|
1
|
Yong JP, Mu XY, Zhou CF, Zhang KK, Gao JQ, Guo ZZ, Zhou SF, Ma Z. Radiofrequency ablation of liver metastases in a patient with pancreatic cancer and long-term survival: A case report. World J Clin Cases 2025; 13:100169. [DOI: 10.12998/wjcc.v13.i20.100169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/05/2024] [Accepted: 03/06/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND According to the GLOBCAN2022 database, pancreatic cancer has become the 6th leading cause of cancer-related death worldwide. The latest statistics suggest that the incidence of pancreatic cancer is increasing at a rate of 0.5% to 1.0% per year, and it is expected to become the 2nd leading cause of tumor-related deaths in the United States by 2030. More than 50% of pancreatic cancer patients have already developed distant metastases at the time of diagnosis, with the liver being the most common site. Patients with pancreatic cancer with liver metastasis (PCLM) have a worse prognosis than those with locally progressed pancreatic cancer, with a median survival of less than six months. Therefore, the outcome of liver metastases is often a vital determinant of the prognosis of patients with PCLM. There are few successful cases of localized treatment for PCLM patients. Our department recently performed local radiofrequency ablation (RFA) treatment for a PCLM patient through an evidence-based medicine approach, with remarkable therapeutic effects.
CASE SUMMARY The patient was admitted to the hospital on May 03, 2018, 3 weeks after pancreatic cancer surgery. In October 2017, the patient presented with lower back pain. No abnormalities were detected via computed tomography (CT), colonoscopy, or gastroscopy. However, on March 18, 2018, the patient was investigated in a foreign hospital via CT, which suggested occupational lesions in the descending part of the duodenum, and magnetic resonance imaging suggested pancreatic occupancy. He was considered to be suffering from pancreatic cancer. He underwent laparoscopic-assisted pancreatic + duodenum + superior mesenteric vein partial resection and reconstruction under general anesthesia on March 26, 2018 at The Affiliated Hospital of Xuzhou Medical University. The pancreas and duodenum were partially resected. Postoperative pathology showed adenocarcinoma of the pancreas (moderately differentiated), partly mucinous carcinoma, invading the mucosal layer of the duodenum; the tumor size was 4.5 cm × 4 cm × 4 cm. There was no apparent nerve or vascular invasion. There was no cancer or involvement of the pancreas section or expected hepatic duct margins. There was no cancer involvement in the gastric and duodenal sections. There was no cancer metastasis to the peripheral lymph nodes of the pancreas (0/9). No metastasis to the gastric lesser curvature or more significant curvature lymph nodes (0/1, 0/5) was detected, and the peri-intestinal lymph nodes showed no cancer metastasis (0/4). Although the gallbladder showed signs of chronic cholecystitis, there was no cancer involvement, and the lymph nodes in Groups 12 and 13 also showed no cancer metastasis (0/6, 0/1). His postoperative recovery was acceptable. CT was performed on May 2018 at our hospital and found the following: (1) Double lung bronchial vascular bundles slightly heavier than normal; (2) Postoperative changes in the pancreas and a retention tube shadow in front of the head of the pancreas; (3) Small cysts in the right lobe of the liver; (4) Abdominopelvic effusion; and (5) Para splenic enlargement. pTNM stage: PT3N0M0. The patient was in the second stage of postoperative pancreatic cancer, with a potential risk of recurrence considering the patient's postoperative body quality deviation. The patient was unable to tolerate the standard multidrug combination and underwent six cycles of single-agent gemcitabine chemotherapy from May 10, 2018 to August 31, 2018 (the specific drug dosage was 1.4 g/d1/d8 gemcitabine injection, which was repeated every 21 days). Efficacy was determined to be stable disease after 2, 4, and 6 cycles. The side effects during treatment were tolerable.
CONCLUSION This case suggests that RFA can serve as a viable local treatment modality for selected patients with PCLM, offering a chance for long-term survival. Such localized interventions, when carefully tailored, may complement systemic therapies in controlling metastatic pancreatic cancer.
Collapse
Affiliation(s)
- Jin-Peng Yong
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Xiao-Yan Mu
- Department of Oncology, Longhua Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai 20001, China
| | - Chao-Feng Zhou
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Ke-Ke Zhang
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Jie-Qiong Gao
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Zhi-Zhong Guo
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Shi-Fan Zhou
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Zhen Ma
- Department of Neurology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
- Department of Oncology, Henan Hospital of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| |
Collapse
|
|
2
|
Li F, Shen F. Metastatic pancreatic cancer with activating BRAF V600E mutations: A case report. World J Clin Cases 2025; 13:101665. [DOI: 10.12998/wjcc.v13.i16.101665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/06/2024] [Accepted: 01/11/2025] [Indexed: 02/10/2025] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is a highly malignant tumor that is resistant to chemotherapy, radiotherapy and immunotherapy. Combination chemotherapy regimens are the standard first-line regimens for metastatic disease, with a median survival < 12 months. Although recurrent genomic alterations such as the BRAF V600E mutation have been reported in PC, evidence supporting the clinical effectiveness of molecularly guided targeted therapies is limited.
CASE SUMMARY We report a case of a 33-year-old male who was referred to our department with weight loss of 5 kg in 2 months, anorexia and abdominal pain. Imaging showed extensive lesions involving the pancreas, liver, bones, muscles and lymph nodes accompanied by elevated carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). Biopsy yielded a diagnosis of PC. Treatment with gemcitabine and nab-paclitaxel was initiated, but the disease progressed in < 2 months even though the patient’s general condition improved. Molecular testing revealed the presence of BRAF mutation. Dabrafenib/trametinib combination therapy was introduced, and the patient was treated for 2 months with a decrease in CA19-9 and CEA levels, but he died after 2 months of treatment.
CONCLUSION BRAF alterations are infrequent in PC. This case highlights the significance of molecular profiling in patients with PC, especially in patients with a high tumor burden.
Collapse
Affiliation(s)
- Fang Li
- Department of Medical Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, Fujian Province, China
- Xiamen Clinical Research Center for Cancer, Xiamen 361015, Fujian Province, China
- Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen 361015, Fujian Province, China
| | - Feng Shen
- Department of Medical Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, Fujian Province, China
- Xiamen Clinical Research Center for Cancer, Xiamen 361015, Fujian Province, China
- Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen 361015, Fujian Province, China
| |
Collapse
|
|
3
|
Imaoka H, Ikeda M, Ozaka M, Oshima K, Okano N, Shimizu S, Tsumura H, Komatsu Y, Yamashita T, Kataoka S, Nagano H, Hisano T, Sasaki M, Kobayashi S, Fukushima T, Mitsunaga S, Furukawa T, Hamauchi S, Ueno M, Furuse J. Phase 1/2 study of liposomal irinotecan plus S-1 for metastatic pancreatic cancer refractory to gemcitabine-based treatment. Eur J Cancer 2025; 222:115424. [PMID: 40252631 DOI: 10.1016/j.ejca.2025.115424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 04/03/2025] [Accepted: 04/11/2025] [Indexed: 04/21/2025]
Abstract
BACKGROUND Liposomal irinotecan (nal-IRI) plus fluorouracil/folinic acid (5-FU/LV) improves survival in gemcitabine-refractory metastatic pancreatic cancer (PC) but requires a central venous port. S-1, an oral fluoropyrimidine with proven efficacy in PC, may replace 5-FU/LV in nal-IRI plus 5-FU/LV, potentially enhancing both convenience and antitumor effect. METHODS This single-arm, open-label, phase 1/2 study included patients with histologically or cytologically confirmed adenocarcinoma, aged 20-80 years, an Eastern Cooperative Oncology Group performance status of 0-1, with metastatic disease, and refractory to gemcitabine-based treatment. The primary endpoint in phase 1 part was the frequency of dose-limiting toxicity (DLT) to nal-IRI plus S-1. The primary endpoint in phase 2 part was overall survival. This trial was registered in the Japan Registry of Clinical Trials database (jRCTs031210040). RESULTS In phase 1 part, one patient with DLT was observed at nal-IRI 70 mg/m2 (day 1) with S-1 80 mg/m2/day (day 1-7) in a 2-week cycle, establishing this as the recommended phase 2 dose (RP2D). Forty-nine patients from phase 1 (n = 6) and phase 2 part (n = 43) were treated with the RP2D, and their results were pooled. Median overall survival was 10.3 months (95 % confidence interval, 8.1-12.0 months). A confirmed partial response was achieved in 10 patients (20.4 %). The most frequent treatment-emergent adverse events were hypoalbuminemia (98.0 %), anemia (98.0 %), and anorexia (81.6 %). There were no treatment-related deaths. CONCLUSIONS This study demonstrated that nal-IRI plus S-1 exhibited promising efficacy and an acceptable safety profile in patients with metastatic PC refractory to gemcitabine-based treatment.
Collapse
Affiliation(s)
- Hiroshi Imaoka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masato Ozaka
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kotoe Oshima
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Naohiro Okano
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Satoshi Shimizu
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Hidetaka Tsumura
- Department of Gastroenterological Oncology, Hyogo Cancer Center, Akashi, Japan
| | - Yoshito Komatsu
- Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Shigeki Kataoka
- Department of Medical Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Terumasa Hisano
- Department of Hepato-Biliary-Pancreatology, NHO Kyushu Cancer Center, Fukuoka, Japan
| | - Mitsuhito Sasaki
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Satoshi Kobayashi
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Taito Fukushima
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Shuichi Mitsunaga
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takaaki Furukawa
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoshi Hamauchi
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Junji Furuse
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| |
Collapse
|
|
4
|
Li X, Chen Y, Qiao G, Ni J, Chen T, Wang Y, Wu C, Zhang Q, Ma T, Gao S, Zhang M, Shen Y, Wu J, Yu J, Que R, Zhang X, Sun K, Xiao W, Jiang T, Bai X, Liang T. 5-Year survival rate over 20 % in pancreatic ductal adenocarcinoma: A retrospective study from a Chinese high-volume center. Cancer Lett 2025; 619:217658. [PMID: 40118244 DOI: 10.1016/j.canlet.2025.217658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 03/18/2025] [Accepted: 03/19/2025] [Indexed: 03/23/2025]
Abstract
Standardized clinical management of pancreatic adenocarcinoma (PDAC) remains challenging and high-volume centers provide essential insights for establishing effective multimodal treatment approaches. This retrospective observational study evaluated the impact of standardized, multimodal clinical management on survival outcomes in patients with PDAC across all stages, based on NCCN guidelines resectability criteria, at a high-volume center. From 2019, 4143 patients were diagnosed with PDAC, with 3268 patients receiving further treatment, including surgical resection and/or systemic therapy. The median overall survival (OS) was 18.5 (95 %CI 17.5-19.4) months for the treated cohort and the 5-year survival rate reached 23.3 %. Patients who underwent surgical resection had significantly improved median OS compared to those who received non-surgical treatments (28.4 months vs. 13.0 months, P < 0.001), with corresponding 5-year survival rates of 31.6 % vs. 15.0 %. Moreover, the patients who received NAT followed by surgical resection had improved survival outcomes compared to those who underwent upfront surgical resection in both resectable (median OS: 37.5 months vs. 28.9 months, P < 0.01) and borderline resectable group (median OS: 31.8 months vs. 18.4 months, P < 0.001). This study demonstrated a 5-year survival rate exceeding 20 % for PDAC across all stages at our center. The application of evidence-based treatment strategies through the multidisciplinary team, accompanying with standardized and comprehensive therapeutic managements, high patient adherence, have been considered as critical determinants in enhancing therapeutic efficacy and improving long-term prognosis for patients with PDAC.
Collapse
Affiliation(s)
- Xiang Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Yiwen Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Guoliang Qiao
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Ni
- Information Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Chen
- Department of Radiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yangyang Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Chengyi Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Tao Ma
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Shunliang Gao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Min Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Yan Shen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Jian Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Jun Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Risheng Que
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Xiaochen Zhang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ke Sun
- Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenbo Xiao
- Department of Radiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tian'an Jiang
- Department of Ultrasound, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China.
| |
Collapse
|
|
5
|
Dreyer SB, Beer P, Hingorani SR, Biankin AV. Improving outcomes of patients with pancreatic cancer. Nat Rev Clin Oncol 2025; 22:439-456. [PMID: 40329051 DOI: 10.1038/s41571-025-01019-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2025] [Indexed: 05/08/2025]
Abstract
Research studies aimed at improving the outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) have brought about limited progress, and in clinical practice, the optimized use of surgery, chemotherapy and supportive care have led to modest improvements in survival that have probably reached a plateau. As a result, PDAC is expected to be the second leading cause of cancer-related death in Western societies within a decade. The development of therapeutic advances in PDAC has been challenging owing to a lack of actionable molecular targets, a typically immunosuppressive microenvironment, and a disease course characterized by rapid progression and clinical deterioration. Yet, the progress in our understanding of PDAC and identification of novel therapeutic opportunities over the past few years is leading to a strong sense of optimism in the field. In this Perspective, we address the aforementioned challenges, including biological aspects of PDAC that make this malignancy particularly difficult to treat. We explore specific areas with potential for therapeutic advances, including targeting mutant KRAS, novel strategies to harness the antitumour immune response and approaches to early detection, and propose mechanisms to improve clinical trial design and to overcome various community and institutional barriers to progress.
Collapse
Affiliation(s)
- Stephan B Dreyer
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
- West of Scotland Hepato-Biliary and Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
- Department of Hepatobiliary Surgery, Royal Liverpool University Hospital, Liverpool, UK
| | - Philip Beer
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
- Hull York Medical School, University of York, York, UK
| | - Sunil R Hingorani
- Department of Internal Medicine, Division of Hemotology/Oncology, University of Nebraska Medical Center, Omaha, NE, USA
- Pancreatic Cancer Center of Excellence, University of Nebraska Medical Center, Omaha, NE, USA
| | - Andrew V Biankin
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.
- West of Scotland Hepato-Biliary and Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
| |
Collapse
|
|
6
|
Leiting JL, Alva-Ruiz R, Yonkus JA, Abdelrahman AM, Lynch IT, Carlson DM, Carr RM, Salomao DR, McWilliams RR, Starlinger PP, Thiels CA, Grotz TE, Warner SG, Cleary SP, Kendrick ML, Smoot RL, Kipp BR, Truty MJ. Molecular KRAS ctDNA Predicts Metastases and Survival in Pancreatic Cancer: A Prospective Cohort Study. Ann Surg Oncol 2025; 32:4453-4463. [PMID: 40067610 PMCID: PMC12049301 DOI: 10.1245/s10434-025-17036-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 02/04/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND Patients with pancreatic ductal adenocarcinoma (PDAC) commonly have occult metastatic dissemination and current standard staging methods have significant limitations in identifying these patients. A clinically available assay allows for the identification of mutant KRAS (mKRAS) circulating tumor DNA (ctDNA) from patient plasma and peritoneal fluid that may identify these patients and impact treatment decision making. We investigated the patterns of diagnostic and prognostic capabilities of mKRAS ctDNA in patients with localized PDAC. METHODS Patients with non-metastatic PDAC were identified and underwent a full staging work-up during their first visit at our institution. Development of metastatic disease and long-term survival outcomes were assessed to compare between the mKRAS testing groups. RESULTS Between 2018 and 2022, 785 patients were evaluated. Among the 785 patients who underwent plasma mKRAS testing, 104 were mKRAS positive. Plasma mKRAS-positive patients were more likely to develop metastatic disease and had worse overall survival. In the 419 patients who underwent peritoneal mKRAS, 123 were mKRAS-positive and were more likely to harbor occult metastases or develop peritoneal rather than hematogenous metastases. For patients who underwent both baseline plasma and peritoneal mKRAS testing, any positive mKRAS test regardless of compartment was associated with worse outcomes. CONCLUSIONS Detection of mKRAS ctDNA in plasma and peritoneal fluid of patients with localized PDAC is not only feasible but also identifies those at high risk of metastatic progression and worse survival outcomes. It allows for better prognostication and can significantly impact subsequent treatment decisions, particularly in patients where an aggressive surgical approach is being considered.
Collapse
Affiliation(s)
- Jennifer L Leiting
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Roberto Alva-Ruiz
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Jennifer A Yonkus
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Amro M Abdelrahman
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Isaac T Lynch
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Danielle M Carlson
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Ryan M Carr
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Diva R Salomao
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Patrick P Starlinger
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Cornelius A Thiels
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Travis E Grotz
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Susanne G Warner
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Sean P Cleary
- Division of General Surgery, University of Toronto, Toronto, ON, Canada
| | - Michael L Kendrick
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Rory L Smoot
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Benjamin R Kipp
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Mark J Truty
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
7
|
Chuong MD, Ashman J, Jethwa K, Kharofa J, Kim H, Koay E, Ludmir E, Miller E, Nelson B, Reyngold M, Sanford N, Chang D. Moving From the Background Toward the Spotlight: A Critical Review of Radiation Therapy for Locally Advanced Pancreas Cancer. Int J Radiat Oncol Biol Phys 2025; 122:294-312. [PMID: 40032056 DOI: 10.1016/j.ijrobp.2025.02.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 01/31/2025] [Accepted: 02/16/2025] [Indexed: 03/05/2025]
Abstract
Radiation therapy (RT) for locally advanced pancreatic cancer (LAPC) continues to be controversial. Advances in both systemic therapy and RT techniques have changed the landscape of LAPC management in recent years. Clinical outcomes of ablative RT have been encouraging, and randomized clinical trials may clarify the role of RT for LAPC. We present a contemporary critical review of key aspects regarding optimal patient selection, radiation dose escalation techniques, novel radiosensitizers and radioprotectors, and treatment response assessment for LAPC.
Collapse
Affiliation(s)
- Michael D Chuong
- Department of Radiation Oncology, Miami Cancer Institute, Miami, Florida.
| | - Jonathan Ashman
- Department of Radiation Oncology, Mayo Clinic Arizona, Scottsdale, Arizona
| | - Krishan Jethwa
- Department of Radiation Oncology, Mayo Clinic Rochester, Rochester, Minnesota
| | - Jordan Kharofa
- Department of Radiation Oncology, University of Cincinnati, Cincinnati, Ohio
| | - Hyun Kim
- Department of Radiation Oncology, Washington University in St. Louis, Missouri.
| | - Eugene Koay
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ethan Ludmir
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eric Miller
- Department of Radiation Oncology, Ohio State University, Columbus, Ohio
| | - Bailey Nelson
- Department of Radiation Oncology, University of Cincinnati, Cincinnati, Ohio
| | - Marsha Reyngold
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nina Sanford
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Daniel Chang
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
| |
Collapse
|
|
8
|
Yamaguchi T, Kitahara S, Matsui A, Okamoto J, Muragaki Y, Masamune K. HIFU induces reprogramming of the tumor immune microenvironment in a pancreatic cancer mouse model. Med Mol Morphol 2025; 58:137-148. [PMID: 39870899 DOI: 10.1007/s00795-025-00419-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 01/06/2025] [Indexed: 01/29/2025]
Abstract
This study evaluates the effects of different high-intensity focused ultrasound irradiation (HIFU) methods on local tumor suppression and systemic antitumor effects, including the abscopal effect, in a mouse model of pancreatic cancer. To ascertain the efficacy of the treatment, pancreatic cancer cells were injected into the thighs of mice and HIFU was applied on one side using continuous waves or trigger pulse waves. Then, tumor volume, tissue changes, and immune marker levels were analyzed. Both the irradiation methods suppressed tumor growth, with the trigger pulse wave showing stronger effects and the difference being significant. Tumor suppression was also observed on the non-irradiated side, suggesting an abscopal effect. These effects vary depending on the irradiation method used. We conclude that HIFU induces both local tumor suppression and a systemic immune response, suggesting its potential for combination with immunotherapy for the treatment of pancreatic cancer.
Collapse
Affiliation(s)
- Toshihiro Yamaguchi
- Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku, Tokyo, 162-8666, Japan
| | - Shuji Kitahara
- Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku, Tokyo, 162-8666, Japan.
| | - Aya Matsui
- Department of Vascular Physiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8640, Japan
| | - Jun Okamoto
- SONIRE Therapeutics Inc., Nihonbashi Life Science, Building 2 803, 3-11-5 Nihonbashi Honcho, Chuo-Ku 103-0023, Tokyo, Japan
| | - Yoshihiro Muragaki
- Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku, Tokyo, 162-8666, Japan
- Center for Advanced Medical Engineering Research and Development, Kobe University, 1-5-1 Minatojima Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Ken Masamune
- Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku, Tokyo, 162-8666, Japan.
| |
Collapse
|
|
9
|
Reiss KA, Soares KC, Torphy RJ, Gyawali B. Treatment Innovations in Pancreatic Cancer: Putting Patient Priorities First. Am Soc Clin Oncol Educ Book 2025; 45:e473204. [PMID: 40173379 DOI: 10.1200/edbk-25-473204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2025]
Abstract
Pancreatic adenocarcinoma remains one of the most aggressive and difficult-to-treat solid tumor malignancies, with a high mortality-to-incidence ratio. Globally, pancreatic cancer ranks 12th in terms of incidence but sixth for mortality signifying its aggressive behavior and limited treatment options. While the mortality rates for many other solid tumors have substantially improved over the past few decades, temporal trends in pancreatic cancer mortality rates are quite sobering. In the United States, from 2000 to 2020, the mortality rates from pancreatic cancer have increased, whereas at the same time, mortality rates from other cancers, such as lung, colorectal, or kidney, have fallen appreciably. Is this for lack of treatment innovation? How do we improve survival for patients with pancreatic cancer? In this chapter, we discuss the recent advances and future directions with targeted therapies and immunotherapies in the treatment of pancreatic cancer, and provide the reasons for both optimism and caution for the future of systemic treatment of pancreatic cancer.
Collapse
Affiliation(s)
- Kim A Reiss
- Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | - Kevin C Soares
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Robert J Torphy
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Bishal Gyawali
- Department of Oncology, Queen's University, Kingston, Canada
- Division of Cancer Care and Epidemiology, Queen's University, Kingston, Canada
- Department of Public Health Sciences, Queen's University, Kingston, Canada
| |
Collapse
|
|
10
|
Gupta T, Murtaza M. Advancing targeted therapies in pancreatic cancer: Leveraging molecular abberrations for therapeutic success. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 196:19-32. [PMID: 39988056 DOI: 10.1016/j.pbiomolbio.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 02/03/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
Pancreatic cancer is one of the most deadly with poor prognosis and overall survival rate due to the dense stroma in the tumors which often is challenging for the delivery of drug to penetrate deep inside the tumor bed and usually results in the progression of cancer. The conventional treatment such as chemotherapy, radiotherapy or surgery shows a minimal benefit in the survival due to the drug resistance, poor penetration, less radiosensitivity or recurrence of tumor. There is an urgent demand to develop molecular-level targeted therapies to achieve therapeutic efficacy in the pancreatic ductal adenocarcinoma (PDAC) patients. The precision oncology focuses on the unique attributes of the patient such as epigenome, proteome, genome, microbiome, lifestyle and diet habits which contributes to promote oncogenesis. The targeted therapy helps to target the mutated proteins responsible for controlling growth, division and metastasis of tumor in the cancer cells. It is very important to consider all the attributes of the patient to provide the suitable personalized treatment to avoid any severe side effects. In this review, we have laid emphasis on the precision medicine; the utmost priority is to improve the survival of cancer patients by targeting molecular mutations through transmembrane proteins, inhibitors, signaling pathways, immunotherapy, gene therapy or the use of nanocarriers for the delivery at the tumor site. It will become beneficial therapeutic window to be considered for the advanced stage pancreatic cancer patients to prolong their survival rate.
Collapse
Affiliation(s)
- Tanvi Gupta
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan.
| | - Mohd Murtaza
- Fermentation & Microbial Biotechnology Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180016, India.
| |
Collapse
|
|
11
|
Brada LJH, Schouten TJ, Daamen LA, Seelen LWF, Walma MS, van Dam R, de Hingh IH, Liem MSL, de Meijer VE, Patijn GA, Festen S, Stommel MWJ, Bosscha K, Besselink MG, van Santvoort HC, Molenaar IQ. Evaluation of Short and Long-term Outcomes After Resection in Patients With Locally Advanced Versus (Borderline) Resectable Pancreatic Cancer. Ann Surg 2025; 281:1026-1031. [PMID: 38557955 DOI: 10.1097/sla.0000000000006289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
OBJECTIVE To evaluate short and long-term outcomes after pancreatectomy in patients with locally advanced pancreatic cancer (LAPC) compared with patients with (borderline) resectable pancreatic cancer [(B)RPC]. BACKGROUND Selected patients diagnosed with LAPC are increasingly undergoing resection after induction chemotherapy. To evaluate the benefit of this treatment approach, it is helpful to compare outcomes in resected patients with primary LAPC to outcomes in resected patients with primary (B)RPC. METHODS Two prospectively maintained nationwide databases were used for this study. Patients with (B)RPC undergoing upfront tumor resection and patients with resected LAPC after induction therapy were included. Outcomes were postoperative pancreas-specific complications, 90-day mortality, pathologic outcomes, disease-free interval, and overall survival. RESULTS Overall, 879 patients were included; 103 with LAPC (12%) and 776 with (B)RPC (88%). Patients with LAPC had a lower World Health Organization performance score and ageadjusted Charlson Comorbidity Index. Postoperative pancreas-specific complications were comparable between groups, except delayed gastric emptying grade C, which occurred more often in patients with LAPC (9% vs 3%, P = 0.03). Ninety-day mortality was comparable. About half of the patients in both groups [54% in LAPC vs 48% in (B)RPC, P = 0.21] had a radical resection (R0). Disease-free interval was 13 months in both groups ( P = 0.12) and overall survival from the date of diagnosis was 24 months in patients with LAPC and 19 months in patients with (B)RPC ( P = 0.34). CONCLUSIONS In our nationwide prospective databases, pancreas-specific complications, mortality, and survival in patients with LAPC after pancreatectomy are comparable with those undergoing resection for (B)RPC. These outcomes suggest that postoperative morbidity and mortality after tumor resection in carefully selected patients with LAPC are acceptable.
Collapse
Affiliation(s)
- Lilly J H Brada
- Department of Surgery, UMC Utrecht Cancer Center and St Antonius Hospital Nieuwegein, Regional Academic Cancer Center Utrecht, Utrecht, The Netherlands
- Department of Surgery, Amsterdam UMC, Location University of Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
| | - Thijs J Schouten
- Department of Surgery, UMC Utrecht Cancer Center and St Antonius Hospital Nieuwegein, Regional Academic Cancer Center Utrecht, Utrecht, The Netherlands
| | - Lois A Daamen
- Department of Surgery, UMC Utrecht Cancer Center and St Antonius Hospital Nieuwegein, Regional Academic Cancer Center Utrecht, Utrecht, The Netherlands
| | - Leonard W F Seelen
- Department of Surgery, UMC Utrecht Cancer Center and St Antonius Hospital Nieuwegein, Regional Academic Cancer Center Utrecht, Utrecht, The Netherlands
| | - Marieke S Walma
- Department of Surgery, UMC Utrecht Cancer Center and St Antonius Hospital Nieuwegein, Regional Academic Cancer Center Utrecht, Utrecht, The Netherlands
| | - Ronald van Dam
- Department of Surgery, Maastricht UMC+, Maastricht, The Netherlands
- Department of General and Viseral Surgery, University Hospital Aachen, Aachen, Germany
| | - Ignace H de Hingh
- Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Aachen, Maastricht, The Netherlands
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
| | - Mike S L Liem
- Department of Surgery, Medical Spectrum Twente, Enschede, The Netherlands
| | - Vincent E de Meijer
- Department of Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Gijs A Patijn
- Department of Surgery, Isala, Zwolle, The Netherlands
| | | | - Martijn W J Stommel
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Koop Bosscha
- Department of Surgery, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands
| | - Marc G Besselink
- Department of Surgery, Amsterdam UMC, Location University of Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
| | - Hjalmar C van Santvoort
- Department of Surgery, UMC Utrecht Cancer Center and St Antonius Hospital Nieuwegein, Regional Academic Cancer Center Utrecht, Utrecht, The Netherlands
| | - Izaak Quintus Molenaar
- Department of Surgery, UMC Utrecht Cancer Center and St Antonius Hospital Nieuwegein, Regional Academic Cancer Center Utrecht, Utrecht, The Netherlands
| |
Collapse
|
|
12
|
Enzler T, Frankel TL. Pancreatic cancer precursor lesions - Can immunotherapy prevent progression into pancreatic ductal adenocarcinoma? Cancer Lett 2025; 619:217662. [PMID: 40127814 DOI: 10.1016/j.canlet.2025.217662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 02/26/2025] [Accepted: 03/19/2025] [Indexed: 03/26/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a 5-year survival rate of only 12.5 %. Early detection of PDAC or addressing risk factors for PDAC development are ways to improve outcomes. PDAC can arise from precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and less frequent, mucinous cystic neoplasm (MCN), and other rare precursor variants. High-risk precursor lesions harbor a substantial chance of evolving into PDAC. Such lesions can often be found in resected PDAC specimens adjacent to the cancer. Unfortunately, recognizing precursor lesions that need to be resected is often tricky, and resections frequently end in major surgical interventions. Thus, better ways to handle precursor lesions are desperately needed. We mapped the immune microenvironments (IMEs) of PanINs, IPMNs, and MCNs on a cellular level using multiplex immunofluorescence and computational imaging technology and compared the findings to PDACs and normal pancreatic tissues. We found distinct and potentially targetable mechanisms of immunosuppression between the two main precursor lesions, PanIN and IMPN. Immunosuppression in IPMNs seems partly mediated by programmed cell death protein 1 ligand (PD-L1) expression on antigen-presenting cells (APCs). By contrast, elevated numbers of regulatory T cells (Tregs) seem to be key players in the immunosuppression of PanINs. Thus, treating high-risk IPMNs with anti-PD-1 and high-risk PanINs with agents targeting Tregs, such as anti-lymphocyte associated protein 4 (anti-CTLA-4) antibodies, could reverse their immunosuppressive state. Reversal of immunosuppression will restore immunosurveillance and eventually prevent progression into PDAC. We also review relevant published and ongoing non-surgical treatment approaches for high-risk IPMNs and PanINs.
Collapse
Affiliation(s)
- Thomas Enzler
- Department of Medicine, University of Michigan, Ann Arbor, MI, 40109, USA.
| | - Timothy L Frankel
- Department of Surgery, University of Michigan, Ann Arbor, MI, 40109, USA
| |
Collapse
|
|
13
|
Babiker HM, Picozzi V, Chandana SR, Melichar B, Kasi A, Gang J, Gallego J, Bullock A, Chunyi H, Wyrwicz L, Hitre E, Osipov A, de la Fouchardiere C, Ales I, Dragovich T, Lee W, Feeney K, Philip P, Ueno M, Van Cutsem E, Seufferlein T, Macarulla T, PANOVA-3 Study Investigators. Tumor Treating Fields With Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study. J Clin Oncol 2025:JCO2500746. [PMID: 40448572 DOI: 10.1200/jco-25-00746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Collaborators] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 04/25/2025] [Accepted: 05/01/2025] [Indexed: 06/02/2025] Open
Abstract
PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m2 and nab-paclitaxel 125 mg/m2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.
Collapse
Affiliation(s)
| | | | | | - Bohuslav Melichar
- Palacky University and University Hospital Olomouc, Olomouc, Czech Republic
| | - Anup Kasi
- University of Kansas Cancer Center, Kansas City, KS
| | - Jin Gang
- Changhai Hospital, Shanghai, People's Republic of China
| | | | - Andrea Bullock
- Harvard Medical School, Harvard University, Boston, MA
- Beth Israel Deaconess Medical Center, Boston, MA
| | - Hao Chunyi
- Beijing Cancer Hospital, Beijing, People's Republic of China
| | - Lucjan Wyrwicz
- National Institute of Oncology, Maria Sklodowska Curie National Cancer Research Institute, Warsaw, Poland
| | - Erika Hitre
- National Institute of Oncology, Budapest, Hungary
| | | | | | | | | | - Woojin Lee
- National Cancer Center, Goyang, Republic of Korea
| | - Kynan Feeney
- St John of God Murdoch Hospital, Murdoch, WA, Australia
| | | | | | | | | | - Teresa Macarulla
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | |
Collapse
Collaborators
David Spigel, Arsen Osipov, Marc Matrana, Nicholas Blondin, Emil Lou, Rachna Shroff, Douglas Orr, Michael Anderson, Anthony Shields, John Hamm, Andrea Bullock, Sumana Nagireddy, Joanna Kolodney, Tomislav Dragovich, Andrew Coveler, Ajit Maniam, Vincent Picozzi, Judith Sears, Joseph Stilwill, Francis Arena, Mike Cusnir, Anna Niewiaroska, William Small, Anup Kasi, Jason Tache, Sharona Ross, Samer Shihabi, Sunil Gandhi, James Reeves, Garrett Green, Trevor Feinstein, Timothy Huyck, Nadia Ramdin, Robert Marsh, Yixing Jiang, Hassan Hatoum, Sudhir Manda, Mark Kochenderfer, Henrik Illum, Donald Richards, Panagiotis Valilis, Lucas Wong, Sreenivasa Chandana, Herbert Newton, Maen Abdelrahim, David Einspahr, Richard Siegel, Scott McKenney, Mohit Narang, Marc Uemura, Higinia Cardenes, Kannan Thanikachalam, Joshua Raff, Joseph Ye, Deepti Behl, Audrey Kam, Paul DeRose, Ali Tasneem, Warren Brenner, Jennifer De Los Santos, James Wang, Daniel Rausch, Gaurav Trikha, David Park, Nashat Gabrail, Rex Mowat, Khawaja Jahangir, Robert Schumaker, Edward Soffen, Eric Bravin, Mukul Gupta, Hani Babiker, Ivan Bedoya-Apraez, Tyler Kang, Frederic Lemay, Mark Vincent, Richard Letourneau, Martin Fuchs, Thomas Theodor Werner Seufferlein, Christine Doehring, Mike Haberkorn, Arndt Vogel, Karen Russwurm, Jack Chater, Marc Küng, Sabine Schacher, Maria Passhak, Ravit Geva, Ayala Hubert, Salomon Stemmer, Talia Golan, Hélène Senellart, Isabelle Trouilloud, Christelle de la Fouchardière, Jean-Frederic Blan, Luis-Marie Dourthe, Florence Le Roy, Jerôme Martin-Babau, Meher Ben Abdelghani, Richard Greil, Georg Schreil, Armin Gerger, Wolfgang Eisterer, Teresa Macarulla Mercadé, Antonio Cubillo, Francesc Valladares Pons, Carmen Guillen Ponce, Inmaculada Ales Diaz, Fernando Rivera, Javier Gallego Plazas, Ricardo Yaya, Mariano Ponz Sarvise, Bruno Vincenzi, Mario Airoldi, Giovanna Bellotti, Domenico Cristiano Corsi, Lorenzo Antonuzzo, Bohuslav Melichar, Petra Holeckova, Lubos Petruzelka, Rostislav Kotasek, Radim Nemecek, Eric van Cutsem, Jean-Luc van Laethem, Ivan Borbath, Jun Eul Hwang, Sung Yong Oh, Sun Jin Sym, Moon Hee Lee, Jin Young Kim, Sang Cheul Oh, Woo Jin Lee, Joon Oh Park, Jin Won Kim, Myung Ah Lee, Hye Jin Choi, Seok Yun Kang, Hong Jae Chon, Lucjan Wyrwicz, Rodryg Ramlau, Andrzej Mruk, Beata Freier, Ewa Kosakowska, Judit Kocsis, Tibor Csoszi, Erika Hitre, Yousuf Al-Farhat, Ali Bassam, Chunyi Hao, Bo Liang, Shundong Cang, Gang Jin, Changzeng Zuo, Lijie Song, Zheng Wu, Jie Gao, Tao Zhang, Yusheng Wang, Xinaglin Yuan, Zhihua Li, Rufu Chen, Wei Li, Xiujun Cai, Zhizhen Zhu, Yuxian Bai, Chunmei Bai, Thomas Yau, Warren Joubert, Ka Yeung Mark Wong, Gavin Marx, Kynan Feeney, Marion Harris, Ana Misir, Adilson Faccio, Felipe Cruz, Srergio De Azevedo, Ana Paula De Souza Victorino, Tadeu Ferreira de Paiva, Fabio Andre Franke, Katsuki Arima Tiscoski, Gabriel Parolla, Flora Lilno, Mariana Bruno Siqueira, Marcos Lyra, Paulo Hoff, Jose Luis Martinez Lira, Dolores Mendoza Oliva, Arturo Vazquez, Jesus Elvis Cabrera Luviano, Erika Castillo Gutierrez, Vanessa Rosas Camargo, Cristian Chavez Guerra, Osvaldo Hernandez Flores, David Orta Cortez, Saul Campos, Ivan Romarico González Espinoza, Jessica Reyes Contreras, Angel Gomez Villanueva, Omar Zayas Villanueva,
Collapse
|
|
14
|
Vera RE, Fernadez-Barrena MG, Falero JM, Kwon JY, Garza RA, Sigafoos AN, Ross MD, Toruner MD, Toruner M, Tolosa EJ, Almada LL, Huang H, Brekken RA, Fernandez-Zapico ME. Paracrine regulation of pancreatic cancer cell response to chemotherapy by GLI2-Collagen I signaling. J Biol Chem 2025:110311. [PMID: 40449600 DOI: 10.1016/j.jbc.2025.110311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 05/08/2025] [Accepted: 05/25/2025] [Indexed: 06/03/2025] Open
Abstract
Despite the well described role of non-cellular components of the tumor microenvironment (TME) in regulating tumor growth, the molecular events dictating expression and biological functions of key components of the TME remain elusive. Here, using pancreatic cancer (PC) models, we describe a novel mechanism through which the zinc finger transcription factor GLI2 in cancer associated fibroblasts (CAFs) induces expression of COL1A1, which is a major component of Type I Collagen, the most abundant collagen variant in the tumor milieu. Bulk and single nuclei RNA-Seq showed that GLI2 expression in CAF strongly correlates with COL1A1 expression levels, fibrosis, and CAF activation. ChIP-qPCR and expression studies of the PC matrisome identified COL1A1 as the direct target of GLI2 in CAFs. We also provide evidence that GLI2 is an effector that mediates COL1A1 induction by transforming growth factor β1 (TGFβ1). RNA-Seq analysis of PC cells treated with Type I Collagen revealed enrichment of chemotherapeutic gene expression profiles, which includes irinotecan resistance signature. Viability studies confirmed that Type I Collagen promotes irinotecan resistance in PC cells. Altogether, our results uncover a novel role for the TGFβ1-GLI2 axis within CAFs to modulate Type I Collagen expression and promote chemoresistance in PC cells. Together, our findings help increase the understanding of the complex molecular network operating in the TME.
Collapse
Affiliation(s)
- Renzo E Vera
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN
| | | | - Jose M Falero
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN
| | - John Y Kwon
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN
| | - Roberto A Garza
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN
| | - Ashley N Sigafoos
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN
| | - Matthew D Ross
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN
| | - Merih Deniz Toruner
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN
| | - Murat Toruner
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN
| | - Ezequiel J Tolosa
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN
| | - Luciana L Almada
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN
| | - Huocong Huang
- Departments of Surgery and Immunology, Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, TX
| | - Rolf A Brekken
- Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, TX
| | | |
Collapse
|
|
15
|
Mahalingam D, Saeed A, Powell SF, Huerta M, Sahai V, Coveler AL, Davis EJ, Steeghs N, Mulcahy M, Raufi AG, Cavalcante L, Cervantes A, Berlin J, Weisskittel T, Ugolkov A, Mazar AP, Mikrut W, Smith S, Giles FJ, Carneiro BA. Phase II study of elraglusib (9-ING-41), a GSK-3β inhibitor, in combination with gemcitabine plus nab-paclitaxel in previously untreated metastatic pancreatic cancer. ESMO Open 2025; 10:105122. [PMID: 40403387 DOI: 10.1016/j.esmoop.2025.105122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 04/18/2025] [Accepted: 04/22/2025] [Indexed: 05/24/2025] Open
Abstract
INTRODUCTION The purpose of this study was to assess the efficacy and safety of elraglusib (9-ING-41), a GSK-3β inhibitor, in combination with gemcitabine/nab-paclitaxel (GnP) in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC). MATERIAL AND METHODS In a nonrandomized, Simon's two-stage, phase II study, patients with mPDAC received elraglusib 15 mg/kg on days 1 and 4 each week and GnP on days 1, 8, and 15 in a 28-day cycle. The primary endpoint was disease control rate (DCR); secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-emergent adverse events (TEAEs). RESULTS A total of 42 patients, who were enrolled and treated, had a median age of 67 years and were 57.1% male. Overall, 38 patients received elraglusib at 15 mg/kg and 4 at 9.3 mg/kg with GnP. DCR was 35.7% [95% confidence interval (CI) 21.6% to 52.0%], and ORR was 26.2%. The median PFS and OS were 5.4 months (95% CI 4.4-9.2 months) and 11.9 months (95% CI 7.8-16.5 months), respectively. Most common TEAEs were visual impairment (83.3%), fatigue (69%), and nausea (66.7%). Grade ≥3 TEAEs occurred in 85.7% of patients and included neutropenia (52.4%), leukopenia (42.9%), and fatigue (21.4%). The dose of elraglusib was reduced to 9.3 mg/kg due to increased exacerbation of GnP-related toxicities and frequent dose interruptions and reductions of elraglusib. CONCLUSIONS Elraglusib/GnP showed preliminary clinical activity. In terms of safety, elraglusib resulted in a modest exacerbation of GnP-related toxicities, leading to a dose reduction of elraglusib to 9.3 mg/kg twice a week. Based on the initial efficacy and safety data, the study was amended to a randomized phase II study that will evaluate the 9.3 mg/kg dose.
Collapse
Affiliation(s)
| | - A Saeed
- University of Pittsburgh Medical Center (UPMC) and Hillman Cancer Center, Pittsburgh, USA
| | | | - M Huerta
- INCLIVA Biomedical Research Institute, Hospital Clínico, University of Valencia, Valencia, Spain
| | - V Sahai
- University of Michigan, Ann Arbor, USA
| | | | - E J Davis
- Vanderbilt-Ingram Cancer Center, Nashville, USA
| | - N Steeghs
- Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - M Mulcahy
- Northwestern University, Chicago, USA
| | - A G Raufi
- Legorreta Cancer Center, Brown University, Lifespan Cancer Institute, Providence, USA
| | | | - A Cervantes
- INCLIVA Biomedical Research Institute, Hospital Clínico, University of Valencia, Valencia, Spain
| | - J Berlin
- Vanderbilt-Ingram Cancer Center, Nashville, USA
| | | | - A Ugolkov
- Actuate Therapeutics, Inc., Fort Worth, USA
| | - A P Mazar
- Actuate Therapeutics, Inc., Fort Worth, USA
| | - W Mikrut
- Vantage Data Designs, Austin, USA
| | - S Smith
- Courante Oncology, Excelsior, USA
| | - F J Giles
- Developmental Therapeutics LLC, Chicago, USA
| | - B A Carneiro
- Legorreta Cancer Center, Brown University, Lifespan Cancer Institute, Providence, USA
| |
Collapse
|
|
16
|
Konstantinidis I, Tsokkou S, Katsikeros D, Chatzikomnitsa P, Papakonstantinou M, Liampou E, Toutziari E, Giakoustidis D, Bageas P, Papadopoulos V, Giakoustidis A, Papamitsou T. The Role of Nanoparticles in Therapy of Real-World Patients with Pancreatic Cancer: A Scoping Review. Cancers (Basel) 2025; 17:1726. [PMID: 40427222 PMCID: PMC12109742 DOI: 10.3390/cancers17101726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2025] [Revised: 05/07/2025] [Accepted: 05/20/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive and fatal malignancies worldwide, posing a significant global health challenge due to its high mortality rates, late-stage diagnosis, and limited therapeutic efficacy [...].
Collapse
Affiliation(s)
- Ioannis Konstantinidis
- Department of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Sophia Tsokkou
- Department of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
- First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece; (P.C.); (M.P.); (E.L.); (E.T.); (D.G.); (P.B.); (V.P.); (A.G.)
| | - Dimitrios Katsikeros
- Faculty of Medicine, School of Health Sciences, University of Thessaly, 41334 Larissa, Greece;
| | - Paraskevi Chatzikomnitsa
- First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece; (P.C.); (M.P.); (E.L.); (E.T.); (D.G.); (P.B.); (V.P.); (A.G.)
| | - Menelaos Papakonstantinou
- First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece; (P.C.); (M.P.); (E.L.); (E.T.); (D.G.); (P.B.); (V.P.); (A.G.)
| | - Eftychia Liampou
- First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece; (P.C.); (M.P.); (E.L.); (E.T.); (D.G.); (P.B.); (V.P.); (A.G.)
| | - Evdokia Toutziari
- First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece; (P.C.); (M.P.); (E.L.); (E.T.); (D.G.); (P.B.); (V.P.); (A.G.)
| | - Dimitrios Giakoustidis
- First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece; (P.C.); (M.P.); (E.L.); (E.T.); (D.G.); (P.B.); (V.P.); (A.G.)
| | - Petros Bageas
- First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece; (P.C.); (M.P.); (E.L.); (E.T.); (D.G.); (P.B.); (V.P.); (A.G.)
| | - Vasileios Papadopoulos
- First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece; (P.C.); (M.P.); (E.L.); (E.T.); (D.G.); (P.B.); (V.P.); (A.G.)
| | - Alexandros Giakoustidis
- First Department of Surgery, General Hospital Papageorgiou, Aristotle University of Thessaloniki, 56429 Thessaloniki, Greece; (P.C.); (M.P.); (E.L.); (E.T.); (D.G.); (P.B.); (V.P.); (A.G.)
| | - Theodora Papamitsou
- Laboratory of Histology-Embryology, Department of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| |
Collapse
|
|
17
|
Rincon-Torroella J, Dal Molin M, Mog B, Han G, Watson E, Wyhs N, Ishiyama S, Ahmedna T, Minn I, Azad N, Bettegowda C, Papadopoulos N, Kinzler KW, Zhou S, Vogelstein B, Gabrielson K, Sur S. ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1. eLife 2025; 13:RP94488. [PMID: 40391649 PMCID: PMC12092006 DOI: 10.7554/elife.94488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2025] Open
Abstract
Nearly 30% of pancreatic ductal adenocarcinomas (PDACs) exhibit a marked overexpression of monocarboxylate transporter 1 (MCT1) offering a unique opportunity for therapy. However, biochemical inhibitors of MCT1 have proven unsuccessful in clinical trials. In this study, we present an alternative approach using 3-bromopyruvate (3BP) to target MCT1 overexpressing PDACs. 3BP is a cytotoxic agent that is known to be transported into cells via MCT1, but its clinical usefulness has been hampered by difficulties in delivering the drug systemically. We describe here a novel microencapsulated formulation of 3BP (ME3BP-7), which is effective against a variety of PDAC cells in vitro and remains stable in serum. Furthermore, systemically administered ME3BP-7 significantly reduces pancreatic cancer growth and metastatic spread in multiple orthotopic models of pancreatic cancer with manageable toxicity. ME3BP-7 is, therefore, a prototype of a promising new drug, in which the targeting moiety and the cytotoxic moiety are both contained within the same single small molecule.
Collapse
Affiliation(s)
- Jordina Rincon-Torroella
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Neurosurgery, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Marco Dal Molin
- Department of Surgery, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Brian Mog
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Howard Hughes Medical InstituteChevy ChaseUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Biomedical Engineering, Johns Hopkins UniversityBaltimoreUnited States
| | - Gyuri Han
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Evangeline Watson
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Nicolas Wyhs
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Pathology, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Shun Ishiyama
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins UniversityBaltimoreUnited States
| | - Taha Ahmedna
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins UniversityBaltimoreUnited States
| | - Il Minn
- Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Nilofer Azad
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Chetan Bettegowda
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Neurosurgery, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| | - Nickolas Papadopoulos
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| | - Kenneth W Kinzler
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Pathology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| | - Shibin Zhou
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| | - Bert Vogelstein
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Howard Hughes Medical InstituteChevy ChaseUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Pathology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| | - Kathleen Gabrielson
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Pathology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins UniversityBaltimoreUnited States
| | - Surojit Sur
- Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUnited States
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer CenterBaltimoreUnited States
| |
Collapse
|
|
18
|
Ducreux M, Desgrippes R, Rinaldi Y, Di Fiore F, Guimbaud R, Evesque L, Bachet JB, Vanelslander P, Lecomte T, Capitain O, Parzy A, Bolliet M, Etienne PL, Forestier J, El Hajbi F, Bignon AL, Lebrun-Ly V, De Sousa Carvalho N, Texier M, Bouche O. PRODIGE 29-UCGI 26 (NEOPAN): A Phase III Randomized Trial Comparing Chemotherapy With FOLFIRINOX or Gemcitabine in Locally Advanced Pancreatic Carcinoma. J Clin Oncol 2025:JCO2402210. [PMID: 40378359 DOI: 10.1200/jco-24-02210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 03/11/2025] [Accepted: 04/03/2025] [Indexed: 05/18/2025] Open
Abstract
PURPOSE More than 30% of patients with pancreatic cancer are unresectable because of the local extension with a median overall survival (OS) of <1 year. Combination of fluorouracil (FU), oxaliplatin, and irinotecan (FOLFIRINOX) is superior to gemcitabine in the treatment of metastatic pancreatic cancer, but standard of care remains gemcitabine in locally advanced pancreatic cancer (LAPC). METHODS Patients with histologically proven LAPC not suitable for surgery, Eastern Cooperative Oncology Group WHO performance status (PS) ≤1 were eligible. Random assignment was stratified by center, tumor localization (pancreas head yes/no), WHO PS (0 v 1), and age (≤60 years v >60 years). Patients received FOLFIRINOX or gemcitabine for 6 months. The primary end point was progression-free survival (PFS). Main secondary end points were OS, time to treatment failure, quality of life, and safety. One hundred seventy patients (142 events) were needed to detect an increase of 3 months in PFS with 80% power (log-rank test, 5% two-sided α). RESULTS One hundred seventy one patients age 35-84 years were included and followed for a maximum of 5 years. With a median follow-up of 59.6 months (95% CI, 42.3 to not reached), 168 events were observed and the median PFS was 9.7 months (95% CI, 7.0 to 11.7) with FOLFIRINOX versus 7.7 months (95% CI, 6.2 to 9.2) with gemcitabine, hazard ratio (HR), 0.7 (95% CI, 0.5 to 1.0), P = .04. The median OS was 15.7 months (95% CI, 11.9 to 20.4) in the FOLFIRINOX group versus 15.4 months (95% CI, 11.7 to 18.6) in the gemcitabine group, HR, 1.02 (95% CI, 0.73 to 1.43), P = .95. CONCLUSION Results confirm that FOLFIRINOX improves PFS significantly compared with gemcitabine and is well tolerated in LAPC. No significant difference in OS was observed between both groups.
Collapse
Affiliation(s)
- Michel Ducreux
- Gustave Roussy Cancer Center, Tumor Cells Dynamics, INSERM U1279, Université Paris-Saclay, Villejuif, France
| | - Romain Desgrippes
- Hepato-Gastroenterology and Digestive Oncology Department, Centre Hospitalier de Saint Malo, Saint Malo, France
| | | | - Frédéric Di Fiore
- Gastroenterology, CHU Hôpitaux de Rouen-Charles Nicolle, Rouen, France
| | - Rosine Guimbaud
- Digestive Oncology, Centre Hospitalier Rangueil, Toulouse, France
| | | | - Jean-Baptiste Bachet
- Sorbonne University, Hepato-Gastroenterology Department, Groupe Hospitalier Pitié Salpetrière, APHP, Paris, France
| | | | - Thierry Lecomte
- Hepatogastroenterology and Digestive Oncology Departement, Hôpital Trousseau, Chambray-Les-Tours, France
| | - Olivier Capitain
- Medical Oncology, Institut de Cancérologie de l'Ouest-Centre Paul Papin, Angers, France
| | - Aurélie Parzy
- Digestive Pathology, Centre Francois Baclesse, Caen, France
| | - Marion Bolliet
- Gastroenterology, Hôpitaux Civils de Colmar, Colmar, France
| | - Pierre-Luc Etienne
- Medical Oncology, Hôpital Privé des Côtes d'Armor, Plerin sur Mer, France
| | | | - Farid El Hajbi
- Urology and Digestive Oncology, Centre Oscar Lambret, Lille, France
| | | | | | | | - Matthieu Texier
- Biostatistics, Gustave Roussy Institut de Cancérologie, Villejuif, France
| | | |
Collapse
|
|
19
|
Selvi S, Real CM, Gentiluomo M, Balounova K, Vokacova K, Cumova A, Mohlenikova-Duchonova B, Rizzato C, Halasova E, Vodickova L, Smolkova B, Hemminki K, Campa D, Vodicka P. Genomic instability, DNA damage response and telomere homeostasis in pancreatic cancer. Semin Cancer Biol 2025; 113:59-73. [PMID: 40378535 DOI: 10.1016/j.semcancer.2025.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 04/16/2025] [Accepted: 05/04/2025] [Indexed: 05/19/2025]
Abstract
Pancreatic cancer (PC) is becoming one of the most serious health problems at present, but its causes and risk factors are still unclear. One of the drivers in pancreatic carcinogenesis is altered genomic (DNA) integrity with subsequent genomic instability in cancer cells. The latter comprises a) DNA damage response and DNA repair mechanisms, b) DNA replication and mitosis, c) epigenetic regulation, and d) telomere maintenance. In our review we addressed the above aspects in relation to the most abundant and severe form of PC, pancreatic ductal adenocarcinoma (PDAC). In summary, the interactions between the DNA damage response, telomere homeostasis and mitotic regulation are not comprehensively understood at present, including the epigenetic factors entering the trait of genomic stability maintenance. In addition, the complexity of telomere homeostasis in relation to PDAC risk, prognosis and prediction also warrants further investigations.
Collapse
Affiliation(s)
- Saba Selvi
- Institute of Experimental Medicine, Czech Academy of Sciences, Videnska 1083, Prague 4 14200, Czech Republic; Department of Genetics and Microbiology, Faculty of Science, Charles University, Prague 12800, Czech Republic
| | - Carmen Macías Real
- Cancer Predisposition and Biomarkers Group, Instituto de Investigacion Sanitaria de Santiago, Santiago de Compostela, Spain
| | | | - Katerina Balounova
- Institute of Experimental Medicine, Czech Academy of Sciences, Videnska 1083, Prague 4 14200, Czech Republic; Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Klara Vokacova
- Institute of Experimental Medicine, Czech Academy of Sciences, Videnska 1083, Prague 4 14200, Czech Republic
| | - Andrea Cumova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 84505, Slovakia
| | | | - Cosmeri Rizzato
- Department of Biology, University of Pisa, Pisa 56123, Italy
| | - Erika Halasova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4, Martin 03601, Slovakia
| | - Ludmila Vodickova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4, Martin 03601, Slovakia; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, Pilsen 32300, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, Prague 12800, Czech Republic
| | - Bozena Smolkova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 84505, Slovakia
| | - Kari Hemminki
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, Pilsen 32300, Czech Republic; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, FRG 69120, Germany
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa 56123, Italy
| | - Pavel Vodicka
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Mala Hora 4, Martin 03601, Slovakia; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, Pilsen 32300, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, Prague 12800, Czech Republic.
| |
Collapse
|
|
20
|
Ahn D, Lee HK, Bae SH, Na H, Choi KC. Downregulation of transforming growth factor-β2 enhances the chemosensitivity to gemcitabine with diminished metastasis in pancreatic cancers. Biomed Pharmacother 2025; 188:118151. [PMID: 40378770 DOI: 10.1016/j.biopha.2025.118151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 04/27/2025] [Accepted: 05/07/2025] [Indexed: 05/19/2025] Open
Abstract
Pancreatic cancer is characterized by high rates of metastasis, recurrence, and chemoresistance, contributing to its poor prognosis. Transforming growth factor-β2 (TGF-β2), a member of the TGF-β family, plays a pivotal role in promoting cancer cell metastasis and mediating chemoresistance, particularly in advanced stages of tumor progression. However, the precise role of TGF-β in chemoresistance and metastasis in pancreatic cancer has not been studied yet. In the current study, we investigated the potential of human TGF-β2 antisense oligonucleotides (TGF-β2i) to enhance the chemosensitivity to gemcitabine in pancreatic cancer, using human pancreatic cancer cell lines (hPCCs; PANC-1, MIA PaCa-2, and AsPC-1), a co-culture model with human pancreatic stellate cells (hPSCs), a cancer-associated fibroblast-integrated pancreatic cancer organoid model (CIPCO), and an orthotopic xenograft mouse model. TGF-β2i decreased cell proliferation, migration, and viability in hPCCs, and its combination with gemcitabine exhibited a synergistic effect in PANC-1 and MIA PaCa-2 cells. Flow cytometry demonstrated a decrease in CD44 +CD24 +EpCAMHigh cancer stem-like cell populations following TGF-β2i treatment. In co-culture models, hPSCs-induced enhancement of hPCCs migration was attenuated by TGF-β2i. In the CIPCOs, TGF-β2i suppressed the gemcitabine-induced expression of extracellular matrix components such as COL1A1 and VIM. Furthermore, in an orthotopic mouse model generated by co-inoculating hPCCs and hPSCs into the pancreatic wall, co-treatment of TGF-β2i with gemcitabine significantly delayed tumor growth and metastasis to the liver compared to vehicle control. These findings suggest that TGF-β2i enhances chemosensitivity and suppresses metastatic properties by regulating both tumor-intrinsic and -extrinsic factors, indicating that targeting TGF-β2 could be a promising strategy for managing pancreatic cancer.
Collapse
Affiliation(s)
- Dohee Ahn
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Hong Kyu Lee
- Department of Companion Animal Health, College of Biomedical Science & Health, Inje University, Gimhae, Gyeongsangnam-do 50834, Republic of Korea
| | - Sang Hyeok Bae
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Hwayoung Na
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea.
| |
Collapse
|
|
21
|
Chen IM, Johansen JS, Theile S, Silverman LM, Pelz KR, Madsen K, Dajani O, Lim KZM, Lorentzen T, Gaafer O, Koniaris LG, Ferreira AC, Neelon B, Guttridge DC, Ostrowski MC, Zimmers TA, Nielsen D. Randomized Phase II Study of Nab-Paclitaxel and Gemcitabine With or Without Tocilizumab as First-Line Treatment in Advanced Pancreatic Cancer: Survival and Cachexia. J Clin Oncol 2025:JCO2301965. [PMID: 40354592 DOI: 10.1200/jco.23.01965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 03/04/2025] [Accepted: 04/07/2025] [Indexed: 05/14/2025] Open
Abstract
PURPOSE This randomized phase-II trial (ClinicalTrials.gov identifier: NCT02767557) compared efficacy of gemcitabine/nab-paclitaxel (Gem/Nab) with or without the anti-interleukin-6 (IL-6) receptor antibody tocilizumab (Toc) for advanced pancreatic cancer (PC). METHODS A safety cohort received Gem 1,000 mg/m2 and Nab 125 mg/m2 on days 1, 8, and 15, and Toc 8 mg/kg on day 1 for each 28-day cycle. Participants with modified Glasgow prognostic scores of 1 or 2 were randomly assigned 1:1 to receive Gem/Nab/Toc or Gem/Nab. The primary end point was the overall survival (OS) rate at 6 months (OS6). Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety. Exploratory end points were cachexia, quality of life, and biomarkers, including the cachexia-promoting protein, growth differentiation factor 15 (GDF15). RESULTS Overall, 147 patients were treated, including six safety cohort participants. The median follow-up period was 8.1 months (IQR, 4.2-13.9). OS6 was 68.6% (95% CI, 56.3 to 78.1) for the Gem/Nab/Toc group and 62.0% (49.6-72.1) for the Gem/Nab group (P = .409). OS for Gem/Nab/Toc versus Gem/Nab improved at 18 months (27.1% v 7.0%, P = .001). No differences in median OS, PFS, or ORR were observed. Incidence of grade-3+ treatment-related adverse events (TrAEs) was 88.1% for Gem/Nab/Toc and 63.4% for Gem/Nab (P < .001). Gem/Nab/Toc decreased muscle loss versus Gem/Nab, with median change +0.1013% versus -3.430% (P = .0012) at 2 months and +0.7044 versus -3.353% (P = .036) at 4 months. Incidence of muscle loss was 43.48% on Gem/Nab/Toc versus 73.52% on Gem/Nab at 2 months (P = .0045) and 41.82% versus 68.75% (P = .0062) at 4 months. GDF15 was not changed by Gem/Nab or Gem/Nab/Toc. CONCLUSION Although the primary end point was not met and TrAEs were increased by Toc, increased survival at 18 months and reduced muscle wasting support an anticachexia effect of IL-6 blockade independent of GDF15. Further studies could leverage these findings for precision anticachexia therapy.
Collapse
Affiliation(s)
- Inna M Chen
- Department of Oncology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
| | - Julia S Johansen
- Department of Oncology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
- Department of Medicine, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark
| | - Susann Theile
- Department of Oncology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
| | - Libbie M Silverman
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Katherine R Pelz
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Knight Cancer Institute, Portland, OR
| | - Kasper Madsen
- Department of Oncology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
| | - Olav Dajani
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Kevin Z M Lim
- Department of Oncology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
| | - Torben Lorentzen
- Department of Gastroenterology, Unit of Surgical Ultrasound, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
| | - Omnia Gaafer
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
| | - Leonidas G Koniaris
- Department of Surgery, Oregon Health & Science University, Knight Cancer Institute, Portland, OR
| | - Anna C Ferreira
- Department of Biostatistics, Medical University of South Carolina, Hollings Cancer Center, Charleston, SC
| | - Brian Neelon
- Department of Public Health Sciences, Medical University of South Carolina, Hollings Cancer Center, Charleston, SC
| | - Denis C Guttridge
- Department of Pediatrics, Medical University of South Carolina, Hollings Cancer Center, Charleston, SC
| | - Michael C Ostrowski
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Hollings Cancer Center, Charleston, SC
| | - Teresa A Zimmers
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Knight Cancer Institute, Portland, OR
| | - Dorte Nielsen
- Department of Oncology, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark
| |
Collapse
|
|
22
|
Nakamura T, Hatanaka KC, Kawamoto Y, Kaneko S, Ishida K, Harada K, Yuki S, Komatsu Y, Hatanaka Y, Sakamoto N. Lack of association between SLFN11 expression and treatment efficacy or survival outcomes in patients with pancreatic ductal adenocarcinoma. J Cancer Res Clin Oncol 2025; 151:159. [PMID: 40346357 PMCID: PMC12064574 DOI: 10.1007/s00432-025-06216-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 04/27/2025] [Indexed: 05/11/2025]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Despite the use of aggressive combination chemotherapy regimens, outcomes remain unsatisfactory. Schlafen family member 11 (SLFN11) has been reported to regulate the DNA damage response and influence tumor sensitivity to certain chemotherapeutic agents. This study aimed to investigate the expression of SLFN11 in PDAC and its potential as a biomarker for predicting treatment efficacy and survival outcomes. METHODS This retrospective observational cohort study included 158 patients with unresectable or borderline resectable PDAC who received palliative chemotherapy. Patients were classified into three groups: metastatic, locally advanced, and borderline resectable PDAC. Immunohistochemical staining for SLFN11 was performed on biopsy specimens, and expression levels were quantified using the histo-score (H-score). Associations between SLFN11 expression and clinical outcomes, including progression-free survival and overall survival, were analyzed using Kaplan-Meier methods and Cox regression models. RESULTS SLFN11 expression was observed in 54.4% of PDAC tissues. The median H-score for SLFN11 expression was higher in metastatic cases than in locally advanced and borderline resectable cases. However, no significant association was found between SLFN11 expression and the efficacy of chemotherapy or clinical outcomes. CONCLUSION Despite the hypothesized role of SLFN11 as a predictive biomarker for chemotherapy efficacy, no significant association was found between SLFN11 expression and clinical outcomes in PDAC. Further studies with larger cohorts and more detailed staging are needed to clarify the potential utility of SLFN11 as a therapeutic biomarker in PDAC.
Collapse
Affiliation(s)
- Takeaki Nakamura
- Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Kanako C Hatanaka
- Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Japan
| | - Yasuyuki Kawamoto
- Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan.
| | - Shiho Kaneko
- Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Koichi Ishida
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Kazuaki Harada
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Yoshito Komatsu
- Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Yutaka Hatanaka
- Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Japan
- Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| |
Collapse
|
|
23
|
Demyan L, Weiss MJ. Personalized Care for Pancreatic Cancer: Harnessing Patient-Derived Organoids. J Gastrointest Cancer 2025; 56:113. [PMID: 40347361 DOI: 10.1007/s12029-025-01164-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/01/2025] [Indexed: 05/12/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers. Surgical resection combined with appropriate chemotherapy currently offers the best chance for long-term survival and potential cure. However, effective treatment is hindered by the limited chemotherapy options and the absence of reliable clinical tools to guide chemotherapy selection. Patient-derived organoids (PDOs) have emerged as a promising technology with the potential in precision medicine for PDAC. This review provides an overview of pancreatic organoid genesis, explores the role of PDOs in elucidating PDAC biology within clinically relevant contexts, and concludes by examining current literature on the utility of PDOs as biomarkers for personalized treatment strategies.
Collapse
Affiliation(s)
- L Demyan
- Northwell Health, New Hyde Park, USA.
| | - M J Weiss
- Northwell Health, New Hyde Park, USA.
- Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, USA.
| |
Collapse
|
|
24
|
Bolm L, Fraunhoffer N, Dusetti N, Straesser J, Petruch N, Fernandez del Castillo C, Iovanna J. The PancreasView gemcitabine transcriptomic signature predicts response to gemcitabine in patients with resected pancreatic ductal adenocarcinoma. Oncologist 2025; 30:oyaf083. [PMID: 40349133 PMCID: PMC12065937 DOI: 10.1093/oncolo/oyaf083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 03/28/2025] [Indexed: 05/14/2025] Open
Abstract
INTRODUCTION In the current study, we aimed to assess the efficacy of a gemcitabine response predictive signature that is part of the PancreasView transcriptomic predictive tool (Gem + or Gem-). METHODS We used a cohort of pancreatic ductal adenocarcinoma patients treated from the Massachusetts General Hospital who underwent upfront resection. RESULTS In this cohort of 43 patients, 20 (46.5%) received adjuvant gemcitabine (GEM arm) and 23 (53.5%) did not receive any adjuvant chemotherapy. Among the 43 patients, the Gem signature defined a subgroup of 16 patients (37.2%) who were sensitive (Gem+) and 27 (62.8%), who were resistant to gemcitabine (Gem-). The Gem+ patients who received adjuvant gemcitabine had significantly better median disease-free survival (DFS) compared to the Gem- patients (NR until 72 months of follow-up vs 19.0 months; stratified hazard ratio [HR]: 0.19; 95% CI, 0.04-0.86; P = .032) and longer median cancer-specific survival (CSS) (NR until 96 months of follow-up vs 37.0 months; stratified HR: 0.18; 95% CI, 0.04-0.85; P = .030) when treated with gemcitabine. The gemcitabine signature remained an independent predictive factor for DFS (HR: 0.41; 95% CI, 0.19-0.89; P = .024) and CSS (HR: 0.47; 95% CI, 0.22-1.23; P = .059) after adjusting for clinicopathological characteristics in an unstratified univariate Cox hazard model. CONCLUSIONS This validation of the gemcitabine predictive transcriptomic signature in an independent cohort from Massachusetts General Hospital reinforces the robustness and reliability of this tool. This study highlights the potential of the signature to aid in the personalization of chemotherapy and enhance patient outcomes in pancreatic ductal adenocarcinoma.
Collapse
Affiliation(s)
- Louisa Bolm
- Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, United States
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck 23562, Germany
| | - Nicolas Fraunhoffer
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix- Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille 13288, France
- Center for Pharmacological and Botanical Studies, Faculty of Medicine, Buenos Aires University, National Council for Scientific and Technical Research, Buenos Aires C1121ABG, Argentina
| | - Nelson Dusetti
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix- Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille 13288, France
| | - Julia Straesser
- Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, United States
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck 23562, Germany
| | - Natalie Petruch
- Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, United States
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck 23562, Germany
| | | | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix- Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille 13288, France
- Gastroenterology Section, Hospital de Alta Complejidad El Cruce, Florencio Varela, Buenos Aires, 1888, Argentina
- School of Medicine, University Arturo Jauretche, Florencio Varela, Buenos Aires, 1888, Argentina
| |
Collapse
|
|
25
|
Yonemura H, Kuwatani M, Nakajima K, Masamune A, Ogawa M, Sakamoto N. Treatment of Pancreatic Cancer Using Near-Infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Combination with Anticancer Chemotherapeutic Drug. Cancers (Basel) 2025; 17:1584. [PMID: 40361512 PMCID: PMC12071749 DOI: 10.3390/cancers17091584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 04/26/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis, involves an overabundance of fibroblasts and extracellular matrix. Cancer-associated fibroblasts (CAFs) are critical for providing structural support by secreting soluble factors and extracellular matrix proteins into the stroma. We assessed the potential of near-infrared photoimmunotherapy (NIR-PIT) targeting CAFs in PDAC. Methods: PDAC cells (Capan-1 and SUIT-2) and CAFs (hPSC-5) were used. Anti-human fibroblast activation protein (FAP)/podoplanin (PDPN) antibodies were used to bind to CAFs and conjugates with the specific photosensitizer IRDye®700DX (IR700) to investigate the effects of NIR-PIT. Thereafter, BALB/c Slc-nu/nu mice were transplanted with Capan-1 and/or CAFs and treated with gemcitabine (GEM) with or without NIR-PIT. Results: The binding rate of anti-FAP antibody-AlexaFluor®488 conjugate to hPSC-5 cells was high, whereas that of the anti-PDPN antibody-conjugate was not. The incubation of anti-FAP antibody-IR700 conjugate (αFAP-IR700) with hPSC-5 cells for 3 h led to maximal fluorescence on the surface of hPSC-5 cells. When NIR-PIT with αFAP-IR700 was performed in the co-culture group of Capan-1 and hPSC-5 cells, the proliferative capacity of Capan-1 cells decreased to the same level as that when Capan-1 cells were cultured alone (p < 0.05). In vivo, compared with the GEM group, the NIR-PIT with the GEM group showed a significant reduction in the tumor volume (day 28: 79 vs. 382 mm3, p < 0.05). Tumor volumes in the NIR-PIT group were not reduced compared with those in the control group. Conclusions: Combining NIR-PIT with conventional chemotherapy to target CAFs may enhance the anticancer effects on PDAC.
Collapse
Affiliation(s)
- Hiroki Yonemura
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8648, Hokkaido, Japan; (H.Y.); (N.S.)
| | - Masaki Kuwatani
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8648, Hokkaido, Japan; (H.Y.); (N.S.)
| | - Kohei Nakajima
- Laboratory of Bioanalysis and Molecular Imaging, Graduate School of Pharmaceutical Sciences, Hokkaido University, North 12, West 6, Kita-ku, Sapporo 060-0812, Hokkaido, Japan; (K.N.); (M.O.)
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Hospital, Seiryocho1-1, Aoba-ku, Sendai 980-8574, Miyagi, Japan;
| | - Mikako Ogawa
- Laboratory of Bioanalysis and Molecular Imaging, Graduate School of Pharmaceutical Sciences, Hokkaido University, North 12, West 6, Kita-ku, Sapporo 060-0812, Hokkaido, Japan; (K.N.); (M.O.)
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, North 21, West 10, Kita-ku, Sapporo 001-0021, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8648, Hokkaido, Japan; (H.Y.); (N.S.)
| |
Collapse
|
|
26
|
Stoop TF, Wu YHA, Oba A, Ali M, Feld IM, Al-Musawi MH, Jain A, Saiura A, Sauvanet A, Coppola A, Javed AA, Groot Koerkamp B, Miller BN, Hashimoto D, Caputo D, Kleive D, Sereni E, Kazemier G, Belfiori G, Ishida H, van Dam JL, Dembinski J, Akahoshi K, Roberts KJ, Tanaka K, Labori KJ, Falconi M, House MG, Sugimoto M, Tanabe M, Gotohda N, Chatzizacharias N, Krohn PS, Dokmak S, Rodriguez Franco S, Hirano S, Burgdorf SK, Crippa S, Satoi S, Nguyen TK, Yamamoto T, Nakamura T, Ushida Y, Bachu V, Burns WR, Inoue Y, Takahashi Y, Aslami Z, Schulick RD, He J, Messersmith W, Besselink MG, Burkhart RA, Wilmink JW, Del Chiaro M. Survival after neoadjuvant and induction FOLFIRINOX versus gemcitabine-nab-paclitaxel in patients with resected localised pancreatic adenocarcinoma: an international multicentre study. Br J Cancer 2025:10.1038/s41416-025-03025-1. [PMID: 40328917 DOI: 10.1038/s41416-025-03025-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 03/15/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025] Open
Abstract
BACKGROUND It remains unclear whether there is a difference in overall survival (OS) benefit between (m)FOLFIRINOX and gemcitabine-nab-paclitaxel as preoperative regimens for localised pancreatic adenocarcinoma. This study aimed to investigate the outcome of patients with resected localised pancreatic adenocarcinoma following (m)FOLFIRINOX versus gemcitabine-nab-paclitaxel. METHODS International multicentre retrospective study (16 centres, 8 countries, 3 continents), including consecutive patients after pancreatic resection for localised pancreatic adenocarcinoma following 2-6 months preoperative (m)FOLFIRINOX or gemcitabine-nab-paclitaxel (2010-2018). Primary endpoint was OS from start of preoperative chemotherapy. Cox regression analysis was performed to investigate the association of the preoperative chemotherapy regimen with OS, adjusted for confounders at diagnosis. RESULTS Overall, 935 patients were included after resection of localised pancreatic adenocarcinoma following preoperative (m)FOLFIRINOX (65%) or gemcitabine-nab-paclitaxel (35%). Preoperative chemotherapy regimen (m)FOLFIRINOX was not associated with OS (HR = 0.83 [95% CI 0.64-1.08]), compared to gemcitabine-nab-paclitaxel. Interaction analysis showed stronger effect of (m)FOLFIRINOX in patients with a lower (i.e., non-elevated/marginally elevated) serum CA19-9 at diagnosis (pinteraction = 0.032). CONCLUSION This international study found no OS benefit of preoperative (m)FOLFIRINOX in patients with resected localised pancreatic adenocarcinoma compared to gemcitabine-nab-paclitaxel.
Collapse
Affiliation(s)
- Thomas F Stoop
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, The Netherlands.
- Cancer Center Amsterdam, Amsterdam, The Netherlands.
| | - Y H Andrew Wu
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Atsushi Oba
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan
| | - Mahsoem Ali
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam UMC, Location Vrije Universiteit, Department of Surgery, Amsterdam, The Netherlands
| | - Isabel M Feld
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Mohammed H Al-Musawi
- Clinical Trials of Office, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Ajay Jain
- Division of Surgical Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Akio Saiura
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Alain Sauvanet
- Department of HPB Surgery and Liver Transplantation, Hôpital Beaujon, University Paris Cité, INSERM Unité Mixte de Recherche 1149, Clichy, France
| | | | - Ammar A Javed
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
- Division of Surgical Oncology, Department of Surgery, New York University Medical Center, New York City, NY, USA
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Braden N Miller
- Division of Surgical Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | | | - Damiano Caputo
- Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
- Research Unit of General Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Dyre Kleive
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Elisabetta Sereni
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
- Department of General and Pancreatic Surgery, The Pancreas Institute University of Verona, Hospital Trust, Verona, Italy
| | - Geert Kazemier
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam UMC, Location Vrije Universiteit, Department of Surgery, Amsterdam, The Netherlands
| | - Giulio Belfiori
- Pancreatic Surgery, IRCCS San Raffaele Hospital, Vita-Salute University, Milano, Italy
| | - Hirofumi Ishida
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Jacob L van Dam
- Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Jeanne Dembinski
- Department of HPB Surgery and Liver Transplantation, Hôpital Beaujon, University Paris Cité, INSERM Unité Mixte de Recherche 1149, Clichy, France
| | - Keiichi Akahoshi
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keith J Roberts
- Hepato-Pancreato-Biliary Unit, Department of Surgery, University Hospitals of Birmingham, Birmingham, UK
| | - Kimitaka Tanaka
- Department of Gastroenterological Surgery II, Hokkaido University, Faculty of Medicine, Hokkaido, Japan
| | - Knut J Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Massimo Falconi
- Pancreatic Surgery, IRCCS San Raffaele Hospital, Vita-Salute University, Milano, Italy
| | - Michael G House
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Motokazu Sugimoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Minoru Tanabe
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Naoto Gotohda
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Nikolaos Chatzizacharias
- Hepato-Pancreato-Biliary Unit, Department of Surgery, University Hospitals of Birmingham, Birmingham, UK
| | - Paul S Krohn
- Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Safi Dokmak
- Department of HPB Surgery and Liver Transplantation, Hôpital Beaujon, University Paris Cité, INSERM Unité Mixte de Recherche 1149, Clichy, France
| | - Salvador Rodriguez Franco
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Hokkaido University, Faculty of Medicine, Hokkaido, Japan
| | - Stefan K Burgdorf
- Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Stefano Crippa
- Pancreatic Surgery, IRCCS San Raffaele Hospital, Vita-Salute University, Milano, Italy
| | - Sohei Satoi
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | - Trang K Nguyen
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tomohisa Yamamoto
- Department of Gastroenterological Surgery II, Hokkaido University, Faculty of Medicine, Hokkaido, Japan
| | - Toru Nakamura
- Department of Gastroenterological Surgery II, Hokkaido University, Faculty of Medicine, Hokkaido, Japan
| | - Yuta Ushida
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan
| | - Vismaya Bachu
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - William R Burns
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Yosuke Inoue
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan
| | - Yu Takahashi
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan
| | - Zohra Aslami
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Richard D Schulick
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Jin He
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Wells Messersmith
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Marc G Besselink
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Richard A Burkhart
- Division of Hepatobiliary and Pancreatic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Johanna W Wilmink
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam UMC, Location University of Amsterdam, Department of Medical Oncology, Amsterdam, The Netherlands
| | - Marco Del Chiaro
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| |
Collapse
|
|
27
|
Endo G, Ishigaki K, Nakai Y, Nishio H, Fukuda K, Ishida K, Takaoka S, Tokito Y, Fukuda R, Noguchi K, Oyama H, Suzuki T, Sato T, Saito T, Hamada T, Miyabayashi K, Takahara N, Sato Y, Kage H, Oda K, Fujishiro M. Factors associated with actionable gene aberrations in pancreatic cancer based on the C-CAT database. J Gastroenterol 2025:10.1007/s00535-025-02253-9. [PMID: 40314773 DOI: 10.1007/s00535-025-02253-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 04/23/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND Comprehensive genomic profiling (CGP) tests are increasingly used to explore the genomically matched therapies for solid tumors. The aim of this study is to investigate factors associated with actionable gene aberrations in pancreatic cancer (PC) using real-world data from the Center for Advanced Cancer Genome Therapy (C-CAT) database. METHODS Among 6768 patients with unresectable and recurrent PC registered in the C-CAT database between June 2019 and July 2023, we identified 4628 patients who underwent tissue-based CGP tests using either FoundationOne® CDx (F1CDx) or OncoGuide™ NCC Oncopanel (NOP). We investigated the incidence of actionable gene aberrations and the factors associated with their detection. RESULTS The cohort included 3,554 patients who underwent F1CDx and 1128 NOP, with surgical specimens in 50% of the cases. Adenocarcinoma was the predominant subtype (95%), and KRAS mutations were found in 90%. The overall incidence of actionable gene aberrations was 27%. The most common gene abnormalities were BRCA2 (3.4%), followed by ATM (2.9%), ERBB2 (2.8%), PIK3 CA (2.5%), and BRAF (1.9%). Multivariable analysis revealed that acinar cell carcinoma (ACC) (Odds ratio [OR] 1.87, 95% confidence interval [CI] 1.00-2.67), KRAS wild type (KRASWT) (OR 3.09, 95% CI 2.49-3.85), and use of F1CDx (OR 2.38, 95% CI 1.98-2.85) were significantly associated with actionable gene aberrations. CONCLUSIONS Actionable gene aberrations were more likely in cases of ACC, KRASWT, and F1CDx usage. The choice of CGP test should be made on a case-by-case basis, as other factors beyond actionable gene aberrations also need to be considered.
Collapse
Affiliation(s)
- Go Endo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Kazunaga Ishigaki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
- Department of Clinical Oncology, The University of Tokyo Hospital, Tokyo, Japan
| | - Yousuke Nakai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
- Department of Endoscopy and Endoscopic Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Hiroto Nishio
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Koshiro Fukuda
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Kota Ishida
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Shinya Takaoka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
- Department of Endoscopy and Endoscopic Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Yurie Tokito
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Rintaro Fukuda
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Kensaku Noguchi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Hiroki Oyama
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tatsunori Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tatsuya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tomotaka Saito
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tsuyoshi Hamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
- Department of Hepato-Biliary-Pancreatic Medicine, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Koji Miyabayashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Naminatsu Takahara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Yasuyoshi Sato
- Department of Clinical Oncology, The University of Tokyo Hospital, Tokyo, Japan
| | - Hidenori Kage
- Department of Respiratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Katsutoshi Oda
- Department of Clinical Genomics, The University of Tokyo, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan
- Department of Clinical Oncology, The University of Tokyo Hospital, Tokyo, Japan
| |
Collapse
|
|
28
|
Aleixo G, Voruganti T, Sedhom R. Three lessons from "The Fox and the Grapes" to inform precision oncology in the older adult. J Geriatr Oncol 2025; 16:102186. [PMID: 39794225 DOI: 10.1016/j.jgo.2025.102186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025]
Affiliation(s)
- Gabriel Aleixo
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Teja Voruganti
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ramy Sedhom
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA, USA; Penn Center for Cancer Care Innovation, Abramson Cancer Center, Penn Medicine, Philadelphia, PA, USA
| |
Collapse
|
|
29
|
Faisal MS, Hussain I, Ikram MA, Shah SB, Rehman A, Iqbal W. Irinotecan dosing and pharmacogenomics: a comprehensive exploration based on UGT1A1 variants and emerging insights. J Chemother 2025; 37:199-212. [PMID: 38706404 DOI: 10.1080/1120009x.2024.2349444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 04/05/2024] [Accepted: 04/24/2024] [Indexed: 05/07/2024]
Abstract
Irinotecan is a critical anticancer drug used to treat metastatic colorectal cancer and advanced pancreatic ductal adenocarcinoma by obstructing topoisomerase 1; however, it can cause minor-to-severe and life-threatening adverse effects. UDP glucuronosyltransferase family 1 member A1 (UGT1A1) polymorphisms increase the risk of irinotecan-induced neutropenia and diarrhea. Hence, screening for UGT1A1 polymorphisms before irinotecan-based chemotherapy is recommended to minimize toxicity, whereas liposomes offer the potential to deliver irinotecan with fewer side effects in patients with pancreatic ductal adenocarcinoma. This review presents a comprehensive overview of the effects of genotype-guided dosing of irinotecan on UGT1A1*28 and UGT1A1*6 variants, incorporating pharmacogenomic research, optimal regimens for metastatic colorectal and pancreatic cancer treatment using irinotecan, guidelines for toxicity reduction, and an evaluation of the cost-effectiveness of UGT1A1 genotype testing.
Collapse
Affiliation(s)
- Muhammad Saleem Faisal
- Department of Biological Sciences, International Islamic University, Islamabad, Pakistan
| | - Imran Hussain
- Department of Biological Sciences, International Islamic University, Islamabad, Pakistan
| | | | - Syed Babar Shah
- Department of Biological Sciences, International Islamic University, Islamabad, Pakistan
| | - Abdul Rehman
- Department of Biological Sciences, International Islamic University, Islamabad, Pakistan
| | - Wajid Iqbal
- Department of Biological Sciences, International Islamic University, Islamabad, Pakistan
| |
Collapse
|
|
30
|
Henderson NL, Bourne G, Ortiz-Olguin E, Pywell C, Rose JB, Williams GR, Hussaini SMQ, Nipp RD, Rocque G. The impact of electronic patient-reported outcomes presentation during multi-disciplinary tumor board on clinician discussion of older adults' fitness and preferences. J Geriatr Oncol 2025; 16:102225. [PMID: 40120473 DOI: 10.1016/j.jgo.2025.102225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 02/28/2025] [Accepted: 03/14/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Treatment of pancreatic cancer often entails multiple modalities (e.g., chemotherapy, surgery, radiation) that vary in intensity, timing, and toxicity profiles. Some treatment options are only recommended for medically 'fit' patients regardless of age, yet formal fitness measures (such as the geriatric assessment [GA]) and patient preferences are seldom utilized during treatment decision-making. MATERIALS AND METHODS The INtegrating Systematic PatIent-Reported Evaluations into Multi-Disciplinary Tumor Board (INSPIRE-MDTB) intervention involves the presentation of GA and treatment preferences data during tumor board discussions of older patients with stage I-IV pancreatic adenocarcinoma. This qualitative study recorded, transcribed, and inductively analyzed historical (November 2021-February 2022) and intervention (September 2022-June 2023) MDTBs using NVivo software. A constant comparative method was used to establish a grounded scheme representative of clinicians' characterization of patients' fitness and preferences during decision-making. RESULTS Recordings of the primary MDTB presentation of 31 historical and 49 intervention patients with similar sex (52 %; 53 % female), age (m = 68.1; 72.3), race (65 %; 59 % White), and cancer stage (26 %; 22 % stage IV) were included. Although GA was captured for all included patients, it was not discussed in any historical cases, but was in 94 % of intervention cases. When compared to historical controls, INSPIRE patients had more frequent discussions of (1) cancer-related factors (e.g., size, location, rate of progression; 35 % vs. 43 %), (2) individual risk factors (e.g., age, comorbidities, tolerance; 90 % vs 98 %), and (3) psychosocial factors (e.g., health literacy, social support, substance use; 19 % vs 33 %). Identified preference domains were discussed in 39 % of historical and 80 % of intervention patients, with notably higher rates of discussion of patients' concerns regarding physical (0 %; 35 %) and mental/emotional (0 %; 20 %) side effects, ability to work (0 %; 10 %), and the logistics and convenience of treatment (6 %; 14 %). DISCUSSION The INSPIRE intervention enhanced MDTB discussion of patient fitness and preferences and represents a promising approach for fostering consistent and systematic presentation and discussion of patient-reported data, such as the GA and treatment preferences. This adds to our previous findings that INSPIRE was feasible, acceptable, appropriate, and time-effective according to patients and provider participants.
Collapse
Affiliation(s)
- Nicole L Henderson
- O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL, United States of America.
| | - Garrett Bourne
- O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL, United States of America
| | - Etzael Ortiz-Olguin
- O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL, United States of America
| | - Cameron Pywell
- O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL, United States of America
| | - J Bart Rose
- O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL, United States of America
| | - Grant R Williams
- O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL, United States of America
| | - S M Qasim Hussaini
- O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL, United States of America
| | - Ryan D Nipp
- OU Health Stephenson Cancer Center, Oklahoma City, OK, United States of America
| | - Gabrielle Rocque
- O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL, United States of America.
| |
Collapse
|
|
31
|
Maekawa A, Omiya K, Oba A, Inoue Y, Hirose Y, Kobayashi K, Ono Y, Sato T, Sasaki T, Ozaka M, Matsueda K, Mise Y, Takamatsu M, Shigematsu Y, Ito H, Saiura A, Sasahira N, Takahashi Y. Clinical implications of disappearing pancreatic cancer liver metastases: Lessons from colorectal liver metastases. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109635. [PMID: 39879814 DOI: 10.1016/j.ejso.2025.109635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/27/2024] [Accepted: 01/23/2025] [Indexed: 01/31/2025]
Abstract
BACKGROUND The efficacy of local control for pancreatic cancer liver metastases (PCLM), including surgical treatment, remains controversial, with no consensus on the management and clinical significance of disappearing liver metastases (DLMs). This study aimed to evaluate the clinical implications of DLMs in treating PCLM after multi-agent chemotherapy, utilizing contrast-enhanced imaging modalities. METHODS A retrospective analysis was conducted on patients who underwent curative resection for pancreatic cancer with synchronous or metachronous liver metastases between 2014 and 2023. Surgical indications were based on our recently reported ABCD criteria (Anatomical/Biological/Conditional/Duration). Both contrast-enhanced computed tomography (CE-CT) and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) were used to monitor metastatic lesions in the liver. DLMs were defined as tumors undetected on CE-CT post-chemotherapy. RESULTS A total of 58 lesions in 29 patients with PCLM who underwent surgical resection were evaluated. Of the 13 lesions evident on CE-CT, 76.9 % (10/13) contained clinically/pathologically residual tumors. Of the 45 DLMs, 16 (35.6 %) had residual tumors. Twenty-six DLMs (57.8 %) were detected on EOB-MRI or intraoperative screening (contrast-enhanced ultrasonography and palpation), with 42.3 % (11/26) being residual tumors. Nineteen DLMs were undetectable by any modality, of which 26.3 % (5/19) were confirmed to be residual tumors with a median follow-up of 32 months. The median overall survival from initiating treatment for PCLM was 48.5 months. CONCLUSION Integrating EOB-MRI into preoperative evaluations for PCLM enhances the detection of clinically relevant DLMs. Our findings highlight the potential benefits of considering an image-guided surgical approach in selected patients.
Collapse
Affiliation(s)
- Aya Maekawa
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kojiro Omiya
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Atsushi Oba
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
| | - Yosuke Inoue
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuki Hirose
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kosuke Kobayashi
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yoshihiro Ono
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takafumi Sato
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takashi Sasaki
- Department of Gastroenterological Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Masato Ozaka
- Department of Gastroenterological Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kiyoshi Matsueda
- Department of Diagnostic Imaging, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yoshihiro Mise
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Manabu Takamatsu
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yasuyuki Shigematsu
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiromichi Ito
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Akio Saiura
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoki Sasahira
- Department of Gastroenterological Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yu Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
| |
Collapse
|
|
32
|
Chung V, Mizrahi JD, Pant S. Novel Therapies for Pancreatic Cancer. JCO Oncol Pract 2025; 21:613-619. [PMID: 39591547 DOI: 10.1200/op.24.00279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 10/15/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024] Open
Abstract
Pancreatic adenocarcinoma (PDAC) unfortunately remains a highly fatal disease with a 5-year survival rate of only 11%. If surgical resection is not possible, systemic chemotherapy represents the standard-of-care approach to management. Combination chemotherapy regimens using fluorouracil (fluorouracil, oxaliplatin, leucovorin, and irinotecan; and fluorouracil, leucovorin, and oxaliplatin) or gemcitabine with albumin-bound paclitaxel have the potential to improve overall survival for patients with advanced disease. With the increasing understanding of the molecular drivers of pancreatic cancer, novel therapeutic approaches have made incremental progress for these patients. The molecular landscape of PDAC has been studied extensively. Approximately 90% of PDACs harbor mutations in the KRAS gene, a driver mutation that has long been considered undruggable. However, novel KRAS inhibitors have shown therapeutic promise in early-phase clinical trials, with larger studies ongoing. Less frequently encountered genomic aberrations that have therapeutic potential include NRG, BRAF, NTRK, HER2, BRCA, PALB2, and claudin. Immune checkpoint inhibitors have unfortunately yielded disappointing efficacy for the majority of patients with pancreatic cancer, except for those with tumors exhibiting deficiency in mismatch repair proteins. Alternative approaches to incorporate immunotherapy have shown more promise such as use of immune checkpoint inhibitors for selected patients in the maintenance setting and potential vaccine therapies in the postsurgery adjuvant setting. It is vital to perform molecular profiling in all patients with PDAC to identify potential treatment targets, and to enroll patients in clinical trials whenever possible.
Collapse
Affiliation(s)
- Victoria Chung
- Ochsner Medical Center, New Orleans, LA
- MD Anderson Cancer Center, Houston, TX
| | | | | |
Collapse
|
|
33
|
Azeez A, Noel C. Global status of research on quality of life in pancreatic cancer patients: A bibliometric and network analysis from 2005-2024. Clin Res Hepatol Gastroenterol 2025; 49:102595. [PMID: 40210107 DOI: 10.1016/j.clinre.2025.102595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/12/2025]
Abstract
BACKGROUND Pancreatic cancer (PC) is a major global health challenge, with rising incidence and mortality rates, particularly in high-socio-demographic index regions. Given its high mortality and significant morbidity, research on patient quality of life (QoL) has gained momentum, addressing symptom burdens, psychological distress, and treatment-related outcomes. Bibliometric analysis provides a valuable approach to mapping research trends, identifying key contributors, and forecasting future directions. OBJECTIVE This study aimed to map global research on QoL in pancreatic cancer patients, highlighting key findings, challenges, and future directions through bibliometric analysis over the past two decades. METHODS Data for this study were collected from the Web of Science Core Collection (WoSCC) database, using specific search strategies to retrieve relevant documents on the quality of life in pancreatic cancer patients. The data were analysed using the Bibliometrix R package to create knowledge maps and visualize research trends, collaborations, and emerging hotspots in the field. RESULTS A total of 819 articles on pancreatic cancer and quality of life were identified, with an average citation count of 47.13 per article, highlighting moderate academic impact. The research revealed a growing trend in collaborative efforts, with an average of 9.42 co-authors per article and 16 % international collaborations. The United States emerged as the leading contributor, with 203 publications and the highest citation count, followed by France and the United Kingdom. CONCLUSION This bibliometric analysis highlights the growing volume of pancreatic cancer and quality of life research, with a steady annual growth rate of 6.9 % and increasing collaboration, especially from the United States. However, despite the rising number of publications, a decline in citation impact for recent studies suggests a need for continued innovation in therapeutic strategies to improve clinical outcomes.
Collapse
Affiliation(s)
- Adeboye Azeez
- Gastrointestinal Research Unit, Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Free State, Bloemfontein 9300, South Africa.
| | - Colin Noel
- Gastrointestinal Research Unit, Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Free State, Bloemfontein 9300, South Africa
| |
Collapse
|
|
34
|
Doi T, Ishikawa T, Moriguchi M, Itoh Y. Current status of cancer genome medicine for pancreatic ductal adenocarcinoma. Jpn J Clin Oncol 2025; 55:443-452. [PMID: 39893577 DOI: 10.1093/jjco/hyaf012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 01/17/2025] [Indexed: 02/04/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis; however, advancements in cancer genome profiling using next-generation sequencing have provided new perspectives. KRAS mutations are the most frequently observed genomic alterations in patients with PDAC. However, until recently, it was not considered a viable therapeutic target. Although KRAS G12C mutations for which targeted therapies are already available are infrequent in PDAC, treatments targeting KRAS G12D and pan-KRAS are still under development. Similarly, new treatment methods for KRAS, such as chimeric antigen receptor T-cell therapy, have been developed. Several other potential therapeutic targets have been identified for KRAS wild-type PDAC. For instance, immune checkpoint inhibitors have demonstrated efficacy in PDAC treatment with microsatellite instability-high/deficient mismatch repair and tumor mutation burden-high profiles. However, for other PDAC cases with low immunogenicity, combination therapies that enhance the effectiveness of immune checkpoint inhibitors are being considered. Additionally, homologous recombination repair deficiencies, including BRCA1/2 mutations, are prevalent in PDAC and serve as important biomarkers for therapies involving poly (adenosine diphosphate-ribose) polymerase inhibitors and platinum-based therapies. Currently, olaparib is available for maintenance therapy of BRCA1/2 mutation-positive PDAC. Further therapeutic developments are ongoing for genetic abnormalities involving BRAF V600E and the fusion genes RET, NTRK, NRG, ALK, FGFR2, and ROS1. Overcoming advanced PDAC remains a formidable challenge; however, this review outlines the latest therapeutic strategies that are expected to lead to significant advancements.
Collapse
Affiliation(s)
- Toshifumi Doi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
- Cancer Genome Medical Center, University Hospital, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Takeshi Ishikawa
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
- Cancer Genome Medical Center, University Hospital, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
- Department of Medical Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Michihisa Moriguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| |
Collapse
|
|
35
|
Ahmed KS, Marcinak CT, Issaka SM, Ali MM, Zafar SN. Machine Learning to Predict Early Death Despite Pancreaticoduodenectomy. J Surg Res 2025; 310:186-193. [PMID: 40288090 DOI: 10.1016/j.jss.2025.03.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 03/17/2025] [Accepted: 03/22/2025] [Indexed: 04/29/2025]
Abstract
INTRODUCTION About 25% of patients undergoing pancreaticoduodenectomy (PD) for right-sided pancreatic ductal adenocarcinoma (PDAC) die within 1 y of diagnosis. These patients carry all the risks of significant morbidity with no survival advantage when compared to nonsurgical options. We aimed to determine if machine learning models have superior accuracy to traditional regression models at predicting futile surgery in patients with PDAC. METHODS We analyzed data from patients in the National Cancer Database undergoing PD for PDAC between 2004 and 2020. PD was defined as futile if the patient died within 12 mo of cancer diagnosis. We trained predictive models using 80% of the dataset and 16 preoperative input variables. Models included logistic regression, multilayer perceptron, decision tree, random forest, and gradient boosting classifiers. Models were tested on a 20% test set using area under the receiver operating characteristic curve and Brier scores. RESULTS Of the 66,331 patients identified, 34,260 (51.7%) were men, with a median age of 67 y (interquartile range, 59 to 74 y). A total of 16,772 (25.3%) patients met the criteria for futile surgery. The gradient boosting model outperformed other models with an area under the receiver operating characteristic curve of 0.689, followed by logistic regression (0.679), random forest (0.675), and decision tree (0.664). Key predictors of futile PD included advanced age (> 79 y), tumor size ≥ 4 cm, and poor differentiation. Neoadjuvant therapy was associated with lower futility risk. CONCLUSIONS We demonstrated the ability of machine learning models to predict the odds of futile PD with moderate accuracy. Although similar analyses are needed on more granular datasets, our study has important implications for shared decision-making and optimized care for patients with PDAC.
Collapse
Affiliation(s)
- Kaleem S Ahmed
- Division of Surgical Oncology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Clayton T Marcinak
- Division of Surgical Oncology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Sheriff M Issaka
- Division of Surgical Oncology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Muhammad Maisam Ali
- Division of Surgical Oncology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Syed Nabeel Zafar
- Division of Surgical Oncology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
| |
Collapse
|
|
36
|
Kanesada G, Tsunedomi R, Nakagami Y, Matsui H, Shindo Y, Tomochika S, Akita H, Ioka T, Takahashi H, Nagano H. The C11orf24 Gene as a Useful Biomarker for Predicting Severe Neutropenia in Modified FOLFIRINOX for Pancreatic Cancer. Cancer Sci 2025. [PMID: 40285634 DOI: 10.1111/cas.70087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 04/08/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Pancreatic cancer (PC) is an aggressive and lethal tumor with a poor prognosis. FOLFIRINOX improves the prognosis of patients with PC; however, despite UGT1A1 screening, adverse events, such as severe neutropenia, occur frequently. This study aimed to identify the novel biomarkers of severe neutropenia in patients treated with modified FOLFIRINOX (mFFX) for PC. In this study, patients with PC treated with mFFX (n = 71) and gemcitabine plus nab-paclitaxel (GnP) (n = 92) and patients with colorectal cancer treated with FOLFOXIRI (n = 50) were included. Genome-wide screening using whole-exome sequencing was performed during the screening phase. Validation analysis was performed using polymerase chain reaction genotyping, the Cochran-Armitage trend test, and multivariate analysis. The diagnostic performance of combined risk factors for severe neutropenia was examined using logistic regression with leave-one-out cross-validation. Three gene polymorphisms were selected from the screening phase and subjected to the validation phase. In the validation phase, a single nucleotide polymorphism in C11orf24 (c.448C>T, rs901827) was significantly correlated with ≥ Grade 3 neutropenia in mFFX and FOLFOXIRI but not in GnP. Multivariate analysis showed C11orf24 and baseline neutrophil count as independent risk factors for ≥ Grade 3 neutropenia. The diagnostic performance of the neutropenia prediction model showed areas under the curve of 0.754 (sensitivity = 0.605, specificity = 0.848) and 0.856 (sensitivity = 0.800, specificity = 0.893) for ≥ Grade 3 and 4 neutropenia, respectively. The C11orf24 gene and baseline neutrophil count may be useful biomarkers for predicting severe neutropenia following irinotecan-containing triplet chemotherapy.
Collapse
Affiliation(s)
- Gen Kanesada
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Ryouichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
- Research Institute for Cell Design Medical Science, Yamaguchi University, Ube, Yamaguchi, Japan
| | - Yuki Nakagami
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
- Health Data Science Laboratory, Faculty of Data Science, Shimonoseki City University, Shimonoseki, Yamaguchi, Japan
| | - Hiroto Matsui
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Yoshitaro Shindo
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Shinobu Tomochika
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Hirofumi Akita
- Department of Digestive Surgery, Osaka International Cancer Institute, Osaka, Osaka, Japan
| | - Tatsuya Ioka
- Oncology Center, Yamaguchi University Hospital, Ube, Yamaguchi, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
- Research Institute for Cell Design Medical Science, Yamaguchi University, Ube, Yamaguchi, Japan
| |
Collapse
|
|
37
|
Calheiros J, Silva R, Barbosa F, Morais J, Moura SR, Almeida S, Fiorini E, Mulhovo S, Aguiar TQ, Wang T, Ricardo S, Almeida MI, Domingues L, Melo SA, Corbo V, Ferreira MJU, Saraiva L. A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer. J Exp Clin Cancer Res 2025; 44:129. [PMID: 40275348 PMCID: PMC12020112 DOI: 10.1186/s13046-025-03389-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 04/08/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is among the cancer types with poorest prognosis and survival rates primarily due to resistance to standard-of-care therapies, including gemcitabine (GEM) and olaparib. Particularly, wild-type (wt)BRCA tumours, the most prevalent in PDAC, are more resistant to DNA-targeting agents like olaparib, restraining their clinical application. Recently, we disclosed a monoterpene indole alkaloid derivative (BBIT20) as a new inhibitor of homologous recombination (HR) DNA repair with anticancer activity in breast and ovarian cancer. Since inhibition of DNA repair enhances the sensitivity of cancer cells to chemotherapy, we aimed to investigate the anticancer potential of BBIT20 against PDAC, particularly carrying wtBRCA. METHODS In vitro and in vivo PDAC models, particularly human cell lines (including GEM-resistant PDAC cells), patient-derived organoids and xenograft mice of PDAC were used to evaluate the anticancer potential of BBIT20, alone and in combination with GEM or olaparib. Disruption of the BRCA1-BARD1 interaction by BBIT20 was assessed by co-immunoprecipitation, immunofluorescence and yeast two-hybrid assay. RESULTS The potent antiproliferative activity of BBIT20, superior to olaparib, was demonstrated in PDAC cells regardless of BRCA status, by inducing cell cycle arrest, apoptosis, and DNA damage, while downregulating HR. The disruption of DNA double-strand breaks repair by BBIT20 was further reinforced by non-homologous end joining (NHEJ) suppression. The inhibition of BRCA1-BARD1 heterodimer by BBIT20 was demonstrated in PDAC cells and confirmed in a yeast two-hybrid assay. In GEM-resistant PDAC cells, BBIT20 showed potent antiproliferative, anti-migratory and anti-invasive activity, overcoming GEM resistance by inhibiting the multidrug resistance P-glycoprotein, upregulating the intracellular GEM-transporter ENT1, and downregulating GEM resistance-related microRNA-20a and GEM metabolism enzymes as RRM1/2. Furthermore, BBIT20 did not induce resistance in PDAC cells. It inhibited the growth of patient-derived PDAC organoids, by inducing apoptosis, repressing HR, and potentiating olaparib and GEM cytotoxicity. The enhancement of olaparib antitumor activity by BBIT20 was confirmed in xenograft mice of PDAC. Notably, it hindered tumour growth and liver metastasis formation, improving survival of orthotopic xenograft mice of PDAC. Furthermore, its potential as a stroma-targeting agent, reducing fibrotic extracellular matrix and overcoming desmoplasia, associated with an enhancement of immune cell response by depleting PD-L1 expression in tumour tissues, renders BBIT20 even more appealing for combination therapy, particularly with immunotherapy. CONCLUSION These findings underscore the great potential of BBIT20 as a novel multifaceted anticancer drug candidate for PDAC treatment.
Collapse
Grants
- 2020.04613.BD FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior
- 2022.05718.PTDC, 0.54499/LA/P/0008/2020, 10.54499/UIDP/50006/2020, 10.54499/UIDB/50006/2020 FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior
- 2020.06020.BD FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior
- 2022.05718.PTDC, 0.54499/LA/P/0008/2020, 10.54499/UIDP/50006/2020, 10.54499/UIDB/50006/2020 FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior
- 2022.05718.PTDC, 0.54499/LA/P/0008/2020, 10.54499/UIDP/50006/2020, 10.54499/UIDB/50006/2020 FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior
- 2022.05718.PTDC, 0.54499/LA/P/0008/2020, 10.54499/UIDP/50006/2020, 10.54499/UIDB/50006/2020 FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior
- AIRC; IG No 288801 Associazione Italiana Ricerca sul Cancro
- AIRC; IG No 288801 Associazione Italiana Ricerca sul Cancro
- NHI; HHSN26100008 NCI NIH HHS
- National Cancer Institute
Collapse
Affiliation(s)
- Juliana Calheiros
- LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Rita Silva
- LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Filipa Barbosa
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, Lisboa, 1649-003, Portugal
| | - João Morais
- LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Sara Reis Moura
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal
| | - Sofia Almeida
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal
| | - Elena Fiorini
- Department of Engineering for Innovation Medicine (DIMI), University of Verona, 37134, Verona, Italy
| | - Silva Mulhovo
- Centro de Estudos Moçambicanos e de Etnociências (CEMEC), Faculty of Natural Sciences and Mathematics, Pedagogical University, Maputo, 21402161, Mozambique
| | - Tatiana Q Aguiar
- CEB - Centre of Biological Engineering, University of Minho, Braga, 4710-057, Portugal
- LABBELS - Associate Laboratory, Braga/Guimarães, Portugal
| | - Tao Wang
- Institute of Medicine and Pharmacy, Qiqihar Medical University, Qiqihar, Heilongjiang, 161006, China
| | - Sara Ricardo
- Associate Laboratory i4HB - Institute for Health and Bioeconomy and UCIBIO - Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), Gandra, 4585-116, Portugal
| | - Maria Inês Almeida
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal
| | - Lucília Domingues
- CEB - Centre of Biological Engineering, University of Minho, Braga, 4710-057, Portugal
- LABBELS - Associate Laboratory, Braga/Guimarães, Portugal
| | - Sonia A Melo
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen, 4200-135, Porto, Portugal
- Department of Pathology, Faculty of Medicine University of Porto, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal
- Porto Comprehensive Cancer Centre (P.CCC) Raquel Seruca, Porto, Portugal
| | - Vincenzo Corbo
- Department of Engineering for Innovation Medicine (DIMI), University of Verona, 37134, Verona, Italy
| | - Maria-José U Ferreira
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, Lisboa, 1649-003, Portugal.
| | - Lucília Saraiva
- LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal.
| |
Collapse
|
|
38
|
Ciner A, Hosein PJ, Jiang Y, Rassool F. The Interplay Between DNA Repair and the Immune Microenvironment in Pancreatic Cancer. Biomedicines 2025; 13:1031. [PMID: 40426860 PMCID: PMC12108561 DOI: 10.3390/biomedicines13051031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 04/08/2025] [Accepted: 04/15/2025] [Indexed: 05/29/2025] Open
Abstract
This narrative review describes the relationship between DNA repair and the immune microenvironment in pancreatic cancer and its potential clinical relevance. Pancreatic cancer is a devastating disease, often diagnosed at an advanced and incurable stage. BRCA or PALB2 mutations occur in a small subset, disabling accurate DNA double-strand break repair and sensitizing tumors to platinum-based chemotherapy and poly-ADP ribose polymerase inhibitors. While immune checkpoint blockade targeting PD1 and CTLA4 is ineffective for most patients, accumulating translational work indicates that those with BRCA or PALB2 mutations harbor a distinct and more permissive immune microenvironment. The phase 2 TAPUR study and retrospective series demonstrate that combined PD1 and CTLA4 inhibition can be effective for this subgroup of patients. In this manuscript, we review the current treatment landscape, the underlying mechanisms for immune resistance, and the interplay between defective DNA repair and the immune microenvironment in pancreatic cancer.
Collapse
Affiliation(s)
- Aaron Ciner
- Greenebaum Comprehensive Cancer Center, School of Medicine Baltimore, University of Maryland, Baltimore, MD 21201, USA
| | - Peter J. Hosein
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA;
| | - Yixing Jiang
- Greenebaum Comprehensive Cancer Center, School of Medicine Baltimore, University of Maryland, Baltimore, MD 21201, USA
| | - Feyruz Rassool
- Greenebaum Comprehensive Cancer Center, School of Medicine Baltimore, University of Maryland, Baltimore, MD 21201, USA
| |
Collapse
|
|
39
|
Okada Y, Sato Y, Shinomiya R, Miyake T, Takahashi T, Yokoyama R, Mitsui Y, Tomonari T, Okamoto K, Sogabe M, Miyamoto H, Kawano Y, Takayama T. Conditions for effective use of liposomal irinotecan with fluorouracil and leucovorin in unresectable pancreatic cancer after FOLFIRINOX treatment. Int J Clin Oncol 2025:10.1007/s10147-024-02677-y. [PMID: 40266453 DOI: 10.1007/s10147-024-02677-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 12/01/2024] [Indexed: 04/24/2025]
Abstract
BACKGROUND Liposomal irinotecan + fluorouracil/leucovorin (nal-IRI + 5FU/LV) is commonly used as a second- or later-line treatment for pancreatic ductal adenocarcinoma (PDAC) and offers survival benefits. However, its efficacy and safety in patients previously treated with FOLFIRINOX, which includes irinotecan, remain unclear. We evaluated the efficacy and safety of nal-IRI + 5FU/LV in patients with unresectable PDAC who received previous FOLFIRINOX therapy and those who did not. METHODS This retrospective observational study included 42 patients with PDAC who were treated with nal-IRI + 5FU/LV (October 2020-November 2023). Patients were grouped based on prior FOLFIRINOX treatment. RESULTS The progression-free survival (PFS) in patients who previously received modified FOLFIRINOX (mFFX) therapy was shorter than that in patients who did not (2.5 vs. 3.5 months, P = 0.07). When patients with greater than- and less than the cut-off value of irinotecan-free interval (IFI) were classified into the long and short IFI groups, respectively, PFS was significantly longer in the long-IFI group than that in the short IFI group (4.0 vs. 2.1 months, P = 0.01). Moreover, the C-reactive protein/albumin ratio (CAR) was also a significant predictor of PFS (P = 0.03). Furthermore, both factors were found to be independent factors influencing PFS in the univariate Cox regression analysis (P = 0.02 and P = 0.04). CONCLUSION Nal-IRI + 5FU/LV therapy may be a safe and effective option as a second- or later-line treatment, particularly for patients who have not previously received mFFX therapy. For patients who received prior mFFX exposure, a longer IFI and lower CAR may indicate greater potential benefit, thus aiding in more personalized treatment approaches.
Collapse
Affiliation(s)
- Yasuyuki Okada
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Yasushi Sato
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan.
- Department of Community Medicine for Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
| | - Ryo Shinomiya
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Takanori Miyake
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Taku Takahashi
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Reiko Yokoyama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Yasuhiro Mitsui
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Tetsu Tomonari
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Masahiro Sogabe
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Yutaka Kawano
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| |
Collapse
|
|
40
|
Yu R, Ji X, Zhang P, Zhang H, Qu H, Dong W. The potential of chimeric antigen receptor -T cell therapy for endocrine cancer. World J Surg Oncol 2025; 23:153. [PMID: 40264184 PMCID: PMC12012980 DOI: 10.1186/s12957-025-03745-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/07/2025] [Indexed: 04/24/2025] Open
Abstract
Endocrine cancer, a relatively rare and heterogeneous tumor with diverse clinical features. The facile synthesis of hormones further complicates endocrine cancer treatment. Thus, the development of safe and effective systemic treatment approaches, such as chimeric antigen receptor (CAR) T cell therapy, is imperative to enhance the prognosis of patients with endocrine cancer. Although this therapy has achieved good results in the treatment of hematological malignancies, it encounters diverse complications and challenges in the context of endocrine cancer. This review delineates the generation of CAR-T cells, examines the potential of CAR-T cell therapy for endocrine cancer, enumerates pivotal antigens linked to endocrine cancer, encapsulates the challenges confronted with CAR-T cell therapy for endocrine cancer, and expounds upon strategies to overcome these limitations. The primary objective is to provide insightful perspectives that can contribute to the advancement of CAR-T cell therapy in the field of endocrine cancer.
Collapse
Affiliation(s)
- Ruonan Yu
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Xiaoyu Ji
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Ping Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China
| | - Huiling Qu
- Department of Neurology, The General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, Liaoning, 110840, China.
| | - Wenwu Dong
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, 110001, China.
| |
Collapse
|
|
41
|
Liu W, Fang Y, Zhang C, Xiang M, Qi L, Su A, Sun Y. Cost-effectiveness of NALIRIFOX versus Nab-paclitaxel and gemcitabine in previously untreated metastatic pancreatic ductal adenocarcinoma. BMC Gastroenterol 2025; 25:266. [PMID: 40247200 PMCID: PMC12004809 DOI: 10.1186/s12876-025-03867-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 04/08/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND & AIMS The NAPOLI 3 trial demonstrated that compared to the nab-paclitaxel and gemcitabine (GemNab) regimen, the NALIRIFOX (5-fluorouracil, leucovorin, liposomal irinotecan, oxaliplatin) regimen can significantly improve patients' overall survival (OS) and progression-free survival (PFS), and the safety of this regimen is generally controllable. To ensure the appropriateness of the chosen treatment, economic evaluation is essential. Thus, from the perspective of American healthcare systems, we explored the cost-effectiveness comparison between NALIRIFOX or GemNab in treating patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had not previously received treatment. METHODS A three-state partitioned survival model was developed, incorporating a lifetime horizon with a 4-week cycle length. The efficacy data were sourced from the NAPOLI 3 study, while treatment costs, health state utilities, and adverse events (AEs) were obtained from public databases and literature. Applying an annual discount rate of 3%, the analysis focused on total cost, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) as primary outcomes. Conducted within a US healthcare system perspective over a 13-year lifetime horizon, the analysis set willingness-to-pay (WTP) thresholds of $50,000, $100,000 and $150,000 per QALY. Sensitivity analyses were performed to assess the robustness of the model's findings. RESULTS In our base-case analysis, NALIRIFOX group was estimated to achieve an incremental gain of 0.13 QALYs. Compared to the GemNab group, treatment with NALIRIFOX resulted in higher costs ($150,437 vs $130,683). The ICER for NALIRIFOX therapy was calculated to be $155,602.83/QALYs. Sensitivity analysis revealed the model's robustness across a range of parameters. Through probabilistic sensitivity analysis applying Monte Carlo simulation with 1000 iterations, NALIRIFOX therapy was identified as the cost-effective regimen in 45.7% of all iterations at a WTP threshold of $150,000/QALYs. CONCLUSIONS Treatment with NALIRIFOX strategy was estimated to provide a significant clinical advantage over GemNab. According to the model outcomes, NALIRIFOX therapy is borderline cost-effective for treatment-naive patients with mPDAC, slightly exceeding the highest conventional US willingness-to-pay threshold of 150,000/QALY. However, at lower thresholds, such as 100,000/QALY, NALIRIFOX fails to demonstrate cost-effectiveness in all simulations. In addition, NALIRIFOX therapy emerges as a cost-effective treatment strategy at higher willingness-to-pay thresholds or when the drug price is significantly reduced.
Collapse
Affiliation(s)
- Wenjie Liu
- National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District Panjiayuan Nanli No. 17, Beijing, 100021, China
| | - Yuting Fang
- National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District Panjiayuan Nanli No. 17, Beijing, 100021, China
| | - Chao Zhang
- Department of Medical Oncology, Beijing Chaoyang District Sanhuan Cancer Hospital, Beijing, 100122, China
| | - Midan Xiang
- National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District Panjiayuan Nanli No. 17, Beijing, 100021, China
| | - Lijuan Qi
- National Cancer Center, National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang, 065001, China
| | - Aijiang Su
- Department of Medical Oncology, Beijing Chaoyang District Sanhuan Cancer Hospital, Beijing, 100122, China
| | - Yongkun Sun
- National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District Panjiayuan Nanli No. 17, Beijing, 100021, China.
| |
Collapse
|
|
42
|
Lee SS, Kareff SA, Fatoki RA. Locally advanced pancreatic cancer treated with surgical resection after chemotherapy. BMJ Case Rep 2025; 18:e264212. [PMID: 40250859 DOI: 10.1136/bcr-2024-264212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2025] Open
Abstract
Pancreatic cancer is a malignancy with poor prognosis and overall poor response to systemic therapy. Moreover, patients with locally advanced or unresectable tumours have historically worse outcomes compared with those with earlier stages of disease. We report a case of a female patient in the fourth decade with locally advanced pancreatic adenocarcinoma, who received 12 cycles modified FOLFIRINOX (mFOLFIRINOX: fluorouracil/leucovorin/irinotecan/oxaliplatin) chemotherapy, followed by pancreaticoduodenectomy, resulting in a near complete pathological response after definitive surgical treatment. Given the lack of indication for adjuvant therapy, she is considered in remission. The case demonstrates that potentially curative surgical resection can be a viable and sought-after treatment option for patients with locally advanced and/or metastatic pancreatic cancer, as it is not readily available for many patients due to the disease's aggressive nature and presence of advanced stage at diagnosis. It holds meaningful implications for clinical practice and promotes considerations in future advancements in treatment strategies.
Collapse
Affiliation(s)
- Soobin Serena Lee
- University of Miami, University of Miami, Leonard M. Miller School of Medicine, Miami, Florida, USA
| | - Samuel A Kareff
- Baptist Health South Florida, Lynn Cancer Institute, Boca Raton, Florida, USA
| | - Raleigh A Fatoki
- Sylvester Cancer Center, University of Miami Health System, Miami, Florida, USA
| |
Collapse
|
|
43
|
Ohira R, Suzuki R, Asama H, Sugimoto M, Sato K, Shimizu H, Takagi T, Hikichi T, Nakamura J, Kato T, Yanagita T, Ohira H. A Systemic Review and Meta-analysis of the Incidence Rate of Interstitial Lung Disease in Patients with Unresectable Pancreatic Cancer Treated with Gemcitabine and Nab-paclitaxel Combination Therapy in the Japanese Population. Intern Med 2025:5084-24. [PMID: 40222935 DOI: 10.2169/internalmedicine.5084-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/15/2025] Open
Abstract
Background Drug-induced interstitial lung disease (DI-ILD) is an adverse effect of the combination of gemcitabine and nab-paclitaxel (GnP) treatment that has raised concerns because the incidence rate of DI-ILD in the real world is higher than that reported in initial clinical trials. The present study assessed the cumulative incidence rate of DI-ILD among patients treated with GnP based on previously published studies and explored any potential bias in the results. Methods We conducted a meta-analysis in accordance with the PRISMA guidelines. The MEDLINE, Scopus, and Cochrane Library databases were searched from 2013 to 2024, using specific keywords. Randomized controlled trials, prospective studies, retrospective studies, and case-control studies that reported the incidence of interstitial lung disease (ILD) among patients treated with GnP were included. Two reviewers independently extracted the data from the included studies. Results Nine studies involving 1,980 patients were included in this analysis. Nine studies were conducted in Japan. The pooled incidence of DI-ILD was 5.9%. A subgroup analysis revealed that smaller studies reported higher incidence rates (≤200 vs. ≥201 cases: 9.4% vs. 4.1%). There was significant heterogeneity and publication bias, suggesting that the variability in incidence rates was due to the study size and potential biases. Conclusion The pooled incidence of ILD among patients treated with GnP was 5.9%. However, the results should be interpreted with caution because of the heterogeneity and publication bias. Further global studies are required to determine the true incidence of ILD.
Collapse
Affiliation(s)
- Rei Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Rei Suzuki
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Hiroyuki Asama
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Mitsuru Sugimoto
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Kentaro Sato
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Hiroshi Shimizu
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Tadayuki Takagi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Takuto Hikichi
- Department of Endoscopy, Fukushima Medical University Hospital, Japan
| | - Jun Nakamura
- Department of Endoscopy, Fukushima Medical University Hospital, Japan
| | - Tsunetaka Kato
- Department of Endoscopy, Fukushima Medical University Hospital, Japan
| | - Takumi Yanagita
- Department of Endoscopy, Fukushima Medical University Hospital, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| |
Collapse
|
|
44
|
Kim DH, Kim DJ, Park SJ, Jang WJ, Jeong CH. Inhibition of GLS1 and ASCT2 Synergistically Enhances the Anticancer Effects in Pancreatic Cancer Cells. J Microbiol Biotechnol 2025; 35:e2412032. [PMID: 40223274 PMCID: PMC12010092 DOI: 10.4014/jmb.2412.12032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/14/2025] [Accepted: 02/15/2025] [Indexed: 04/15/2025]
Abstract
Pancreatic cancer, a leading cause of cancer-related deaths, is characterized by increased dependence on glutamine metabolism. Telaglenastat (CB-839), a glutaminase (GLS) inhibitor targets glutamine metabolism; however, its efficacy as monotherapy is limited owing to metabolic adaptations. In this study, we demonstrated that CB-839 effectively inhibited cell growth in pancreatic cancer cells, but activated the general control nonderepressible 2 (GCN2)-activating transcription factor 4 (ATF4) signaling pathway. ATF4 knockdown reduced glutamine transporter alanine, serine, and cysteine transporter 2 (ASCT2) expression, glutamine uptake, and cell viability under glutamine deprivation-recovery conditions, confirming its protective role in mitigating glutamine-related metabolic stress. Notably, the combination of CB-839 and the ASCT2 inhibitor V-9302 demonstrated a synergistic effect, significantly suppressing pancreatic cancer cell survival. These findings highlight ATF4 and ASCT2 as crucial therapeutic targets and indicate that dual inhibition of GLS and ASCT2 may enhance treatment outcomes for pancreatic cancer.
Collapse
Affiliation(s)
- Dong-Hwan Kim
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Dong Joon Kim
- Department of Microbiology, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Seong-Jun Park
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Won-Jun Jang
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| | - Chul-Ho Jeong
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea
| |
Collapse
|
|
45
|
Caggiano EG, Hernandez AL, Waldrop T, Liu K, Gatica-Gutierrez H, Vargas-Hernández S, Mims N, Acevedo-Diaz A, Velasquez B, Neil D, Aguilar E, Meyer MD, Echeverria GV, Koong AC, Spiotto MT, Gustavsson AK, Schüler E. Mitochondrial Responses to Conventional and Ultra-high Dose Rate (FLASH) Radiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.03.647049. [PMID: 40291669 PMCID: PMC12026588 DOI: 10.1101/2025.04.03.647049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Purpose Ultra-high dose rate (>40 Gy/s, FLASH) radiation therapy (RT) provides equivalent tumor control while reducing normal tissue toxicity relative to conventional dose rate (CONV) RT. However, the mechanisms underlying the observed FLASH effect are unknown. We hypothesized that the preservation of mitochondrial integrity in nontumorigenic cells by FLASH RT could be a key factor in reducing normal tissue toxicity and improving overall treatment outcomes. Methods We examined mitochondrial health and function after CONV and FLASH in vitro, ex vivo, and in vivo through assays of metabolic flux, mitochondrial membrane potential, mitochondrial reactive oxygen species (ROS), mitochondrial DNA damage and copy number, mitochondrial morphology, and tumor growth and survival. Results In in vitro assays, murine pancreatic cancer (PDAC) cells showed evidence of equal mitochondrial damage in response to CONV and FLASH, but nontumorigenic pancreatic cells were spared by FLASH. These results were recapitulated ex vivo, and mice treated with FLASH showed higher response rates and longer survival time than mice treated with CONV in an in vivo tumor model. Conclusions Collectively, these results suggest that FLASH spares mitochondrial function in nontumorigenic cells, but not in PDAC cells, relative to CONV. The preservation of mitochondrial integrity in nontumorigenic cells may be a key mechanism underlying the reduced normal tissue toxicity observed with FLASH RT.
Collapse
|
|
46
|
Liang KL, Azad NS. Immune-Based Strategies for Pancreatic Cancer in the Adjuvant Setting. Cancers (Basel) 2025; 17:1246. [PMID: 40227779 PMCID: PMC11988091 DOI: 10.3390/cancers17071246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/31/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the United States, with poor overall survival across all stages. Less than 20% of patients are eligible for curative surgical resection at diagnosis, and despite adjuvant chemotherapy, most will experience disease recurrence within two years. The incorporation of immune-based strategies in the adjuvant setting remains an area of intense investigation with unrealized promise. It offers the potential of providing durable disease control for micro-metastatic disease following curative intent surgery and enabling personalized treatments based on mutational neoantigen profiles derived from resected specimens. However, most of these attempts have failed to demonstrate significant clinical success, likely due to the immunosuppressive tumor microenvironment (TME) and individual genetic heterogeneity. Despite these challenges, immune-based strategies, such as therapeutic vaccines targeted towards neoantigens, have demonstrated promise via immune activation and induction of T-cell tumor infiltration. In this review, we will highlight the foundational lessons learned from previous clinical trials of adjuvant immunotherapy, discussing the knowledge gained from analyses of trials with disappointing results. In addition, we will discuss how these data have been incorporated to design new agents and study concepts that are proving to be exciting in more recent trials, such as shared antigen vaccines and combination therapy with immune-checkpoint inhibitors and chemotherapy. This review will evaluate novel approaches in ongoing and future clinical studies and provide insight into how these immune-based strategies might evolve to address the unique challenges for treatment of PDAC in the adjuvant setting.
Collapse
Affiliation(s)
| | - Nilofer S. Azad
- Department of Oncology, Sidney Kimmel Comprehensive Cancer, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
| |
Collapse
|
|
47
|
Powell J, Viniotis AF, Irwin C, Jameson GS, Caldwell L, Borazanci EH. Retrospective analysis of capecitabine maintenance therapy in pancreatic ductal adenocarcinoma. Ther Adv Med Oncol 2025; 17:17588359251321894. [PMID: 40290464 PMCID: PMC12032433 DOI: 10.1177/17588359251321894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 01/28/2025] [Indexed: 04/30/2025] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PC) is an aggressive form of cancer treated with chemotherapy regimens such as leucovorin, 5-fluorouracil (5-FU), irinotecan, oxaliplatin (FOLFIRINOX), and gemcitabine plus albumin-bound paclitaxel (nab-Paclitaxel). Maintenance chemotherapy is increasingly being studied as an option for patients with a prior response to chemotherapy, prolonged stable disease, and those unable to tolerate the toxicities of traditional chemotherapy. Objective Our retrospective analysis aims to evaluate the effectiveness and tolerability of capecitabine as maintenance therapy in patients with PC. Design Thirty-three patients treated for PC with capecitabine (an oral formulation of 5-FU) maintenance therapy at our single institution between 8/01/2013 and 9/02/2021 were identified on chart review via the electronic medical record (EMR). Methods Kaplan-Meier curves were fit to evaluate patient progression-free survival (PFS) and overall survival (OS). Results Thirty-three individuals were identified: 21 males and 12 females, with a median age of 69 years. Fifteen of 33 had stage IV PC. Nineteen had progression of disease; 8 completed therapy and transitioned to observation or other treatments; 2 did not tolerate treatment; and 4 were still undergoing treatment. The median PFS was 13.01 months (396.0 days), and the median OS was 28.42 months (865.0 days). Conclusion Maintenance with capecitabine seems safe and may represent a valuable option in patients with advanced PC controlled using FOLFIRINOX or gemcitabine/nab-Paclitaxel induction treatment.
Collapse
Affiliation(s)
- Jordan Powell
- The University of Arizona College of Medicine, Phoenix, AZ, USA
| | - Alexa F. Viniotis
- HonorHealth Thompson Peak Internal Medicine Residency, 7400 E Thompson Peak Parkway, Scottsdale, AZ 85255, USA
| | - Chase Irwin
- The University of Arizona College of Medicine, Phoenix, AZ, USA
| | - Gayle S. Jameson
- HonorHealth Research and Innovation Institute, Scottsdale, AZ, USA
| | - Lana Caldwell
- HonorHealth Research and Innovation Institute, Scottsdale, AZ, USA
| | | |
Collapse
|
|
48
|
Sezgin Y, Karhan O, Aldemir MN, Ürün M, Erçek BM, Urakcı Z, Arvas H, Tunç S, Erdem M, Yerlikaya H, İleri S, Aydın İ, Bicer A, Kömüroğlu AU, Majidova N, Gökçek S, Demir H, Yıldız S, Akbaş S, Özen E, Kahya BU, Sali M, Anık H, Aykut T, Araz M, Alkan A, Özçelik M, Sakin A, Aykan MB, Mehtıyev M, Demir B, Başer MN, Sönmez M, Gültürk İ, Avcı N, Urvay S, Arıcı MÖ, Kalender ME, Yıldırım M, Solmaz AA, Gürbüz M, Ergün Y. Efficacy of gemcitabine plus nab-paclitaxel in second-line treatment of metastatic pancreatic cancer. Sci Rep 2025; 15:11675. [PMID: 40188172 PMCID: PMC11972389 DOI: 10.1038/s41598-025-96157-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 03/26/2025] [Indexed: 04/07/2025] Open
Abstract
Despite numerous studies on second-line therapies in metastatic pancreatic cancer, there is no randomized study evaluating the efficacy of gemcitabine plus nab-paclitaxel as a second-line treatment. This study aims to examine the efficacy of gemcitabine plus nab-paclitaxel in second-line therapy. In this retrospective study, a total of 218 patients from 23 centers were included. The primary endpoint was progression-free survival (PFS), secondary endpoints included overall survival (OS), treatment efficacy based on ECOG performance status (PS), and tumor marker (CEA, CA 19 - 9) levels. In the second-line treatment with gemcitabine plus nab-paclitaxel, the median PFS was 5.1 months (95% CI, 5.6 to 7.1), and the median OS was 8.6 months (95% CI, 7.3 to 10.0). Median PFS was 6.6 months in patients with normal CEA levels compared to 4.4 months in patients with high CEA levels (P = 0.01). Median PFS was 6 months in patients with ECOG PS 0-1 compared to 3.8 months in patients with PS 2 (P < 0.01). This study demonstrates the contribution of gemcitabine plus nab-paclitaxel in both OS and PFS in second-line treatment of metastatic pancreatic cancer. It was found to be a good option especially for young patients with good ECOG PS.
Collapse
Affiliation(s)
- Yasin Sezgin
- Department of Medical Oncology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey.
| | - Oğur Karhan
- Department of Medical Oncology, Faculty of Medicine, Harran University, Şanlıurfa, Turkey
| | - Mehmet Naci Aldemir
- Department of Medical Oncology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey
| | - Muslih Ürün
- Department of Medical Oncology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey
| | - Berrak Mermit Erçek
- Department of Medical Oncology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey
| | - Zuhat Urakcı
- Department of Medical Oncology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Hayati Arvas
- Department of Medical Oncology, Faculty of Medicine, Dicle University, Diyarbakır, Turkey
| | - Sezai Tunç
- Urfa Mehmet Akif Inan Regional Training Research Hospital Oncology Department, Şanlıurfa, Turkey
| | - Mehmet Erdem
- Department of Internal Medicine, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey
| | - Halis Yerlikaya
- Diyarbakır private Batı Hospital Medical Oncology Department, Diyarbakır, Turkey
| | - Serdar İleri
- Gazi Yaşargil Regional Training Research Hospital Oncology Department, Diyarbakır, Turkey
| | - İbrahim Aydın
- Department of Internal Medicine, Van Regional Training Research Hospital, Van, Turkey
| | - Abdurrahman Bicer
- Department of Internal Medicine, Van Regional Training Research Hospital, Van, Turkey
| | - Ahmet Ufuk Kömüroğlu
- Health Service Vocational School of Higher Education, Van Yüzüncü Yıl University, Van, Turkey
| | - Nargiz Majidova
- Department of Medical Oncology, Faculty of Medicine, Marmara University, Istanbul, Turkey
| | - Savaş Gökçek
- Department of Medical Oncology, Faculty of Medicine, Eyül University, İzmir, Turkey
| | - Hacer Demir
- Department of Medical Oncology, Faculty of Medicine, Afyon Karahisar University, Afyonkarahisar, Turkey
| | - Sedat Yıldız
- Department of Medical Oncology, Faculty of Medicine, Afyon Karahisar University, Afyonkarahisar, Turkey
| | - Sinem Akbaş
- Department of Medical Oncology, Faculty of Medicine, Koç University, Istanbul, Turkey
| | - Esra Özen
- Department of Medical Oncology, Faculty of Medicine, Sakarya University, Sakarya, Turkey
| | - Burcu Ulaş Kahya
- Department of Medical Oncology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Mürsel Sali
- Department of Medical Oncology, Faculty of Medicine, Uludağ University, Bursa, Turkey
| | - Hicran Anık
- Abdurrahman Yurtaslan Regional Training Research Hospital Oncology Department, Ankara, Turkey
| | - Talat Aykut
- Department of Medical Oncology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Murat Araz
- Department of Medical Oncology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Ali Alkan
- Department of Medical Oncology, Faculty of Medicine, Muğla Sıtkı Kocaman University, Muğla, Turkey
| | - Melike Özçelik
- Ümraniye Regional Training Research Hospital Oncology Department, Istanbul, Turkey
| | - Abudllah Sakin
- İstanbul Private Medicalpark Hospital Medical Oncology Department, Istanbul, Turkey
| | - Musa Barış Aykan
- Gülhane Regional Training Research Hospital Oncology Department, Ankara, Turkey
| | - Mirmehdi Mehtıyev
- Department of Medical Oncology, Bilkent City Hospital, Ankara, Turkey
| | - Bilgin Demir
- Faculty of Medicine, Department of Medical Oncology, Adana Menderes University, Aydın, Turkey
| | - Mehmet Nuri Başer
- Faculty of Medicine, Department of Medical Oncology, Adana Menderes University, Aydın, Turkey
| | - Müge Sönmez
- Department of Medical Oncology, Faculty of Medicine, Department of Medical Oncology, Ordu State Hospital, Sanko University, 26 İstanbul Regional, Istanbul, Turkey
| | - İlkay Gültürk
- Department of Medical Oncology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey
| | - Nilüver Avcı
- Department of Medical Oncology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey
| | - Semiha Urvay
- Department of Medical Oncology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey
| | - Mustafa Özgür Arıcı
- Department of Medical Oncology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey
| | - Mehmet Emin Kalender
- Department of Medical Oncology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey
| | - Mustafa Yıldırım
- Department of Medical Oncology, Faculty of Medicine, Van Yüzüncü Yıl University, Van, Turkey
| | - Ali Alper Solmaz
- Department of Medical Oncology, Adana City Hospital, Adana, Turkey
| | - Mustafa Gürbüz
- Department of Medical Oncology, Adana City Hospital, Adana, Turkey
| | - Yakup Ergün
- Department of Medical Oncology, Diyarbakır Private Bower Hospital, Diyarbakır, Turkey
| |
Collapse
|
|
49
|
Stoop TF, Javed AA, Oba A, Koerkamp BG, Seufferlein T, Wilmink JW, Besselink MG. Pancreatic cancer. Lancet 2025; 405:1182-1202. [PMID: 40187844 DOI: 10.1016/s0140-6736(25)00261-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 01/31/2025] [Accepted: 02/05/2025] [Indexed: 04/07/2025]
Abstract
Pancreatic cancer is frequently a lethal disease with an aggressive tumour biology often presenting with non-specific symptoms. Median survival is approximately 4 months with a 5-year survival of 13%. Surveillance is recommended in individuals with familial pancreatic cancer, specific mutations, and high-risk intraductal papillary mucinous neoplasm, as they are at high risk of developing pancreatic cancer. Chemotherapy combined with surgical resection remains the cornerstone of treatment. However, only a small subset of patients are candidates for surgery. Multi-agent chemotherapy has improved survival in the palliative setting for patients with metastatic disease, as (neo)adjuvant and induction therapy have in patients with borderline resectable and locally advanced pancreatic. Given that pancreatic cancer is predicted to become the second leading cause of cancer-related death by 2030, novel therapies are urgently needed.
Collapse
Affiliation(s)
- Thomas F Stoop
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, Netherlands; Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Ammar A Javed
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, Netherlands; Cancer Center Amsterdam, Amsterdam, Netherlands; Division of Surgical Oncology, Department of Surgery, New York University Medical Center, New York, NY, USA
| | - Atsushi Oba
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan; Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Thomas Seufferlein
- Department of International Medicine I, Ulm University Hospital, Ulm, Germany
| | - Johanna W Wilmink
- Department of Medical Oncology, Amsterdam, Netherlands; Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Marc G Besselink
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, Netherlands; Cancer Center Amsterdam, Amsterdam, Netherlands.
| |
Collapse
|
|
50
|
Picozzi VJ, Mandelson MT, Najjar A, Li M, Harb DE, Kort JJ. Pancreatic enzyme replacement therapy in advanced adenocarcinoma of the pancreas improved overall survival: a retrospective, single institution study. Oncologist 2025; 30:oyaf014. [PMID: 40231659 PMCID: PMC11997656 DOI: 10.1093/oncolo/oyaf014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 01/08/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Weight loss and exocrine pancreatic insufficiency are common in advanced pancreatic ductal adenocarcinoma (PDAC) and are associated with adverse outcomes. However, there is limited evidence on the impact of pancreatic enzyme replacement therapy (PERT) in patients with advanced PDAC. PATIENTS AND METHODS We retrospectively studied 501 patients with advanced PDAC and exocrine pancreatic insufficiency from the Virginia Mason Pancreas Cancer Program Data Resource treated between 2010 and 2019 with first-line chemotherapy. Clinical outcomes were compared between those who received PERT and those who did not at 8 weeks after chemotherapy start. RESULTS In total 188 (38%) patients received PERT; 313 patients (62%) did not. PERT patients experienced less weight loss (-1.5 vs -2.5 kg, P = .04), less decline in the prognostic nutrition index -1.9 vs -3.0, P = .01), and a greater reduction in the additive score of the Patient-Generated Subjective Global Assessment (-8.4 vs --6.0, P = .02). Importantly, median (95% CI) overall survival (OS) was significantly longer in the PERT vs non-PERT group (17.1 months vs 12.5 months, respectively P = .001), and the adjusted hazards ratio indicated superior median OS in patients prescribed PERT (HR = 0.73, P < .001). CONCLUSIONS Our findings suggest that treatment of exocrine pancreatic insufficiency (EPI) in advanced PDAC is associated with improvements in nutrition and overall survival.
Collapse
Affiliation(s)
- Vincent J Picozzi
- Virginia Mason Hospital and Medical Center, Seattle, WA 98111, United States
| | | | - Anas Najjar
- Benaroya Research Institute, Seattle, WA 98101, United States
| | - Moming Li
- Data and Statistical Sciences, AbbVie Inc., North Chicago, IL 60064, United States
| | - Diala E Harb
- US Medical Affairs, AbbVie Inc., Mettawa, IL 60045, United States
| | - Jens J Kort
- US Medical Affairs, AbbVie Inc., Mettawa, IL 60045, United States
| |
Collapse
|