Chemotherapy For Pancreatic Cancer Research Articles

Metabolic tumor burden as a prognostic indicator after neoadjuvant chemotherapy in pancreatic cancer.

There is no standardized assessment for evaluating response although neoadjuvant chemotherapy (NAT) is widely accepted for borderline resectable or locally advanced pancreatic cancer (BRPC or LAPC). This study was aimed to evaluate NAT response using positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG-PET/CT) parameters alongside carbohydrate antigen (CA) 19-9 levels. Patients who underwent surgery after NAT for BRPC and LAPC between 2017 and 2021 were identified. The study assessed the prognostic value of PET-derived parameters after NAT, determining cutoff values using the K-adaptive partitioning method. It created four groups based on the elevation or normalization of PET parameters and CA19-9 levels, comparing survival between these groups. Of 200 eligible patients, FOLFIRINOX and gemcitabine-based NAT were administered in 167 and 34 patients, respectively (mean NAT cycles, 8.3). In a multivariate analysis, metabolic tumor volume (MTV) demonstrated the most robust performance in assessing response (HR 3.11, 95% CI 1.73-5.58, P<0.001) based on cut-off value of 2.4. Patients with decreased MTV had significantly better survival than those with elevated MTV among individuals with CA19-9 levels <37IU/L (median survival; 35.5 vs. 20.9mo, P<0.001) and CA19-9 levels ≥37IU/L (median survival; 34.3 vs. 17.8mo, P=0.03). In patients suspected to be Lewis antigen negative, predictive performance of MTV was found to be limited (P=0.84). Elevated MTV is an influential prognostic factor for worse survival, regardless of post-NAT CA19-9 levels. These results could be helpful in identifying patients with a poor prognosis despite normalization of CA19-9 levels after NAT.

LOAd703, an oncolytic virus-based immunostimulatory gene therapy, combined with chemotherapy for unresectable or metastatic pancreatic cancer (LOKON001): results from arm 1 of a non-randomised, single-centre, phase 1/2 study

Pancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumour regression in preclinical models. The aim of this study was to evaluate the safety and feasibility of combining LOAd703 with chemotherapy for advanced pancreatic ductal adenocarcinoma. LOKON001 was a non-randomised, phase 1/2 study conducted at the Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA, and consisted of two arms conducted sequentially; the results of arm 1 are presented here. In arm 1, patients 18 years or older with previously treated or treatment-naive unresectable or metastatic pancreatic ductal adenocarcinoma were treated with standard 28-day cycles of intravenous nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (up to 12 cycles) and intratumoural injections of LOAd703 every 2 weeks. Patients were assigned using Bayesian optimal interval design to receive 500 μL of LOAd703 at 5 × 1010 (dose 1), 1 × 1011 (dose 2), or 5 × 1011 (dose 3) viral particles per injection, injected endoscopically or percutaneously into the pancreatic tumour or a metastasis for six injections. The primary endpoints were safety and treatment-emergent immune response in patients who received at least one dose of LOAd703, and antitumour activity was a secondary endpoint. This study was registered with ClinicalTrials.gov, NCT02705196, arm 2 is ongoing and open to new participants. Between Dec 2, 2016, and Oct 17, 2019, 23 patients were assessed for eligibility, leading to 22 patients being enrolled. One patient withdrew consent, resulting in 21 patients (13 [62%] men and eight [38%] women) assigned to a dose group (three to dose 1, four to dose 2, and 14 to dose 3). 21 patients were evaluable for safety. Median follow-up time was 6 months (IQR 4-10), and data cutoff was Jan 5, 2023. The most common treatment-emergent adverse events overall were anaemia (96 [8%] of 1237 events), lymphopenia (86 [7%] events), hyperglycaemia (70 [6%] events), leukopenia (63 [5%] events), hypertension (62 [5%] events), and hypoalbuminaemia (61 [5%] events). The most common adverse events attributed to LOAd703 were fever (14 [67%] of 21 patients), fatigue (eight [38%]), chills (seven [33%]), and elevated liver enzymes (alanine aminotransferase in five [24%], alkaline phosphatase in four [19%], and aspartate aminotransferase in four [19%]), all of which were grade 1-2, except for a transient grade 3 aminotransferase elevation occurring at dose 3. A maximum tolerated dose was not reached, thereby establishing dose 3 as the highest-evaluated safe dose when combined with nab-paclitaxel plus gemcitabine. Proportions of CD8+ effector memory cells and adenovirus-specific T cells increased after LOAd703 injections in 15 (94%) of 16 patients for whom T-cell assays could be performed. Eight (44%, 95% CI 25-66) of 18 patients evaluable for activity had an objective response. Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing. Lokon Pharma, the Swedish Cancer Society, and the Swedish Research Council.

Gemcitabine elaidate and ONC201 combination therapy for inhibiting pancreatic cancer in a KRAS mutated syngeneic mouse model

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to excessive toxicity. ONC201 is a dual PI3K/AKT and MEK pathway inhibitor with an excellent safety profile that targets death receptor 5 (DR5) to induce apoptosis. Gemcitabine (GEM) is a first-line chemotherapy in PC, but it is metabolically unstable and can be stabilized by a prodrug approach. In this study, phospho-Akt, phospho-mTOR, and phospho-ERK protein expressions were evaluated in patient PDAC-tissues (n = 10). We used lipid-gemcitabine (L_GEM) conjugate, which is more stable and enters the cells by passive diffusion. Further, we evaluated the efficacy of L_GEM and ONC201 in PC cells and “KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) triple mutant xenograft tumor-bearing mice. PDAC patient tissues showed significantly higher levels of p-AKT (Ser473), p-ERK (T202/T204), and p-mTOR compared to surrounding non-cancerous tissues. ONC201 in combination with L_GEM, showed a superior inhibitory effect on the growth of MIA PaCa-2 cells. In our in-vivo study, we found that ONC201 and L_GEM combination prevented neoplastic proliferation via AKT/ERK blockade to overcome chemoresistance and increased T-cell tumor surveillance. Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate the effect of GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

Clinical efficacy and safety of erlotinib combined with chemotherapy in the treatment of advanced pancreatic cancer: A meta-analysis.

Advanced pancreatic cancer is resistant to chemotherapeutic drugs, resulting in limited treatment efficacy and poor prognosis. Combined administration of the chemotherapeutic gemcitabine and erlotinib is considered a potential first-line treatment for advanced pancreatic cancer. However, their comparative benefits and potential risks remain unclear. To assess the clinical efficacy and safety of erlotinib combined with other chemotherapy regimens for the treatment of advanced pancreatic cancer. Literature on the clinical efficacy and safety of erlotinib combined with chemotherapy for advanced pancreatic cancer was retrieved through an online search. The retrieved literature was subjected to a methodological qualitative assessment and was analyzed using the RevMan 5.3 software. Ten randomized controlled trials involving 2444 patients with advanced pancreatic cancer were included in the meta-analysis. Compared with chemotherapeutic treatment, erlotinib combined with chemotherapy significantly prolonged the progression-free survival time of pancreatic cancer patients [hazard ratio (HR) = 0.78, 95%CI: 0.66-0.92, P = 0.003]. Meanwhile, the overall survival (HR= 0.99, 95%CI: 0.72-1.37, and P = 0.95) and disease control rate (OR = 0.93, 95%CI: 0.45-0.91, P = 0.84) were not significantly favorable. In terms of safety, the erlotinib and chemotherapy combination was associated with a significantly higher risk of diarrhea (OR = 3.59, 95%CI: 1.63-7.90, P < 0.05) and rash (OR = 3.63, 95%CI: 1.64-8.01, P < 0.05) compared with single-agent chemotherapy. Moreover, the risk of vomiting (OR = 1.27, 95%CI: 0.62-2.59, P = 0.51), regurgitation/anorexia (OR = 1.61, 95%CI: 0.25-10.31, P = 0.62), and infection (OR = 0.72, 95%CI: 0.28-1.87, P = 0.50) were not significant in either group. Compared with a single chemotherapeutic modality, erlotinib combined with gemcitabine can prolong progression-free survival in pancreatic cancer, but does not improve survival benefit or disease control rate, and can increase the risk of diarrhea and rash.

Are measures and related symptoms of cachexia recorded as outcomes in gastrointestinal cancer chemotherapy clinical trials?

Cachexia is prevalent in gastrointestinal cancers and worsens patient outcomes and chemotherapy compliance. We examined to what extent registered gastrointestinal cancer chemotherapy clinical trials record measures and related symptoms of cachexia as outcomes, and whether these were associated with trial characteristics. Four public trial registries (2012-2022) were accessed for Phase II and/or III randomized controlled pancreatic, gastric, and colorectal cancer chemotherapy trial protocols. Trial outcome measures of overall survival and toxicity/side effects, and those related to cachexia [physical activity, weight/body mass index (BMI), dietary limitations, caloric intake, lean muscle mass] and symptoms (appetite loss, diarrhoea, pain, fatigue/insomnia, constipation, nausea, vomiting, and oral mucositis) were extracted, along with the number and types of performance status and patient-reported outcomes (PROs) tools. Data were summarized descriptively. Chi-square tests examined associations between outcomes and trial characteristics (cancer type, trial location, funding source, PROs tools, and commencement year). Statistical significance was set at P<0.05. We included 540 trial protocols (pancreatic (35.2%), colorectal (33.3%) and gastric (31.5%)), with most trials from Europe (44.1%). Trial lead investigator was from academia (28.3%), industry (27.6%) and government (26.3%). Allied health professional involvement (26.9%) occurred at eligibility. Adjuvant therapy in trials was mainly treatment-related (68.1%). Additional medication included anti-nausea (2.2%) and analgesia (0.9%). Trial protocols mostly recorded overall survival (90.4%) and toxicity (78.9%), and the symptoms appetite loss (26.1%) and diarrhoea (19.1%), with the other symptoms recorded in <10% of the trials. Reporting of physical activity (P=0.001), dietary limitations (P=0.002), lean muscle mass (P=0.027), appetite loss (P<0.001), pain (P=0.001), nausea (P=0.012), and oral mucositis (P=0.049) varied depending cancer type. Toxicity/side effects (P=0.022), physical activity (P<0.001), appetite loss, nausea, and vomiting (all P<0.001), diarrhoea (P=0.010), pain (P=0.001), fatigue/insomnia (P=0.001) varied depending on the trial location. Trial funding was predominantly from private/industry (34.3%) and influenced the reporting of overall survival (P=0.049), weight/BMI (P=0.005), caloric intake (P=0.015), and pain (P=0.031). Performance status and PROs tools were mentioned in 91.2% and 46.3% of the trials, respectively. Trials that incorporated PROs tools were more likely to report cachexia related outcomes, except for overall survival, lean muscle mass, and oral mucositis. The proportion of trials measuring weight/BMI increased with trial commencement year (P=0.04). Cachexia-related outcomes were under-recorded in gastrointestinal cancer chemotherapy trials. As trial patients experience a high symptom burden, cachexia-relevant measures and symptoms should be assessed throughout the trial, and integrated with primary endpoints to support their progress.

Metabolic responses to the occurrence and chemotherapy of pancreatic cancer: biomarker identification and prognosis prediction

As the most malignant tumor, the prognosis of pancreatic cancer is not ideal even in the small number of patients who can undergo radical surgery. As a highly heterogeneous tumor, chemotherapy resistance is a major factor leading to decreased efficacy and postoperative recurrence of pancreatic cancer. In this study, nuclear magnetic resonance (NMR)-based metabolomics was applied to identify serum metabolic characteristics of pancreatic ductal adenocarcinoma (PDAC) and screen the potential biomarkers for its diagnosis. Metabolic changes of patients with different CA19-9 levels during postoperative chemotherapy were also monitored and compared to identify the differential metabolites that may affect the efficacy of chemotherapy. Finally, 19 potential serum biomarkers were screened to serve the diagnosis of PDAC, and significant metabolic differences between the two CA19-9 stratifications of PDAC were involved in energy metabolism, lipid metabolism, amino acid metabolism, and citric acid metabolism. Enrichment analysis of metabolic pathways revealed six shared pathways by PDAC and chemotherapy such as alanine, aspartate and glutamate metabolism, arginine biosynthesis, glutamine and glutamate metabolism, citrate cycle, pyruvate metabolism, and glycogolysis/gluconeogeneis. The similarity between the metabolic characteristics of PDAC and the metabolic responses to chemotherapy provided a reference for clinical prediction of benefits of postoperative chemotherapy in PDAC patients.

Abstract 2129: Efficacy and underlying mechanisms of surufatinib combined with PD-1 monoclonal antibody and chemotherapy in pancreatic cancer

Abstract Background: A phase 1b/2 study (NCT05218889) of surufatinib combined with camrelizumab, nab-paclitaxel, and S-1 (NASCA) as first-line therapy for metastatic pancreatic adenocarcinoma has shown promising results, potentially overcoming the limitations of current pancreatic immunotherapies. Animal studies are underway to further explore the synergistic effects and mechanisms of this combined therapeutic approach. Methods: Genetically engineered KPC mouse cells were used to establish a subcutaneous transplantation tumor model in female mice, which were then divided into control group, AG group (nab-paclitaxel + gemcitabine), and NASCA group. Tumor metrics were recorded until euthanasia after 21 days. Blood and tumor samples were analyzed using Flow Cytometry. Results: Compared with the control group, the NASCA and AG groups demonstrated tumor volume reductions of 14.7% (p=0.172) and -0.4% (p=0.972) on day 7, respectively. At day 14, the reductions were 48.8% and 29.9% (p&amp;lt;0.001*, p=0.002*). At day 21, the reductions were 37.4% and 21.5% (p=0.001*, p=0.144). The tumor growth inhibitions (TGIs) for NASCA and AG group were 56.7% (p&amp;lt;0.001*) and 21.2% (p=0.36), respectively. Compare to AG group, the tumor volume reduction in NASCA group were 15.1% (p=0.050*), 26.9% (p=0.001*) and 20.3% (p=0.116), respectively. And the TGIs for NASCA group compare AG group was 45.0% (p=0.020*). Distinguishingly, the NASCA group, when compared to the AG group, had a heightened proportion of M1 macrophages (28.5% vs. 15.5%, p=0.019*), mCD68+ Macrophages (99.7% vs. 99.1%, p=0,014*) and mPD-1+/mCD8+ T cells (24.8% vs. 9.8%, p=0.03*). Furthermore, T-regulatory cells (T-regs) in peripheral blood demonstrated uniformity across the groups, were no statistically. RNA-seq analysis revealed that the NASCA significantly suppressed multiple anti-angiogenic pathways while enhancing the cytokine pathway (p=0.005*), indicating potential immune system activation. Conclusion: The NASCA group outperformed the AG group in controlling tumor growth and early tumor shrinkage, potentially due to macrophage polarization regulation. Further research is vital to understand the benefits of integrating targeted therapy, immunotherapy, and chemotherapy for pancreatic cancer. Citation Format: Nan Zhang, Ru Jia, Guanghai Dai. Efficacy and underlying mechanisms of surufatinib combined with PD-1 monoclonal antibody and chemotherapy in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2129.

Abstract 3274: Trefoil factor 1 suppresses stemness and enhances chemosensitivity of pancreatic cancer

Abstract Background and Aims: Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer. Methods: To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRASG12D/LSL-p53R172H/TFF1−/−) were analyzed by immunohistochemistry (IHC). To explore the efficacy of extracellular administration of TFF1, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines, a xenograft mouse model and a transgenic mouse model. Results: The deficiency of TFF1 was associated with increased EMT markers of cancer cells (Snail and Zeb1) in mouse models of pancreatic cancer, KPC. Analysis of the survival of patients who underwent chemotherapy for recurrent pancreatic cancer revealed that the expression of TFF1 in cancer cells was associated with better survival. Also, in the mouse model of pancreatic cancer, KPC mice showed improved survival when treated with gemcitabine, the KPC/TFF1KO mice did not. Pancreatic cancer cell lines were administered with gemcitabine and/or chemically synthesized TFF1, revealing that addition of TFF1 downregulated gemcitabine-induced EMT markers (Snail, Slug, ZEB1, and αSMA), Wnt pathway activation (β-catenin, TCF7, and EPHB3). In addition, TFF1 inhibited the expression of cancer stemness markers (CD133 and NANOG3) and the ability to form tumor sphere. Importantly, TFF1 accelerated the apoptosis of cancer cells induced by gemcitabine in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model. Also, KPC mice with combined treatment showed the better survival rather than gemcitabine-alone treatment, with lower expression of CD133, high expression of ZEB1, and lower nuclear translocation of β-catenin. Conclusion: These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity. Citation Format: Junpei Yamaguchi, Toshio Kokuryo, Yukihiro Yokoyama, Masaki Sunagawa, Taisuke Baba, Tomoki Ebata. Trefoil factor 1 suppresses stemness and enhances chemosensitivity of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3274.

Abstract 3167: Impact of gemcitabine modification on redox-driven responses in pancreatic cancer organoids cultured in distinct 3D microenvironments

Abstract Pancreatic ductal adenocarcinoma (PDAC) poses a formidable challenge in oncology, characterized by its high lethality and limited treatment options. The advanced stage at diagnosis, aggressive metastasis, and the constrained efficacy of conventional therapeutic drugs collectively contribute to the grim prognosis associated with PDAC. Gemcitabine, a nucleoside analog and the longstanding standard chemotherapy for pancreatic cancer, encounters a significant hurdle in its efficacy due to the development of resistance. To establish a cancer-acquired resistance model applicable to Gem-modified drugs, it is crucial to account for the dense extracellular matrix (ECM) composition characteristic of PDAC. In this investigation, we employ three-dimensional (3D) cell culture models, specifically utilizing pancreatic cancer patient-derived organoids (PDOs) within a 3D matrix with tunable density and stiffness by incorporating variations in transglutaminase crosslinking rates. PDAC cells from different patients exhibit diverse adaptations within these altered gel matrix environments, manifesting differences in morphology, doubling time, and responses to drugs. Notably, PDAC cells display pronounced stemness characteristics in the dense matrix, featuring a more rounded and compact appearance and an increase in ABC transporters.Addressing the challenge of gemcitabine resistance, modifications such as gemcitabine conjugates with stearate (Gem-S) have shown promise in preclinical studies. Exploring the effects of both Gem and Gem-S in a viscoelastic-specific ECM model derived from PDAC patient-derived organoids, distinct responses based on matrix stiffness come to light. The physical properties of the matrix exert a significant influence on cellular function, thereby impacting the effectiveness of therapeutic agents. Intriguingly, within a stiffer environment, Gem-S demonstrates higher sensitivity compared to Gem, suggesting the potential application of Gem-S in the dense pathological PDAC environment. Further investigation reveals that Gem-S treatment induces a noteworthy increase in reactive oxygen species (ROS) and HIF-1 expression compared to Gem. Surprisingly, the role of multidrug transporters in Gem-S sensitivity is limited, while the downregulation of NRF (Nrf2) after Gem-S treatment hints at distinct mechanisms underlying the development of drug resistance. This study provides valuable insights into the intricate interplay between gemcitabine resistance and the PDAC microenvironment. Understanding the matrix-specific responses opens avenues for tailored therapeutic interventions, offering the potential for improved outcomes in PDAC patients. Citation Format: Bo Han, Shuqing Zhao, Edward Agyare, Xueyou Zhu, Jose Trevino, Sherise Rogers, Enrique Velazquez, Jason Brant, Payam Eliahoo, Jonathan Barajas, Ba Xuan Hoang. Impact of gemcitabine modification on redox-driven responses in pancreatic cancer organoids cultured in distinct 3D microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3167.

Abstract 1010: Feasibility of serial microbiome collection in a multi-site neoadjuvant pancreatic cancer clinical trial allowing for a diverse patient population

Abstract Background: Pancreatic cancer portends a very poor prognosis. It is the third leading cause of cancer deaths in the United States. African Americans have a 50- 90% increased incidence of pancreatic cancer in comparison to other racial groups. 20% of patients present with operable disease and will have a median overall survival of 2.5 years if able to undergo surgical resection. There is a desperate need to discover novel ways of treating pancreatic cancer. Understanding of the microbiome may be informative to overcoming chemotherapy resistance, toxicity and improving outcomes and disparities. The aim of this study is to (1) identify changes in the microbiota during neoadjuvant treatment of pancreatic ductal adenocarcinoma that correlate with treatment response and (2) identify changes in the microbiota during neoadjuvant treatment of pancreatic ductal adenocarcinoma that correlate with treatment toxicity in a diverse patient population. Methods: Patients with resectable or borderline resectable pancreatic cancer who are enrolled in a multi-site clinical trial (NCT03483038) receiving neoadjuvant NEO-Nali-IRI (oxaliplatin, liposomal irinotecan and 5- FU) followed by surgical resection were asked to provide serial microbiome collections of saliva, urine (collected in clinic), and stool with a dietary log during the following four (or five) time points: at baseline, mid-therapy (after C4), at completion of chemotherapy (after C8), after radiation if applicable, and at 4-6 weeks post-operative. Participants were given stool collection kits during clinic visits for home sample acquisition. All stool samples were mailed to the University of Florida Health Cancer Center Microbiome Biorepository. Demographics, stage, medical history and concurrent medications including antimicrobics and probiotics, chemotherapy dose-reductions, delays, discontinuations, adverse events, safety adverse events, attribution of causality, and hospitalizations were obtained. Outcomes include imaging response using RECIST criteria, CA 19-9 trend, development of metastatic disease, and the ability to proceed to definitive surgical resection. DNA will be extracted from stool and analyzed using 16S rRNA sequencing methods to determine signatures and alpha/beta biodiversity. Descriptive statistics and correlative analysis will be reported. Continuous and categorical variables will be compared with Student’s t-test and Chi-squared test. Multiple groups will be compared by ANOVA. Kaplan-Meier logistic regression will be performed to compare outcomes between the different microbiota groupings. Conclusion: Serial microbiome collection from a multi-site clinical trial is feasible during neoadjuvant chemotherapy for pancreatic cancer and can increase the diversity of the sample population. Citation Format: Sherise Rogers, Ryan Thomas, Ibrahim Nassour, Ilyas Sahin, Brian Ramnaraign, Karen Russell, Steven Hughes, Kathryn Hitchcock, Omar Kayaleh, Anita Turk, Maisey Ratcliff, Thomas George. Feasibility of serial microbiome collection in a multi-site neoadjuvant pancreatic cancer clinical trial allowing for a diverse patient population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1010.

Abstract 2514: Adjuvant chemotherapy drug response-related gene detection using JASPAC01 pancreatic cancer resection cohort

Abstract Background of Purpose: Although various multidisciplinary treatments have been attempted for pancreatic cancer, sufficient improvement in prognosis has not been achieved. It is necessary to establish biomarkers that can predict the malignant potential for each patient and the therapeutic effect of chemotherapy in order to select the optimal treatment for each individual case.This study was designed as a companion study to the phase III comparative study (JASPAC 01 of gemcitabine (GEM) and S-1 therapy as adjuvant chemotherapy after pancreatectomy. Among the 22 candidate biomarker genes that have been reported to be involved in pancreatic cancer treatment prognosis, we focused on E2F transcription factor 7 (E2F7), which is associated with a significantly poor overall survival rate when highly expressed. E2F7 is one of the target proteins of p53 and has been reported to be involved in cell cycle regulation. We examined the possibility of E2F7 expression in pancreatic cancer surgery and the effect of adjuvant chemotherapy. Patients and Methods: After optimizing the E2F7 imunostaining protocol, we scored E2F7 protein expression using the slides from excised tissues from JASPAC 01 registered cases. We investigated the relationship between malignancy and treatment efficacy using the case cohort treatment allocation information, clinicopathological information, and prognosis data. Results: Immunostaining was performed on approximately 330 resected pancreatic cancer specimens from 24 facilities nationwide. Of the 311 patients for whom E2F7 protein expression could be scored, 202 patients who completed the assigned treatment were included in the analysis. In 88 cases with high E2F7 expression, no significant difference in clinicopathological factors was observed between the S-1 treatment group and the GEM treatment group, but the S-1 treatment group showed better recurrence-free survival (RFS, P=0.066) and overall survival (OS, P=0.015) were observed. On the other hand, in the 114 patients with low E2F7 expression, there was no significant difference in clinicopathological factors between the two groups (RFS, P=0.168, OS: P=0.276). High E2F7 expression in pancreatic cancer tissues may affect S-1 sensitivity, GEM resistance, or both. Conclusions: It is considered that high expression E2F7 in pancreatic cancer may affect the therapeutic efficacy of GEM and S-1, which are frequently used in adjuvant chemotherapy for pancreatic cancer. Citation Format: Yukiyasu Okamura, Tomohisa Otsu, Masamichi Hayashi, Ryo Ashida, Katsuhiko Uesaka. Adjuvant chemotherapy drug response-related gene detection using JASPAC01 pancreatic cancer resection cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2514.

Impact of time from diagnosis to chemotherapy on prognosis in advanced pancreatic cancer.

Due to the aggressive nature and poor prognosis of advanced pancreatic cancer, prompt initiation of treatment is critical. We investigated the effect of the interval between cancer diagnosis and initiation of chemotherapy on survival in patients with advanced pancreatic cancer. In this retrospective, single-centre study, consecutive patients with advanced pancreatic cancer between April 2013 and March 2022 were analyzed. Data were extracted from the electronic medical records of patients who received chemotherapy for metastatic, locally advanced or resectable pancreatic cancer or who received chemotherapy due to either being intolerant of or declining surgery. We compared overall survival between two groups: the early waiting time group (waiting time≤30days from diagnosis to chemotherapy initiation) and the elective waiting time group (waiting time≥31days). Prognostic factors, including biliary drainage, were considered. The impact of waiting time on survival was assessed by univariate and multivariate analyses with Cox proportional hazard models. A 1:1 propensity score matching approach was used to balance bias, accounting for significant poor prognosis factors, age and sex. The study involved 137 patients. Overall survival exhibited no statistically significant difference between the early and elective waiting time groups (207 and 261days, P=0.2518). Univariate and multivariate analyses identified poor performance status and metastasis presence as predictors of worse prognosis. This finding persisted post propensity score matching (275 and 222days, P=0.8223). Our study revealed that initiating chemotherapy ˃30days later does not significantly affect treatment efficacy compared to within 30days of diagnosis.

Safety of biliary drainage with 6-mm metallic stent for preoperative obstructive jaundice in pancreatic cancer: PURPLE SIX STUDY.

The 10-mm self-expandable metal stent (SEMS) is the standard for endoscopic transpapillary biliary drainage before pancreatic cancer surgery. However, the efficacy of stents thinner than 10mm has not been adequately validated. Therefore, we aimed to evaluate the safety of a 6-mm fully covered SEMS (FCSEMS) for distal malignant biliary obstruction (DMBO) during preoperative chemotherapy for pancreatic cancer. This was a single-arm, multicenter, prospective phase II study of endoscopic transpapillary initial biliary drainage for DMBO before pancreatic cancer surgery. The primary endpoint was stent-related adverse events, and the key secondary endpoint was the non-recurrent biliary obstruction (non-RBO) rate during the observation period for both resectable (R) and borderline resectable (BR) pancreatic cancers. The study enrolled 33 patients, among whom 32 received the study treatment. There were 23 and 9 cases of R and BR pancreatic cancers, respectively. The technical and clinical success rates were 97.0% and 90.1%, respectively. The stent-related adverse event rate was 3.1% (n=1, acute pancreatitis) (95% confidential interval, 0.00-16.2), which met the criteria to be considered safe. The overall non-RBO rate during the observation period (median 96days) was 78.1% (82.6% and 66.7% for R and BR pancreatic cancer cases, respectively). The 6-mm FCSEMS is an extremely safe metallic stent with a low stent-related adverse event rate of 3.1% for preoperative biliary drainage in pancreatic cancer. It is considered the optimal stent for preoperative biliary drainage in terms of the non-RBO rate. UMIN Clinical Trial Registry (UMIN-CTR 000041704).

Disruption of Super-Enhancers in Activated Pancreatic Stellate Cells Facilitates Chemotherapy and Immunotherapy in Pancreatic Cancer.

One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated pancreatic stellate cells (a-PSCs). These a-PSCs generate abundant extracellular matrix and secrete various cytokines to form biophysical and biochemical barriers, impeding drug access to tumor tissues. Therefore, it is imperative to develop a strategy for reversing PSC activation and thereby removing the barriers to facilitate PDAC drug treatment. Herein, by integrating chromatin immunoprecipitation (ChIP)-seq, Assays for Transposase-Accessible Chromatin (ATAC)-seq, and RNA-seq techniques, this work reveals that super-enhancers (SEs) promote the expression of various genes involved in PSC activation. Disruption of SE-associated transcription with JQ1 reverses the activated phenotype of a-PSCs and decreases stromal fibrosis in both orthotopic and patient-derived xenograft (PDX) models. More importantly, disruption of SEs by JQ1 treatments promotes vascularization, facilitates drug delivery, and alters the immune landscape in PDAC, thereby improving the efficacies of both chemotherapy (with gemcitabine) and immunotherapy (with IL-12). In summary, this study not only elucidates the contribution of SEs of a-PSCs in shaping the PDAC tumor microenvironment but also highlights that targeting SEs in a-PSCs may become a gate-opening strategy that benefits PDAC drug therapy by removing stromal barriers.

Value of diffusion kurtosis MR imaging and conventional diffusion weighed imaging for evaluating response to first-line chemotherapy in unresectable pancreatic cancer

ObjectiveTo investigate the diagnostic value of diffusion kurtosis magnetic resonance imaging (DKI) and conventional diffusion-weighted imaging (DWI) for evaluating the response to first-line chemotherapy in unresectable pancreatic cancer.Materials and methodsWe retrospectively analyzed 21 patients with clinically and pathologically confirmed unresected pancreatic cancer who received palliative chemotherapy. Three-tesla MRI examinations containing DWI sequences with b values of 0, 100, 700, 1400, and 2100 s/mm2 were performed before and after chemotherapy. Parameters included the apparent diffusion coefficient (ADC), mean diffusion coefficient (MD), and mean diffusional kurtosis (MK). The performances of the DWI and DKI parameters in distinguishing the response to chemotherapy were evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Overall survival (OS) was calculated from the date of first treatment to the date of death or the latest follow-up date.ResultsThe ADCchange and MDchange were significantly higher in the responding group (PR group) than in the nonresponding group (non-PR group) (ADCchange: 0.21 ± 0.05 vs. 0.11 ± 0.09, P = 0.02; MDchange: 0.37 ± 0.24 vs. 0.10 ± 0.12, P = 0.002). No statistical significance was shown when comparing ADCpre, ADCpost, MKpre, MKpost, MKchange, MDpre, and MDpost between the PR and non-PR groups. The ROC curve analysis indicated that MDchange (AUC = 0.898, cutoff value = 0.7143) performed better than ADCchange (AUC = 0.806, cutoff value = 0.1369) in predicting the response to chemotherapy.ConclusionThe ADCchange and MDchange demonstrated strong potential for evaluating the response to chemotherapy in unresectable pancreatic cancer. The MDchange showed higher specificity in the classification of PR and non-PR than the ADCchange. Other parameters, including ADCpre, ADCpost, MKpre, MKpost, MKchange, MDpre, and MDpost, are not suitable for response evaluation. The combined model SUMchange demonstrated superior performance compared to the individual DWI and DKI models. Further experiments are needed to evaluate the potential of DWI and DKI parameters in predicting the prognosis of patients with unresectable pancreatic cancer.

C-Reactive Protein-to-Albumin Ratio to Predict Tolerability of S-1 as an Adjuvant Chemotherapy in Pancreatic Cancer.

Adjuvant chemotherapy (AC) with S-1 after radical surgery for resectable pancreatic cancer (PC) has shown a significant survival advantage over surgery alone. Consequently, ensuring that patients receive a consistent, uninterrupted S-1 regimen is of paramount importance. This study aimed to investigate whether the C-reactive protein-to-albumin ratio (CAR) could predict S-1 AC completion in PC patients without dropout due to adverse events (AEs). We retrospectively enrolled 95 patients who underwent radical pancreatectomy and S-1 AC for PC between January 2010 and December 2022. A statistical analysis was conducted to explore the correlation of predictive markers with S-1 completion, defined as continuous oral administration for 6 months. Among the 95 enrolled patients, 66 (69.5%) completed S-1, and 29 (30.5%) failed. Receiver operating characteristic curve analysis revealed 0.05 as the optimal CAR threshold to predict S-1 completion. Univariate and multivariate analyses further validated that a CAR ≥ 0.05 was independently correlated with S-1 completion (p < 0.001 and p = 0.006, respectively). Furthermore, a significant association was established between a higher CAR at initiation of oral administration and acceptable recurrence-free and overall survival (p = 0.003 and p < 0.001, respectively). CAR ≥ 0.05 serves as a predictive marker for difficulty in completing S-1 treatment as AC for PC due to AEs.

Suppression of hypoxia-induced CAV1 autophagic degradation enhances nanoalbumin-paclitaxel transcytosis and improves therapeutic activity in pancreatic cancer

Nanoalbumin-paclitaxel (nab-paclitaxel) is a standard chemotherapy for pancreatic cancer but has shown limited efficacy. However, the mechanism through which circulating nab-paclitaxel passes through the tumour vascular endothelium has not been determined. In our study, a new nonradioactive and highly sensitive method for analysing nab-paclitaxel transcytosis was established. Based on these methods, we found that hypoxia significantly enhanced the autophagic degradation of CAV1 and therefore attenuated caveolae-mediated nab-paclitaxel transcytosis across endothelial cells (ECs). In a proof-of-concept experiment, higher levels of CAV1, accompanied by lower levels of LC3B, were observed in the vascular endothelium of pancreatic cancer tissues collected from patients who showed a good response to nab-paclitaxel compared with those from patients who showed a poor response to nab-paclitaxel. Furthermore, both in vivo and in vitro studies confirmed that suppressing the autophagic degradation of CAV1 via EC-specific ATG5 knockdown or hydroxychloroquine sulfate (HCQ) treatment significantly enhanced nab-paclitaxel translocation across the endothelial barrier into pancreatic cancer cells and amplified the inhibitory effect of nab-paclitaxel on pancreatic tumour growth. The stimulation of CAV1 expression by EC-specific overexpression of exogenous CAV1 or administration of gemcitabine hydrochloride (GE) had the same effect. These results demonstrated that suppressing CAV1 autophagic degradation is a novel translatable strategy for enhancing nab-paclitaxel chemotherapeutic activity in the treatment of pancreatic cancer.

Programmed Remodeling of the Tumor Milieu to Enhance NK Cell Immunotherapy Combined with Chemotherapy for Pancreatic Cancer.

Natural killer (NK) cell-based adoptive immunotherapy has demonstrated encouraging therapeutic effects in clinical trials for hematological cancers. However, the effectiveness of treatment for solid tumors remains a challenge due to insufficient recruitment and infiltration of NK cells into tumor tissues. Herein, a programmed nanoremodeler (DAS@P/H/pp) is designed to remodel dense physical stromal barriers and for dysregulation of the chemokine of the tumor environment to enhance the recruitment and infiltration of NK cells in tumors. The DAS@P/H/pp is triggered by the acidic tumor environment, resulting in charge reversal and subsequent hyaluronidase (HAase) release. HAase effectively degrades the extracellular matrix, promoting the delivery of immunoregulatory molecules and chemotherapy drugs into deep tumor tissues. In mouse models of pancreatic cancer, this nanomediated strategy for the programmed remodeling of the tumor microenvironment significantly boosts the recruitment of NK92 cells and their tumor cell-killing capabilities under the supervision of multiplexed near-infrared-II fluorescence.

Perspectives on chemotherapy-induced toxicities in pancreatic cancer

Despite breakthroughs in screening, identification, and therapy, pancreatic cancer (PC) remains a serious issue in cancer-related mortality. This comprehensive review investigates the long-term and latent effects of chemotherapy in PC, focusing on commonly used medicines such as gemcitabine, docetaxel, irinotecan, nab-paclitaxel, and others. Gemcitabine, a common PC medication, causes a variety of adverse effects, including myelosuppression and weariness. Combination therapy, such as docetaxel and irinotecan, enhance toxicity, resulting in problems such as neutropenia and gastrointestinal difficulties. Significantly, chemotherapy-related complications, such as thrombosis and cardiac difficulties connected to paclitaxel, present serious concerns. Erlotinib, gefitinib, vatalanib, and sunitinib studies show significant side effects. Despite ongoing challenges, determining the causes of the low objective response rate in gemcitabine-refractory patients remains challenging. The study emphasizes the importance of future advances in cancer etiology, arguing for large, straightforward studies examining combination chemotherapies to improve tolerance and minimize chemotherapy-induced sequelae. This overview serves as a thorough guide for physicians, researchers, and policymakers as they navigate the complex terrain of PC chemotherapy, providing significant insights to improve patient care.

Safety and efficacy of chemotherapy for patients with unresectable pancreatic cancer concomitant with collagen disease: A multicenter retrospective observational study.

650 Background: In patients with collagen disease, such as rheumatoid arthritis, steroids and immunomodulators are often used for treatment. These treatments increase the risk of adverse events, including infections; thus, cancer patients with collagen disease are often excluded from clinical trials of chemotherapy for cancer. Therefore, evidence is lacking regarding the safety and efficacy of chemotherapy for pancreatic cancer concomitant with collagen diseases. Methods: This was a multicenter, retrospective study in Japan. Patients who started first-line chemotherapy or chemoradiotherapy for unresectable pancreatic cancer between January 2015 and December 2019 and had concurrent collagen diseases were included. We evaluated adverse events (AEs), discontinuation of anticancer treatment due to AEs, progression-free survival (PFS) and overall survival (OS). Results: A total of 52 patients were enrolled from 20 institutions in Japan, and a total of 101 regimens were administered. Concomitant collagen diseases included rheumatoid arthritis (n=35), systemic lupus erythematosus (n=5), Sjögren's syndrome (n=4), vasculitis syndrome (n=3), dermatomyositis/polymyositis (n=2), polymyalgia rheumatica (n=1), systemic sclerosis (n=1), and Behçet’s disease (n=1). The most common regimens for pancreatic cancer were gemcitabine/nab-paclitaxel (GnP, n=40), S-1 monotherapy (n=18), gemcitabine monotherapy (n=15), modified FOLFIRINOX (n=10), S-1 concurrent radiotherapy (n=5), and FOLFOX (n=4). Treatment discontinuation due to AEs occurred in 21 regimens (20.8%). The most common causes of discontinuation were thrombosis in 4 regimens, interstitial lung disease (ILD) in 3 regimens, and fatigue in 3 regimens. Infection as an adverse event was observed in 7 regimens (6.9%). By regimen, GnP had the highest discontinuation rate for adverse events of 37.5% and an incidence of ILD of 15.0%. The median PFS was 5.6 months in first-line therapy, and the median OS was 11.1 months. By regimen, the median PFS (5.8 months) and median OS (13.3 months) for metastatic patients receiving first-line GnP were comparable to those in previous reports on GnP for patients without collagen disease. Conclusions: Patients with pancreatic cancer concomitant with collagen disease have a high discontinuation rate due to AEs, and attention should be given to the occurrence of thrombosis and ILD.