent prognostic factor for overall survival (hazard ratio [HR] 2.66, p = 0.004), along with lymph-node ratio (HR 4.2, p = 0.002) and age at diagnosis (HR 2.63, p = 0.01). The pancreatic tumor microenvironment plays an integral role in tumor aggressiveness, and our previous in vitro data suggest that hypercapnia promotes an aggressive, more resistant phenotype. Herein, we show that in early-stage pancreatic cancer, hypercapnic tissue signatures corresponded with a worse overall survival.

Preoperative therapy confers survival advantage in early-stage pancreatic cancer

Background: Five-year overall survival (OS) for resected pancreatic ductal adenocarcinoma (PDAC) remains poor at 16.3%. In clinical stage (CS) I-II PDAC, CA19-9 levels < 98U/mL portend a favorable prognosis, while surgical resection improves survival irrespective of CA19-9 levels. Currently, 40% of patients with PDAC are unable to complete adjuvant therapy. We evaluated the role of therapy for early-stage resectable PDAC based on pre-operative CA19-9 levels.

National landscape of the treatment of early-stage pancreatic cancer

Background: While advances in systemic therapy and optimal treatment sequencing of pancreatic adenocarcinoma (PDAC) have been made in recent years, nihilism towards management of PDAC persists and serves as a barrier to effective treatment delivery. The aim of this study was to examine national trends in the treatment of early-stage PDAC.

Association between type 2 diabetes and 5-year overall survival in early-stage pancreatic cancer: a retrospective cohort study.

This study examined the association between type 2 diabetes mellitus (T2DM) and 5-year overall survival (OS) in patients with pancreatic cancer (PC). This retrospective cohort study included patients diagnosed with stage I/II PC at Shengjing Hospital of China Medical University from January 2012 to December 2017. All patients had pancreatic ductal adenocarcinoma or its subtypes. The outcome was the 5-year OS rate based on data from the patient charts. Data analysis was performed using SPSS 22.0. A total of 238 patients were included: 72 with T2DM and 166 without T2DM. There were significant differences in blood glucose levels and OS between the two groups (all P < 0.05). The median OS was 11.4 (95% confidence interval CI [8.49-14.31]) months in the T2DM group and 16.3 (95% CI [12.44-20.16], P = 0.023) months in the non-T2DM group. After adjustment for confounders, T2DM was an independent factor affecting 5-year OS (P = 0.010). Compared with non-T2DM patients, T2DM patients had a higher risk of death (HR = 1.475, 95% CI [1.096-1.985]). T2DM is associated with 5-year OS in patients with PC.

A Novel PiRNA Enhances CA19-9 Sensitivity for Pancreatic Cancer Identification by Liquid Biopsy.

Pancreatic cancer is one of the deadliest tumours worldwide, and its poor prognosis is due to an inability to detect the disease at the early stages, thereby creating an urgent need to develop non-invasive biomarkers. P-element-induced wimpy testis (PIWI) proteins work together with piwi-interacting RNAs (piRNAs) to perform epigenetic regulation and as such hold great potential as biomarkers for pancreatic cancer. PIWIL2 and PIWIL4 are associated with better prognosis, while PIWIL1 and PIWIL3 involvement appears to be associated with carcinogenesis. We aimed to discover PIWIL3- and PIWIL4-modulated piRNAs and determine their potential mechanisms in pancreatic cancer and the clinical implications. PIWIL3 or PIWIL4 was downregulated in pancreatic cancer-derived cell lines or in a non-tumour cell line. Differentially expressed piRNAs were analysed by next generation sequencing of small RNA. Nine fresh-frozen samples from solid human pancreases (three healthy pancreases, three intraductal papillary mucinous neoplasms, and three early-stage pancreatic cancers) were included in the sequencing analysis. Two piRNAs associated with PIWIL3 (piR-168112 and piR-162725) were identified in the neoplastic cells; in untransformed samples, we identified one piRNA associated with PIWIL4 (pir-366845). After validation in pancreatic cancer-derived cell lines and one untransformed pancreatic cell line, these piRNAs were evaluated in plasma samples from healthy donors (n = 27) or patients with pancreatic cancer (n = 45). Interestingly, piR-162725 expression identified pancreatic cancer patients versus healthy donors in liquid biopsies. Moreover, the potential of the serum carbohydrate antigen 19-9 (CA19-9) biomarker to identify pancreatic cancer patients was greatly enhanced when combined with piR-162725 detection. The enhanced diagnostic potential for the early detection of pancreatic cancer in liquid biopsies of these new small non-coding RNAs will likely improve the prognosis and management of this deadly cancer.

HPB P04 The DISSECT trial, ‘The effect of periaDventitIal SMA diSsECTion on margin status during pancreaticoduodenectomy for resectable pancreatic cancer’ Results of safety and feasibility pilot study

Abstract Background Survival following pancreatic cancer resection remains poor despite advances in adjuvant and neoadjuvant therapy. The incidence of positive margin status (R1) is high and an R1 resection is associated with poorer survival. The most commonly positive margin is the SMA, accounting for between 47–77% of R1 resections. Periadventitial dissection of the SMA includes the lymphoneural tissue around the adventitia in addition to the ‘mesopancreas’ in the resection specimen and is used to varying extent across different centres. Theoretically this technique should reduce R1 resection rate, however, there is a lack of prospective evidence in the published literature. Methods The DISSECT trial is a single centre, randomised control trial. All patients with a resectable as per NCCN staging criteria head of pancreas tumour are randomised to either ‘periadventitial SMA dissection’ or ‘no periadventitial SMA dissection’ (1:1 block randomisation, sealed envelope system). A standardised technique for length and circumference of dissection is used and intra-operative photography with blinded assessment of dissection status ensures quality control. This safety and feasibility stage assesses recruitment, technique and complications and will be followed by a study powered to detect the primary outcome of reduction in positive SMA margin status. Primary outcomes to be assessed in the fully powered study will be the SMA margin status as detailed by the AJCC 8th edition. Secondary outcomes are status of other margins, length of stay, complications, overall and disease-free survival, complications, and adjuvant treatment details. These are assessed prospectively by an investigator blinded to the study arm. Results For the feasibility stage, the following criteria were set to proceed: recruitment of 20 patients in 6 months, at least 80% of recruited patients to undergo correct arm of randomisation, and an increase in complication rate of no more than 10%. Within the first 6 months, 32 patients were successfully recruited and randomised. 6 were excluded post-randomisation but before SMA approach (N=2 cancelled and not re-booked, N=2 abandoned after opening, N=2 converted to total pancreatectomy). N=3 were eligible but not recruited, (2 refused after approach and 1 was missed due to research team capacity). N=25 (96.2%) underwent their allocated study arm (confirmed by blinded photo assessment). For potentially procedure related complications (SMA bleed, post-operative haemorrhage, chyle leak, collection, and anastomotic leak) there was an overall rate of 38.5%, with no significant difference between the 2 arms (42.9% in No SMA dissection arm and 33.3% in the SMA dissection arm). There were no incidences of SMA branch bleed in the SMA dissection arm and a single post-operative haemorrhage in the SMA dissection arm that was due to a mesenteric venous bleed. Conclusions The DISSECT trial is a randomised controlled trial that aims to evaluate the use of a standardised technique of periadventitial SMA dissection to reduce the rate of R1 resection in early stages of pancreatic cancer. The feasibility and safety pilot is complete and demonstrates successful recruitment and randomisation, excellent adherence to randomisation arm and no operative concerns from the surgical team. The study will now proceed to full recruitment with complications and blinded photo reviews for quality control assessed contemporaneously. Primary and secondary outcomes will be recorded prospectively by a member of the research team blinded to randomisation arm.

Role of circulating exosomal biomarkers and their diagnostic accuracy in pancreatic cancer.

New biomarkers have the potential to facilitate early diagnosis of pancreatic cancer (PC). Circulating exosomes are cell-derived protein complexes containing RNA that can be used as indicators of cancer development. The aim of this review is to evaluate the current literature involving PC patient groups for highly accurate exosomal biomarkers. The literature search followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight-hundred and seventy-five studies were identified across various databases (Ovid MEDLINE, Embase, and Cochrane) published between 2009 and 2020. Nine studies fulfilled the inclusion criteria: human PC patients, diagnosis as outcome of interest, serum biomarker of exosomal content, reporting of diagnostic values, and disease progress. Area under the curve (AUC) of the exosomal biomarker was compared against that of CA19-9. Nine papers were reviewed for relevant outcomes based on the inclusion criteria. These studies involved 565 participants (331 PC, 234 controls; male/female ratio 1.21; mean age 64.1). Tumor staging was reported in all studies, with 45.6% of PC patients diagnosed with early-stage PC (T1-2). The mRNA panel (ARG1, CD63, CK18, Erbb3, GAPDH, H3F3A, KRAS, ODC1) and GPC 1 reported the highest performing sensitivity and specificity at 100% each. The microRNA panel (miR-10b, miR-21, miR-30c, miR-181a, and miR-let7a), mRNA panel (ARG1, CD63, CK18, Erbb3, GAPDH, H3F3A, KRAS, ODC1), and GPC 1 showed a perfect AUC of 1.0. Five studies compared the AUC of the exosomal biomarker against CA19-9, each being superior to that of CA19-9. The potential of exosomal biomarkers remains promising in PC diagnosis. Standardization of future studies will allow for larger comparative analyses and overcoming contrasting findings.

Abstract B040: In silico drug design using KRASG12C as a theranostic target for pancreatic cancer

Abstract Pancreatic cancer is one of the most lethal malignancies worldwide, it often results in therapeutic failure and unfavorable outcome because of the absence of screening strategies, difficulties in tumor early detection due to the lack of specific signs/symptoms and aggressive behavior of the disease. Early detection of this cancer is a challenge with the technology we have, its late detection results in a poor outcome and reduced quality of life for the patient. The treatment success depends on surgical intervention, which is not always possible. Thus, trying to find alterations that occur in the early stages of pancreatic cancer is needed. Taking into consideration that the accumulation of genetic and epigenetic alterations results in a complex and heterogeneous disease, each patient has a unique tumor. The heterogeneity of cancer is not restricted to inter-patient differences but, intra-tumoral heterogeneity contributes to functional properties of tumor cell subclones, including proliferative capacity and progression to aggressive phenotypes such as drug tolerance and metastatic potential. Driver mutations are responsible for malignant transformation and tumor progression across different cancer types. One of the most common driver mutations are those leading to the constitutive activation of KRAS oncogene, a GTPase enzyme responsible for cell proliferation and survival that is frequently mutated in pancreatic cancer. Gain-of-function mutation of KRAS gene leads to a protein constitutively activated, which stimulates the proliferation of tumor cells. The c.34G&amp;gt;T missense mutation (rs121913530) causes the substitution of glycine for cysteine in the encoded protein KRASG12C; this mutation has been related to poorer prognosis and therapy resistance in lung cancer. As KRAS occurs before the progression of pancreatic cancer to invasive carcinoma, it is a promising target for new biomarker development. We design three near-infrared probe-drug conjugate directed to the KRASG12C and to predict in silico the best orientation and conformation of the test compounds bound to the KRAS G12C (PDB code: 6OIM), the PyRx program was used, which uses AutoDock Vina as docking software. Based on these profiles and structures of the compounds, AutoDock Vina infers the possible pharmacological interactions and allows the most promising compounds to be classified according to the studied biological activity, using the empirical score function for this classification. The AMG 510 (established inhibitor) and GDP (endogenous activator) were used as a reference to establish the docking box coordinates. The binding energy of the three compounds predicted by docking was analyzed and classified according to the binding affinity described in Kcal/mol. The tested compounds show an excellent affinity for this protein based on the binding energy results obtained by docking using the crystallized KRAS G12C protein. Therefore, they could be great candidates for further chemical synthesis studies aiming to improve diagnosis, treatment, and patient survival in pancreatic cancer. Citation Format: Barbara M. Barbosa, Allana C. F. Martins, Roberto S. Gomes, Claudia A. Rainho. In silico drug design using KRASG12C as a theranostic target for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B040.

Abstract A027: Validation of an early-stage pancreatic cancer classification model using 5-Hydroxymethylation profiles in plasma-derived cell-free DNA

Abstract Background: Pancreatic cancer outcomes are poor, mostly due to the detection of cancer at late stages. Early-detection enables prompt initiation of treatment and has been reported to significantly improve outcomes. We have developed a novel sequencing-based epigenomics technology for cancer early-detection that enriches 5-hydroxymethylcytosine (5hmC) loci in cell-free DNA (cfDNA), and via machine learning algorithms, enables the detection of pancreatic cancer. Method: Whole-blood was obtained from a training cohort of 660 individuals (consisting of 132 pancreatic cancers (PaCa) and 528 non-cancers) and a validation cohort of 593 individuals (consisting of 86 PaCa and 507 non-cancers). cfDNA was isolated from plasma and 5hmC and whole-genome libraries were sequenced. Logistic regression algorithms were employed using 5hmC feature sets combined with physical characteristics to optimally partition cancers from non-cancers. Results: We trained and cross-validated a binomial logistic-regression model on PaCa and non-cancer samples. Cross validation of the training model yielded an overall sensitivity of 65.9%, early-stage (stage I-II) sensitivity of 57.1% and a specificity of 98%. The model was further validated on an independent set and yielded an overall sensitivity of 64%, early-stage sensitivity of 64.7% and a specificity of 98%. Conclusion: Our results demonstrate that plasma-derived cfDNA 5hmC profiles enable the detection of PaCa in early-stage disease providing a valuable tool especially for those individuals at high risk. A larger clinical study (NODMED: NCT05188586) is underway to validate the test in a high-risk population that would most benefit from early-detection. Citation Format: Anna Bergamaschi, David Haan, Micah Collins, Gulfem Guler, Melissa Peters, Lauren Gigliotti, Shimul Chowdhury, Wayne Volkmuth, Samuel Levy. Validation of an early-stage pancreatic cancer classification model using 5-Hydroxymethylation profiles in plasma-derived cell-free DNA [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A027.

Diagnostic yield of liquid-based cytology in serial pancreatic juice aspiration cytological examination.

ObjectivesSerial pancreatic juice aspiration cytological examination (SPACE) via endoscopic retrograde cholangiopancreatography is a useful diagnostic method for early‐stage pancreatic cancer, such as carcinoma in situ that are difficult to diagnose by endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA). However, the diagnostic accuracy of SPACE is low, which is attributed to problems regarding specimen treatment. Hence, we evaluated the diagnostic efficacy of liquid‐based cytology (LBC) in pancreatic juice cytology for pancreatic cancer.MethodsWe retrospectively analyzed 24 patients with suspected pancreatic cancer that was difficult to diagnose by endoscopic ultrasound‐guided fine needle aspiration who underwent SPACE using LBC between April 2017 and April 2021.ResultsThe most common reason for performing SPACE was localized stenosis of the main pancreatic duct without a mass. Eleven patients were diagnosed with malignancy after surgical resection, nine of whom had pancreatic ductal adenocarcinoma. Ten patients were diagnosed as benign after a follow‐up of more than 1 year. The nine cases of malignancy were diagnosed before surgical resection by SPACE using LBC, with a sensitivity of 81.8% and specificity of 100%. The overall diagnostic accuracy was 91.7%. A total of 152 LBC examinations were performed via SPACE, with an adequate sample collection rate of 88.9%. No adverse events, including acute pancreatitis, occurred after endoscopic retrograde cholangiopancreatography.ConclusionSPACE with LBC offers good diagnostic efficacy in patients with pancreatic cancer that is difficult to diagnose by endoscopic ultrasound‐guided fine needle aspiration.