|
1
|
Reshkin SJ, Cardone RA, Koltai T. Genetic Signature of Human Pancreatic Cancer and Personalized Targeting. Cells 2024; 13:602. [PMID: 38607041 PMCID: PMC11011857 DOI: 10.3390/cells13070602] [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: 02/12/2024] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/13/2024] Open
Abstract
Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.
Collapse
Affiliation(s)
- Stephan J. Reshkin
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Tomas Koltai
- Oncomed, Via Pier Capponi 6, 50132 Florence, Italy
| |
Collapse
|
|
2
|
Chang XY, Wu Y, Li Y, Wang J, Chen J. Intraductal papillary mucinous neoplasms of the pancreas: Clinical association with KRAS. Mol Med Rep 2018; 17:8061-8068. [PMID: 29658583 PMCID: PMC5983980 DOI: 10.3892/mmr.2018.8875] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 01/18/2018] [Indexed: 12/30/2022] Open
Abstract
Intraductal papillary mucinous neoplasms of the pancreas (IPMN) are among the most important precancerous lesions in the pancreas. V‑Ki‑ras 2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most important genes involved in pancreatic neoplasms, and exhibits a high mutation rate in pancreatic ductal adenocarcinomas and pancreatic intraepithelial neoplasia. The present study aimed to further elucidate the associations among IPMN subtypes (gastric, intestinal, pancreatobiliary and oncocytic), pathological classifications [low‑grade, intermediate‑grade, and high‑grade IPMN, and associated minimally invasive carcinoma (invasive depth ≤0.5 cm) and advanced invasive carcinoma (invasive depth >0.5 cm)]. A total of 56 cases of IPMN were studied using scorpion amplified refractory mutation system analysis of KRAS mutations, pathological features and prognosis. KRAS mutations were identified in 50% (28/56 cases). The frequency was 60% (9/15 cases) in gastric‑type, 52.6% (10/19 cases) in intestinal‑type, 47.3% (9/19 cases) in pancreatobiliary‑type and zero (0/3 cases) in oncocytic‑type IPMN. Except for oncocytic type IPMN, the frequencies of KRAS mutations in IPMN with low, intermediate and high grade, and IPMN‑associated carcinoma were 58.3% (7/12 cases), 27.3% (3/11 cases), 80% (4/5 cases) and 56% (14/25 cases), respectively. With more advanced dysplasia and invasion, the prevalence of KRAS mutations in intestinal‑type IPMN increased (P=0.012). The Kaplan‑Meier survival curve demonstrated that survival rate was not associated with KRAS mutation (log‑rank test; P=0.308). The prevalence of KRAS mutations was lowest in intestinal‑type IPMN, and was in proportion to the degree of dysplasia and invasion. Therefore, KRAS mutation in IPMN does not correlate with histological subtype, dysplasia grade, depth of invasion or survival.
Collapse
Affiliation(s)
- Xiao Yan Chang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing 100730, P.R. China
| | - Yan Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing 100730, P.R. China
| | - Yuan Li
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing 100730, P.R. China
| | - Jing Wang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing 100730, P.R. China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing 100730, P.R. China
| |
Collapse
|
|
3
|
The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting. Crit Rev Oncol Hematol 2017; 111:7-19. [PMID: 28259298 DOI: 10.1016/j.critrevonc.2017.01.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 11/15/2016] [Accepted: 01/05/2017] [Indexed: 01/17/2023] Open
Abstract
RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90%). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence. In this review, we discuss the central role of K-RAS mutations and their tremendous diversity of biological properties by the interconnected regulation of signaling pathways (MAPKs, NF-κB, PI3K, Ral…). In pancreatic ductal adenocarcinoma, transcriptome analysis and preclinical animal models showed that K-RAS mutation alters biological behavior of PDAC cells (promoting proliferation, migration and invasion, evading growth suppressors, regulating mucin pattern, and miRNA expression). K-RAS also impacts tumor microenvironment and PDAC metabolism reprogramming. Finally we discuss therapeutic targeting strategies of K-RAS that have been developed without significant clinical success so far. As K-RAS is considered as the undruggable target, targeting its multiple effectors and target genes should be considered as potential alternatives.
Collapse
|
|
4
|
Rizzato C, Campa D, Talar-Wojnarowska R, Halloran C, Kupcinskas J, Butturini G, Mohelníková-Duchoňová B, Sperti C, Tjaden C, Ghaneh P, Hackert T, Funel N, Giese N, Tavano F, Pezzilli R, Pedata M, Pasquali C, Gazouli M, Mambrini A, Souček P, di Sebastiano P, Capurso G, Cantore M, Oliverius M, Offringa R, Małecka-Panas E, Strobel O, Scarpa A, Canzian F. Association of genetic polymorphisms with survival of pancreatic ductal adenocarcinoma patients. Carcinogenesis 2016; 37:957-964. [PMID: 27497070 DOI: 10.1093/carcin/bgw080] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 07/30/2016] [Indexed: 02/05/2023] Open
Abstract
Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10(-5)) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials.
Collapse
Affiliation(s)
- Cosmeri Rizzato
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany, Department of Translational Research and New Technologies in Medicine and Surgery and
| | - Daniele Campa
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany, Department of Biology, University of Pisa, Pisa, Italy
| | | | - Christopher Halloran
- Department of Molecular and Clinical Cancer Medicine, NIHR Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, UK
| | - Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Giovanni Butturini
- Unit of Surgery B, The Pancreas Institute, Department of Surgery and Oncology, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy
| | | | - Cosimo Sperti
- Department of Surgery, Gastroenterology and Oncology, University of Padua, Padua, Italy
| | - Christine Tjaden
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Paula Ghaneh
- Department of Molecular and Clinical Cancer Medicine, NIHR Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, UK
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Niccola Funel
- Department of Translational Research and New Technologies in Medicine and Surgery and
| | - Nathalia Giese
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Francesca Tavano
- Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo (FG), Italy
| | - Raffaele Pezzilli
- Pancreas Unit, Department of Digestive Disease, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | | | - Claudio Pasquali
- Department of Surgery, Gastroenterology and Oncology, University of Padua, Padua, Italy
| | - Maria Gazouli
- Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece
| | - Andrea Mambrini
- Oncological Department, ASL 1 Massa Carrara, Massa Carrara, Italy
| | - Pavel Souček
- Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic
| | - Pierluigi di Sebastiano
- Department of Surgery, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy
| | - Gabriele Capurso
- Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy
| | - Maurizio Cantore
- Oncological Department, ASL 1 Massa Carrara, Massa Carrara, Italy
| | - Martin Oliverius
- Transplant Surgery Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Rienk Offringa
- Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany and
| | - Ewa Małecka-Panas
- Department of Digestive Tract Diseases, Medical University of Łódź, Łódź, Poland
| | - Oliver Strobel
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Aldo Scarpa
- ARC-NET, Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany,
| |
Collapse
|
|
5
|
Li T, Zheng Y, Sun H, Zhuang R, Liu J, Liu T, Cai W. K-Ras mutation detection in liquid biopsy and tumor tissue as prognostic biomarker in patients with pancreatic cancer: a systematic review with meta-analysis. Med Oncol 2016; 33:61. [PMID: 27225938 DOI: 10.1007/s12032-016-0777-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 05/14/2016] [Indexed: 01/06/2023]
Abstract
K-Ras gene mutations have been found in most pancreatic cancers; however, conflicting data on the prognostic value of K-Ras mutations in pancreatic cancer have been published. We conducted a meta-analysis to assess its prognostic significance. Literature searches of PubMed, EMBASE, Cochrane Library, Web of Science and Google Scholar were performed through December 2015 to identify publications exploring the association of K-Ras mutation with overall survival. Forty eligible studies involving 3427 patients with pancreatic cancer were included in the present meta-analysis. Our analysis showed a hazard ratio (HR) of negative association with survival of 1.61 [95 % confidence interval (CI) 1.36-1.90; p < 0.01] in K-Ras mutant pancreatic cancer patients. In subgroup analyses, K-Ras mutations detected in tumor tissues and in liquid biopsies had HRs of 1.37 (95 % CI 1.20-1.57; p < 0.01) and 3.16 (95 % CI 2.1-4.71; p < 0.01), respectively. In addition, the HR was higher when K-Ras mutations were detected in fresh frozen samples (HR = 2.01, 95 % CI 1.28-3.16, p = 0.002) than in formalin-fixed, paraffin-embedded (FFPE) samples (HR = 1.29, 95 % CI 1.12-1.49, p < 0.01). Though K-Ras alterations are more frequent among non-East Asian individuals than East Asian individuals, there were no significant differences in HRs of survival between the two ethnic subgroups. In conclusion, this meta-analysis suggests that K-Ras mutations are associated with a worse overall survival in pancreatic cancer patients, especially when mutations are detected in liquid biopsies or fresh frozen tumor tissue samples.
Collapse
Affiliation(s)
- Tao Li
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China
| | - Yuanting Zheng
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China
| | - Hong Sun
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China
| | - Rongyuan Zhuang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Liu
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weimin Cai
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China.
| |
Collapse
|
|
6
|
Bournet B, Buscail C, Muscari F, Cordelier P, Buscail L. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities. Eur J Cancer 2016; 54:75-83. [DOI: 10.1016/j.ejca.2015.11.012] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 11/08/2015] [Accepted: 11/11/2015] [Indexed: 02/07/2023]
|
|
7
|
Zhu SK. Role of precision medicine in pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2016; 24:4752. [DOI: 10.11569/wcjd.v24.i36.4752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
|
|
8
|
KRAS mutations in pancreatic circulating tumor cells: a pilot study. Tumour Biol 2015; 37:7547-54. [PMID: 26684803 DOI: 10.1007/s13277-015-4589-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Accepted: 12/03/2015] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is most often diagnosed in a metastatic stage. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic dissemination. We aimed to isolate and characterize CTC to evaluate their significance as prognostic markers in PDAC. Blood obtained from healthy donors and patients with PDAC before therapy was filtered with ScreenCell® filtration devices for size-based CTC isolation. Captured cells were analyzed by immunofluorescence for an epithelial to mesenchymal transition (EMT) marker (zinc finger E-box binding homebox 1 (ZEB1)) and an epithelial antigen (cytokeratin (CK)). Molecular analysis of parallel specimens evaluated the KRAS mutation status of the CTC. The survival of each patient after study was recorded. As demonstrated by either cytology or finding of a KRAS mutation, CTC were detected in 18 of 21 patients (86 %) with proven PDAC: 8 out of 10 patients (80 %) with early stage (UICC IIA/IIB) and 10 out of 11 (91 %) with late stage (UICC III/IV) disease. CTC were not found in any of the 10 control patients (p < 0.001). The presence of CTC did not adversely affect median survival: 16 months in CTC-positive (n = 18) vs. 10 months in CTC-negative (n = 3) patients. Neither ZEB1 nor cytological characteristics correlated with overall survival, although ZEB1 was found almost exclusively in CTC of patients with established metastases. Patients with a CTC KRAS mutation (CTC-KRAS (mut)) had a substantially better survival, 19.4 vs. 7.4 months than patients with wild type KRAS (p = 0.015). With ScreenCell filtration, CTC are commonly found in PDAC (86 %). Molecular and genetic characterization, including mutations such as KRAS, may prove useful for prognosis.
Collapse
|
|
9
|
Low frequency of KRAS mutation in pancreatic ductal adenocarcinomas in Korean patients and its prognostic value. Pancreas 2015; 44:484-92. [PMID: 25513781 DOI: 10.1097/mpa.0000000000000280] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Low prevalence and prognostic relevance of KRAS mutations in Korean pancreatic ductal adenocarcinomas (PDACs) need to be validated with sensitive detection method. METHODS Peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping was used to precisely detect KRAS mutation in 72 paraffinized tumor samples and was validated by pancreatic cell lines to compare the efficiency of direct sequencing. RESULTS The PNA-mediated PCR clamping detected mutant allele proportions of as low as 0.5% against a background of wild-type DNA and was 20-fold more sensitive than direct sequencing through the validation of pancreatic cell lines. Peptide nucleic acid-mediated PCR clamping detected KRAS mutations in 47.2% of 72 PDACs. Low tumor cellularity and low PCR amplification efficiency led to be undetected or failed by direct sequencing in pancreatic paraffinized samples.KRAS mutations were an independent worse prognostic factor predicting a reduced progression-free survival rate in the postoperative chemotherapy group. CONCLUSIONS Peptide nucleic acid clamp real-time PCR was a sensitive method for detecting KRAS status in paraffinized PDAC samples. We identified a low KRAS mutation rate among the Korean PDAC patients using PNA clamp real-time PCR, potentially implicating epidemiological characteristics. The low KRAS mutation rate and its prognostic role may suggest the further survival benefit in Korean PDAC patients.
Collapse
|
|
10
|
Gong J, Muñoz AR, Chan D, Ghosh R, Kumar AP. STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth. Oncotarget 2015; 5:2529-41. [PMID: 24796733 PMCID: PMC4058024 DOI: 10.18632/oncotarget.1810] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The dismal 5-year survival (<5%) for pancreatic cancer (PanCA) underscores the need for developing effective therapeutic options. Recent studies from our laboratory have shown that Nexrutine® (Nx), a bark extract from Phellodendron amurense exhibits excellent anticancer activity in human pancreatic cancer cells through inhibition of inflammatory signaling via STAT3/NFκB/Cox-2. Given the apparent high oxidative stress and autophagic activity in pancreatic tumors, we investigated the potential of Nx to modulate autophagy, reactive oxygen species (ROS), and their crosstalk. Our results show that Nx inhibits autophagy and decreases ROS generation. Pharmacological inhibition of autophagy led to decreased ROS generation and proliferation with no significant effect on apoptosis. Further, using combination index analysis we also found that combination of late-stage autophagy inhibitor with Nx exhibited a moderate synergistic to additive effect. Additionally, genetic or pharmacological inactivation of STAT3 reduced LC3-II levels and expression indicating a possible role for STAT3 in transcriptional regulation of autophagy. Since both inflammatory and oxidative stress signaling activate STAT3, our data implicates that STAT3 plays a vital role in the regulation of autophagy through its contributions to the positive feedback loop between ROS and autophagy. Overall, our findings reveal an important role for STAT3/LC3/ROS in Nx-mediated anti-pancreatic cancer effects.
Collapse
Affiliation(s)
- Jingjing Gong
- Department of Urology, The University of Texas Health Science Center, San Antonio, TX
| | | | | | | | - Addanki P Kumar
- Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX
| |
Collapse
|
|
11
|
Bournet B, Gayral M, Torrisani J, Selves J, Cordelier P, Buscail L. Role of endoscopic ultrasound in the molecular diagnosis of pancreatic cancer. World J Gastroenterol 2014; 20:10758-10768. [PMID: 25152579 PMCID: PMC4138456 DOI: 10.3748/wjg.v20.i31.10758] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/12/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma remains one of the most deadly types of tumor. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a safe, cost-effective, and accurate technique for evaluating and staging pancreatic tumors. However, EUS-FNA may be inconclusive or doubtful in up to 20% of cases. This review underlines the clinical interest of the molecular analysis of samples obtained by EUS-FNA in assessing diagnosis or prognosis of pancreatic cancer, especially in locally advanced tumors. On EUS-FNA materials DNA, mRNA and miRNA can be extracted, amplified, quantified and subjected to methylation assay. Kras mutation assay, improves diagnosis of pancreatic cancer. When facing to clinical and radiological presentations of pseudo-tumorous chronic pancreatitis, wild-type Kras is evocative of benignity. Conversely, in front of a pancreatic mass suspected of malignancy, a mutated Kras is highly evocative of pancreatic adenocarcinoma. This strategy can reduce false-negative diagnoses, avoids the delay of making decisions and reduces loss of surgical resectability. Similar approaches are conducted using analysis of miRNA expression as well as Mucin or markers of invasion (S100P, S100A6, PLAT or PLAU). Beyond the diagnosis approach, the prediction of response to treatment can be also investigated form biomarkers expression within EUS-FNA materials.
Collapse
|
|
12
|
Rembielak AI, Jain P, Jackson AS, Green MM, Santorelli GR, Whitfield GA, Crellin A, Garcia-Alonso A, Radhakrishna G, Cullen J, Taylor MB, Swindell R, West CM, Valle J, Saleem A, Price PM. Phase II Trial of Cetuximab and Conformal Radiotherapy Only in Locally Advanced Pancreatic Cancer with Concurrent Tissue Sampling Feasibility Study. Transl Oncol 2014; 7:55-64. [PMID: 24772208 PMCID: PMC3998695 DOI: 10.1593/tlo.13724] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 02/07/2014] [Accepted: 02/10/2014] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Preclinical data have indicated the anti-epidermal growth factor receptor (EGFR) agent cetuximab (Erbitux) as a radiosensitizer in pancreatic cancer, but this has not been specifically addressed in a clinical study. We report the results of an original study initiated in 2007, where cetuximab was tested with radiotherapy (RT) alone in locally advanced pancreatic cancer in a phase II trial (PACER). METHODS Patients (n = 21) received cetuximab loading dose (400 mg/m(2)) and weekly dose (250 mg/m(2)) during RT (50.4 Gy in 28 fractions). Toxicity and disease response end point data were prospectively assessed. A feasibility study of on-trial patient blood and skin sampling was incorporated. RESULTS Treatment was well tolerated, and toxicity was low; most patients (71%) experienced acute toxicities of grade 2 or less. Six months posttreatment, stable local disease was achieved in 90% of evaluable patients, but only 33% were free from metastatic progression. Median overall survival was 7.5 months, and actuarial survival was 33% at 1 year and 11% at 3 years, reflecting swift metastatic progression in some patients but good long-term control of localized disease in others. High-grade acneiform rash (P = .0027), posttreatment stable disease (P = .0059), and pretreatment cancer antigen 19.9 (CA19.9) level (P = .0042) associated with extended survival. Patient skin and blood samples yielded sufficient RNA and good quality protein, respectively. CONCLUSIONS The results indicate that cetuximab inhibits EGFR-mediated radioresistance to achieve excellent local control with minimal toxicity but does not sufficiently control metastatic progression in all patients. Translational studies of patient tissue samples may yield molecular information that may enable individual treatment response prediction.
Collapse
Affiliation(s)
- Agata I Rembielak
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom ; The Christie National Health Service (NHS) Foundation Trust, Manchester, United Kingdom
| | - Pooja Jain
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom ; The Christie National Health Service (NHS) Foundation Trust, Manchester, United Kingdom
| | - Andrew S Jackson
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom ; The Christie National Health Service (NHS) Foundation Trust, Manchester, United Kingdom
| | - Melanie M Green
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom ; Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Gillian R Santorelli
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom
| | - Gillian A Whitfield
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom ; The Christie National Health Service (NHS) Foundation Trust, Manchester, United Kingdom
| | | | - Angel Garcia-Alonso
- North Wales Cancer Treatment Centre, Betsi Cadwaladr University Health Board, Rhyl, United Kingdom
| | | | - James Cullen
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom
| | - M Ben Taylor
- The Christie National Health Service (NHS) Foundation Trust, Manchester, United Kingdom
| | - Ric Swindell
- The Christie National Health Service (NHS) Foundation Trust, Manchester, United Kingdom
| | - Catharine M West
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom
| | - Juan Valle
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom ; The Christie National Health Service (NHS) Foundation Trust, Manchester, United Kingdom
| | - Azeem Saleem
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom ; Imanova Centre for Imaging Sciences, Hammersmith Hospital, London, United Kingdom
| | - Patricia M Price
- Academic Department of Radiation Oncology, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom ; Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| |
Collapse
|
|
13
|
Bournet B, Dufresne M, Selves J, Torrisani J, Cordelier P, Buscail L. OncogèneKraset cancer du pancréas. Med Sci (Paris) 2013; 29:991-7. [DOI: 10.1051/medsci/20132911015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
|