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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.
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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
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2
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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.
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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
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3
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Varghese AM, Perry MA, Chou JF, Nandakumar S, Muldoon D, Erakky A, Zucker A, Fong C, Mehine M, Nguyen B, Basturk O, Balogun F, Kelsen DP, Brannon AR, Mandelker D, Vakiani E, Park W, Yu KH, Stadler ZK, Schattner MA, Jarnagin WR, Wei AC, Chakravarty D, Capanu M, Schultz N, Berger MF, Iacobuzio-Donahue CA, Bandlamudi C, O'Reilly EM. Clinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall survival. Nat Med 2025; 31:466-477. [PMID: 39753968 PMCID: PMC11835752 DOI: 10.1038/s41591-024-03362-3] [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: 02/26/2024] [Accepted: 10/17/2024] [Indexed: 01/11/2025]
Abstract
Nearly all pancreatic adenocarcinomas (PDAC) are genomically characterized by KRAS exon 2 mutations. Most patients with PDAC present with advanced disease and are treated with cytotoxic therapy. Genomic biomarkers prognostic of disease outcomes have been challenging to identify. Herein leveraging a cohort of 2,336 patients spanning all disease stages, we characterize the genomic and clinical correlates of outcomes in PDAC. We show that a genomic subtype of KRAS wild-type tumors is associated with early disease onset, distinct somatic and germline features, and significantly better overall survival. Allelic imbalances at the KRAS locus are widespread. KRAS mutant allele dosage gains, observed in one in five (20%) KRAS-mutated diploid tumors, are correlated with advanced disease and demonstrate prognostic potential across disease stages. With the rapidly expanding landscape of KRAS targeting, our findings have potential implications for clinical practice and for understanding de novo and acquired resistance to RAS therapeutics.
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Affiliation(s)
- Anna M Varghese
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Maria A Perry
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Joanne F Chou
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Subhiksha Nandakumar
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Daniel Muldoon
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Amanda Erakky
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Amanda Zucker
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Christopher Fong
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Miika Mehine
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Bastien Nguyen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Olca Basturk
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Fiyinfolu Balogun
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - David P Kelsen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - A Rose Brannon
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Diana Mandelker
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Efsevia Vakiani
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Wungki Park
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Kenneth H Yu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Zsofia K Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Mark A Schattner
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - William R Jarnagin
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Alice C Wei
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Debyani Chakravarty
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Marinela Capanu
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Nikolaus Schultz
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Michael F Berger
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Christine A Iacobuzio-Donahue
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Chaitanya Bandlamudi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
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Buckley CW, O’Reilly EM. Next-generation therapies for pancreatic cancer. Expert Rev Gastroenterol Hepatol 2024; 18:55-72. [PMID: 38415709 PMCID: PMC10960610 DOI: 10.1080/17474124.2024.2322648] [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: 11/23/2023] [Accepted: 02/20/2024] [Indexed: 02/29/2024]
Abstract
INTRODUCTION Pancreas ductal adenocarcinoma (PDAC) is a frequently lethal malignancy that poses unique therapeutic challenges. The current mainstay of therapy for metastatic PDAC (mPDAC) is cytotoxic chemotherapy. NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, oxaliplatin) is an emerging standard of care in the metastatic setting. An evolving understanding of PDAC pathogenesis is driving a shift toward targeted therapy. Olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor, has regulatory approval for maintenance therapy in BRCA-mutated mPDAC along with other targeted agents receiving disease-agnostic approvals including for PDAC with rare fusions and mismatch repair deficiency. Ongoing research continues to identify and evaluate an expanding array of targeted therapies for PDAC. AREAS COVERED This review provides a brief overview of standard therapies for PDAC and an emphasis on current and emerging targeted therapies. EXPERT OPINION There is notable potential for targeted therapies for KRAS-mutated PDAC with opportunity for meaningful benefit for a sizable portion of patients with this disease. Further, emerging approaches are focused on novel immune, tumor microenvironment, and synthetic lethality strategies.
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Affiliation(s)
- Conor W. Buckley
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Eileen M. O’Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
- Weill Cornell Medicine, New York, USA
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5
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Micaily I, Blais EM, Carhart R, Lam S, Cohen SJ, Cannaday SJ, Halverson D, Matrisian LM, DeArbeloa P, Thach D, Petricoin E, Pishvaian MJ, Lavu H, Yeo CJ, Mallick AB. Association of Pancreatic Adenocarcinoma Location With DNA Damage Response Status and Response to Platinum-Based Therapy. JCO Precis Oncol 2023; 7:e2200648. [PMID: 38085059 DOI: 10.1200/po.22.00648] [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: 11/21/2022] [Revised: 01/21/2023] [Accepted: 07/12/2023] [Indexed: 12/18/2023] Open
Abstract
PURPOSE Pancreatic adenocarcinoma is an aggressive disease with poor clinical outcomes. Primary pancreatic tumors originating from the head of the pancreas (H) have different prognostic implications than tumors arising from the body and tail (BT). This is thought to be largely due to anatomic differences, as molecular underpinnings of survival have not been fully explored. We hypothesized that differences in the primary site of H and BT tumors might account for differential molecular outcomes and response to chemotherapy. METHODS Retrospective data from a single high-volume academic center were analyzed for hypothesis generation. A large-scale, real-world retrospective cohort of 2015 patients with next-generation sequencing (NGS) results were analyzed from a Real-World Evidence database. Progression-free survival (PFS) was evaluated from the initiation of first line of therapy for advanced disease until discontinuation because of progression. HR and P values were computed via Cox regression between first-line FOLFIRINOX and gemcitabine/nanoparticle albumin-bound (gem/nab) paclitaxel. Differences in frequencies of genomic alterations between H and BT were analyzed by Fisher's exact test. RESULTS Genomic alterations in the DNA damage response (DDR) pathway (such as BRCA1, BRCA2, and PALB2) were enriched (unadjusted P value = .00244) in BT tumors (21.7% of 618) relative to H tumors (15.6% of 942) where BRCA2 was a top contributor within this pathway. Median PFS in BT tumors on first-line FOLFIRINOX was longer than first line gem/nab-paclitaxel (P = .006393); this difference was not identified in H tumors (P = .5546). CONCLUSION DDR pathway alterations including BRCA1/BRCA2/PALB2 are known predictors of increased benefit from platinum-based chemotherapy. NGS testing for germline and somatic mutations remains important in pancreatic ductal adenocarcinoma, especially in BT tumors where DDR pathway alterations may be more common than in H tumors.
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Affiliation(s)
- Ida Micaily
- Department of Medical Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA
| | | | | | - Sophia Lam
- Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA
| | | | - Shawna J Cannaday
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA
| | | | | | | | | | | | | | - Harish Lavu
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA
| | - Charles J Yeo
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA
| | - Atrayee Basu Mallick
- Department of Medical Oncology, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA
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6
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Ashok Kumar P, Serinelli S, Zaccarini DJ, Huang R, Danziger N, Janovitz T, Basnet A, Sivapiragasam A, Graziano S, Ross JS. Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma. Front Oncol 2023; 13:1169586. [PMID: 37404765 PMCID: PMC10315669 DOI: 10.3389/fonc.2023.1169586] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 06/07/2023] [Indexed: 07/06/2023] Open
Abstract
Introduction KRAS mutation is a common occurrence in Pancreatic Ductal Adenocarcinoma (PDA) and is a driver mutation for disease development and progression. KRAS wild-type PDA may constitute a distinct molecular and clinical subtype. We used the Foundation one data to analyze the difference in Genomic Alterations (GAs) that occur in KRAS mutated and wild-type PDA. Methods Comprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed. Results and discussion Our cohort had 9444 cases of advanced PDA. 8723 (92.37%) patients had KRAS mutation. 721 (7.63%) patients were KRAS wild-type. Among potentially targetable mutations, GAs more common in KRAS wild-type included ERBB2 (mutated vs wild-type: 1.7% vs 6.8%, p <0.0001), BRAF (mutated vs wild-type: 0.5% vs 17.9%, p <0.0001), PIK3CA (mutated vs wild-type: 2.3% vs 6.5%, p <0.001), FGFR2 (mutated vs wild-type: 0.1% vs 4.4%, p <0.0001), ATM (mutated vs wild-type: 3.6% vs 6.8%, p <0.0001). On analyzing untargetable GAs, the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001), CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001), CDKN2B (mutated vs wild-type: 28.9% vs 23%, p =0.007), SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001) and MTAP (mutated vs wild-type: 21.7% vs 18%, p =0.02). ARID1A (mutated vs wild-type: 7.7% vs 13.6%, p <0.0001 and RB1(mutated vs wild-type: 2% vs 4%, p =0.01) were more prevalent in the wild-type subgroup. Mean TMB was higher in the KRAS wild-type subgroup (mutated vs wild-type: 2.3 vs 3.6, p <0.0001). High TMB, defined as TMB > 10 mut/mB (mutated vs wild-type: 1% vs 6.3%, p <0.0001) and very-high TMB, defined as TMB >20 mut/mB (mutated vs wild-type: 0.5% vs 2.4%, p <0.0001) favored the wild-type. PD-L1 high expression was similar between the 2 groups (mutated vs wild-type: 5.7% vs 6%,). GA associated with immune checkpoint inhibitors (ICPIs) response including PBRM1 (mutated vs wild-type: 0.7% vs 3.2%, p <0.0001) and MDM2 (mutated vs wild-type: 1.3% vs 4.4%, p <0.0001) were more likely to be seen in KRAS wild-type PDA.
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Affiliation(s)
| | - Serenella Serinelli
- Department of Pathology, Upstate Medical University, Syracuse, NY, United States
| | - Daniel J. Zaccarini
- Department of Pathology, Upstate Medical University, Syracuse, NY, United States
| | | | | | | | - Alina Basnet
- Upstate Cancer Center, Upstate Medical University, Syracuse, NY, United States
| | | | - Stephen Graziano
- Upstate Cancer Center, Upstate Medical University, Syracuse, NY, United States
| | - Jeffrey S. Ross
- Department of Pathology, Upstate Medical University, Syracuse, NY, United States
- Foundation Medicine, Cambridge, MA, United States
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Shin JE, An HJ, Park HS, Kim H, Shim BY. Efficacy of dabrafenib/trametinib in pancreatic ductal adenocarcinoma with BRAF NVTAP deletion: A case report. Front Oncol 2022; 12:976450. [PMID: 36505826 PMCID: PMC9731151 DOI: 10.3389/fonc.2022.976450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/01/2022] [Indexed: 11/25/2022] Open
Abstract
Studies have been actively conducted to identify actionable mutations and incorporate them into clinical practice in pancreatic ductal adenocarcinoma (PDAC), which is known to have a poor prognosis with traditional cytotoxic chemotherapy. A BRAF point mutation in V600E is commonly reported in KRAS wild-type PDAC, and targeting BRAF_V600E is already being applied to various carcinomas, including PDAC. Accumulated evidence also shows that not only BRAF_V600E but also short in-frame deletions of BRAF have an oncogenic function. Here, we report that a patient with BRAF N486_P490 deletion initiated on dabrafenib or trametinib, a BRAF inhibitor, and a MEK inhibitor, respectively, after cytotoxic chemotherapy failure. The patient then presented with a partial response.
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Turpin A, Neuzillet C, Colle E, Dusetti N, Nicolle R, Cros J, de Mestier L, Bachet JB, Hammel P. Therapeutic advances in metastatic pancreatic cancer: a focus on targeted therapies. Ther Adv Med Oncol 2022; 14:17588359221118019. [PMID: 36090800 PMCID: PMC9459481 DOI: 10.1177/17588359221118019] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 07/18/2022] [Indexed: 12/12/2022] Open
Abstract
Mortality from pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide and effective new treatments are urgently needed. The current treatment of metastatic PDAC in fit patients is based on two chemotherapy combinations (FOLFIRINOX and gemcitabine plus nab-paclitaxel) which were validated more than 8 years ago. Although almost all treatments targeting specific molecular alterations have failed so far when administered to unselected patients, encouraging results were observed in the small subpopulations of patients with germline BRCA 1/2 mutations, and somatic gene fusions (neurotrophic tyrosine receptor kinase, Neuregulin 1, which are enriched in KRAS wild-type PDAC), KRAS G12C mutations, or microsatellite instability. While targeted tumor metabolism therapies and immunotherapy have been disappointing, they are still under investigation in combination with other drugs. Optimizing pharmacokinetics and adapting available chemotherapies based on molecular signatures are other promising avenues of research. This review evaluates the current expectations and limits of available treatments and analyses the existing trials. A permanent search for actionable vulnerabilities in PDAC tumor cells and microenvironments will probably result in a more personalized therapeutic approach, keeping in mind that supportive care must also play a major role if real clinical efficacy is to be achieved in these patients.
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Affiliation(s)
- Anthony Turpin
- Department of Medical Oncology, CNRS UMR9020,
Inserm UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to
Therapies, University Lille, CHU Lille, Lille, France
| | - Cindy Neuzillet
- Department of Medical Oncology, Curie
Institute, Versailles Saint-Quentin University, Paris-Saclay University,
Saint-Cloud, France
| | - Elise Colle
- Department of Digestive and Medical Oncology,
Hospital Paul Brousse (AP-HP), Villejuif, University of Paris Saclay,
France
| | - Nelson Dusetti
- Cancer Research Center of Marseille, CRCM,
Inserm, CNRS, Paoli-Calmettes Institut, Aix-Marseille University, Marseille,
France
| | - Rémy Nicolle
- Centre de Recherche sur l’Inflammation, INSERM,
U1149, CNRS, ERL 8252, Université de Paris Cité, Paris, France
| | - Jérôme Cros
- Department of Pathology, University of Paris
Cité, Hospital Beaujon (AP-HP), Clichy, France
| | - Louis de Mestier
- Department of Gastroenterology and
Pancreatology, University of Paris Cité, Hospital Beaujon (AP-HP), Clichy,
France
| | - Jean-Baptiste Bachet
- Department of Gastroenterology and Digestive
Oncology, Pitié-Salpêtrière Hospital, Sorbonne University, UPMC University,
Paris, France
| | - Pascal Hammel
- Department of Digestive and Medical Oncology,
Hôpital Paul Brousse (AP-HP), 12 Avenue Paul Vaillant-Couturier, Villejuif
94800, University of Paris Saclay, France
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9
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Xu ZH, Wang WQ, Liu L, Lou WH. A special subtype: Revealing the potential intervention and great value of KRAS wildtype pancreatic cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188751. [PMID: 35732240 DOI: 10.1016/j.bbcan.2022.188751] [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: 03/30/2022] [Revised: 06/11/2022] [Accepted: 06/13/2022] [Indexed: 11/22/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer and has devastating consequences on affected families and society. Its dismal prognosis is attributed to poor specificity of symptoms during early stages. It is widely believed that PDAC patients with the wildtype (WT) KRAS gene benefit more from currently available treatments than those with KRAS mutations. The oncogenic genetic changes alternations generally found in KRAS wildtype PDAC are related to either the KRAS pathway or microsatellite instability/mismatch repair deficiency (MSI/dMMR), which enable the application of tailored treatments based on each patient's genetic characteristics. This review focuses on targeted therapies against alternative tumour mechanisms in KRAS WT PDAC.
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Affiliation(s)
- Zhi-Hang Xu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Wen-Hui Lou
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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10
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Hosein AN, Dougan SK, Aguirre AJ, Maitra A. Translational advances in pancreatic ductal adenocarcinoma therapy. NATURE CANCER 2022; 3:272-286. [PMID: 35352061 DOI: 10.1038/s43018-022-00349-2] [Citation(s) in RCA: 142] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 02/23/2022] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is most frequently detected at advanced stages, limiting treatment options to systemic chemotherapy with modest clinical responses. Here, we review recent advances in targeted therapy and immunotherapy for treating subtypes of PDAC with diverse molecular alterations. We focus on the current preclinical and clinical evidence supporting the potential of these approaches and the promise of combinatorial regimens to improve the lives of patients with PDAC.
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Affiliation(s)
- Abdel Nasser Hosein
- Division of Hematology & Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Advocate Aurora Health, Vince Lombardi Cancer Clinic, Sheboygan, WI, USA.
| | - Stephanie K Dougan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Immunology, Harvard Medical School, Boston, MA, USA.
| | - Andrew J Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Anirban Maitra
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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11
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Yang Y, Ding Y, Gong Y, Zhao S, Li M, Li X, Song G, Zhai B, Liu J, Shao Y, Zhu L, Pang J, Ma Y, Ou Q, Wu X, Zhang Z. The genetic landscape of pancreatic head ductal adenocarcinoma in China and prognosis stratification. BMC Cancer 2022; 22:186. [PMID: 35180847 PMCID: PMC8855595 DOI: 10.1186/s12885-022-09279-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 02/07/2022] [Indexed: 12/14/2022] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is the major subtype of pancreatic cancer and head PDACs show distinct characteristics from body/tail PDACs. With limited studies based on Asian population, the mutational landscape of Asian PDAC remains unclear. Methods One hundred fifty-one Chinese patients with head PDAC were selected and underwent targeted 425-gene sequencing. Genomic alterations, tumor mutational burden, and microsatellite instability were analyzed and compared with a TCGA cohort. Results The genomic landscape of Chinese and Western head PDAC had identical frequently-mutated genes including KRAS, TP53, SMAD4, and CDKN2A. KRAS hotspot in both cohorts was codon 12 but Chinese PDACs containing more G12V but fewer G12R variants. Potentially pathogenic fusions, CHD2-BRAF and KANK1-MET were identified in two KRAS wild-type patients. Serum cancer antigens CA125 and CA19-9 were positively associated with SMAD4 alterations while high CEA was enriched in wild-type CDKN2A subgroup. The probability of vascular invasion was lower in patients with RNF43 alterations. The nomogram developed including histology grade, the mutation status of SMAD4, TGFBR2, and PREX2 could calculate the risk score of prognoses validated by Chinese and TCGA cohort. Conclusions Chinese head PDAC contained more KRAS G12V mutation than Western population. The well-performed nomogram may improve post-operation care in real-world practice. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09279-9.
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Affiliation(s)
- Yefan Yang
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Ying Ding
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Yuxi Gong
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Sha Zhao
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Mingna Li
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Xiao Li
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Guoxin Song
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Boya Zhai
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Jin Liu
- Clinical Medicine Research Institution, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Yang Shao
- Nanjing Geneseeq Technology Inc, Nanjing, 210032, Jiangsu Province, China
| | - Liuqing Zhu
- Nanjing Geneseeq Technology Inc, Nanjing, 210032, Jiangsu Province, China
| | - Jiaohui Pang
- Nanjing Geneseeq Technology Inc, Nanjing, 210032, Jiangsu Province, China
| | - Yutong Ma
- Nanjing Geneseeq Technology Inc, Nanjing, 210032, Jiangsu Province, China
| | - Qiuxiang Ou
- Nanjing Geneseeq Technology Inc, Nanjing, 210032, Jiangsu Province, China
| | - Xue Wu
- Nanjing Geneseeq Technology Inc, Nanjing, 210032, Jiangsu Province, China
| | - Zhihong Zhang
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China.
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12
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Li HS, Yang K, Wang Y. Remarkable response of BRAFV600E-mutated metastatic pancreatic cancer to BRAF/MEK inhibition: a case report. Gastroenterol Rep (Oxf) 2021; 10:goab031. [PMID: 35382161 PMCID: PMC8972987 DOI: 10.1093/gastro/goab031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 05/27/2021] [Accepted: 06/17/2021] [Indexed: 11/14/2022] Open
Affiliation(s)
- Hong-Shuai Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Ke Yang
- Department of Medical Oncology, Cancer Hospital of HuanXing, Chaoyang District, Beijing, P. R. China
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
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13
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Lellouche L, Palmieri LJ, Dermine S, Brezault C, Chaussade S, Coriat R. Systemic therapy in metastatic pancreatic adenocarcinoma: current practice and perspectives. Ther Adv Med Oncol 2021; 13:17588359211018539. [PMID: 34285720 PMCID: PMC8264726 DOI: 10.1177/17588359211018539] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/29/2021] [Indexed: 12/25/2022] Open
Abstract
Major breakthroughs have been achieved in the management of metastatic pancreatic ductal adenocarcinoma (PDAC) with FOLFIRINOX (5-fluorouracil + irinotecan + oxaliplatin) and gemcitabine plus nab-paclitaxel approved as a first-line therapy, although the prognosis is still poor. At progression, patients who maintain a good performance status (PS) can benefit from second-line chemotherapy. To address the concern of achieving tumor control while maintaining a good quality of life, maintenance therapy is a concept that has now emerged. After a FOLFIRINOX induction treatment, maintenance with 5-fluorouracil (5-FU) seems to offer a promising approach. Although not confirmed in large, prospective trials, gemcitabine alone as a maintenance therapy following induction treatment with gemcitabine plus nab-paclitaxel could be an option, while a small subset of patients with a germline mutation of breast cancer gene (BRCA) can benefit from the polyadenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib. The rate of PDAC with molecular alterations that could lead to a specific therapy is up to 25%. The Food and Drug Administration (FDA) recently approved larotrectinib for patients with any tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and pembrolizumab for patients with a mismatch repair deficiency in a second-line setting, including PDAC. Research focused on targeted therapy and immunotherapy is active and could improve patients' outcomes in the near future.
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Affiliation(s)
- Lisa Lellouche
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, APHP. Centre, Paris, France
- Faculté de Médecine Paris Centre, Université de Paris, Paris, France
| | - Lola-Jade Palmieri
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, APHP. Centre, 27 rue du faubourg St Jacques, Paris, 75014, France
- Faculté de Médecine Paris Centre, Université de Paris, Paris, 75006, France
| | - Solène Dermine
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, APHP. Centre, Paris, France
- Faculté de Médecine Paris Centre, Université de Paris, Paris, France
| | - Catherine Brezault
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Paris, France
| | - Stanislas Chaussade
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, APHP. Centre, Paris, France
- Faculté de Médecine Paris Centre, Université de Paris, Paris, France
| | - Romain Coriat
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, APHP. Centre, Paris, France
- Faculté de Médecine Paris Centre, Université de Paris, Paris, France
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14
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Molecularly targeted therapy for advanced gastrointestinal noncolorectal cancer treatment: how to choose? Past, present, future. Anticancer Drugs 2021; 32:593-601. [PMID: 33929995 DOI: 10.1097/cad.0000000000001071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Gastrointestinal cancer is a leading cause of death worldwide. Conventional cytotoxic chemotherapy has been the backbone of advanced gastrointestinal cancer treatment for decades and still represents a key element of the therapeutic armamentarium. However, only small increments in survival outcomes have been reached. New clinical trials are designed, including classic chemotherapy in association with either small-molecule inhibitors or mAb. During the past few years, remarkable progress in molecular biology of gastrointestinal noncolorectal cancers, the discovery of specific targets and the resulting development of systemic drugs that block critical kinases and several molecular pathways have all contributed to progress. New biological agents with molecularly targeted therapies are now available or currently included in clinical trials (EGFR inhibitors (i), antiangiogenic agents, c-METi, IDHi, FGFR2i, BRAFi, Pi3Ki/AKTi/mTORi, NTRKi). When we focus on the current state of precision medicine for gastrointestinal malignancies, it becomes apparent that there is a mixed history of success and failure. The aim of this review is to focus on the studies that have been completed to date with target therapies and to understand which of these are currently the accepted choice in clinical practice and which need further confirmation and approval for inclusion in guidelines. All these findings will enable to guide clinical practice for oncologists in the design of the next round of clinical trials.
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15
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Zheng-Lin B, O'Reilly EM. Pancreatic ductal adenocarcinoma in the era of precision medicine. Semin Oncol 2021; 48:19-33. [PMID: 33637355 PMCID: PMC8355264 DOI: 10.1053/j.seminoncol.2021.01.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 01/21/2021] [Indexed: 12/13/2022]
Abstract
The paradigm for treatment of PDAC is shifting from a "one size fits all" of cytotoxic therapy to a precision medicine approach based on specific predictive biomarkers for a subset of patients. As the genomic landscape of pancreatic carcinogenesis has become increasingly defined, several oncogenic alterations have emerged as actionable targets and their use has been validated in novel approaches such as targeting mutated germline DNA damage response genes (BRCA) and mismatch deficiency (dMMR/MSI-H) or blockade of rare somatic oncogenic fusions. Chemotherapy selection based on transcriptomic subtypes and developing stroma- and immune-modulating strategies have yielded encouraging results and may open therapeutic refinement to a broader PDAC population. Notwithstanding, a series of negative late-stage trials over the last year continue to underscore the inherent challenges in the treatment of PDAC. Multifactorial therapy resistance warrants further exploration in PDAC "omics" and tumor-stroma-immune cells crosstalk. Herein, we discuss precision medicine approaches applied to the treatment of PDAC, its current state and future perspective.
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Affiliation(s)
- Binbin Zheng-Lin
- Department of Medicine, Icahn School of Medicine at Mount Sinai Morningside and Mount Sinai West, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY, USA; David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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16
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Al-Share B, Hammad N, Diab M. Pancreatic adenocarcinoma: molecular drivers and the role of targeted therapy. Cancer Metastasis Rev 2021; 40:355-371. [PMID: 33398620 DOI: 10.1007/s10555-020-09948-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/15/2020] [Indexed: 01/05/2023]
Abstract
Prognosis from pancreatic ductal adenocarcinoma (PDAC) continues to be poor despite the many efforts channeled to improve its management. Although the mainstay treatment is still traditional chemotherapy, recent advances highlighted a promising potential for targeted therapy in the management of this disease. Those advances emphasize the significance of timely genomic profiling of tumor tissue as well as germline testing of patients to identify potential markers of targeted therapy. While targeted therapy is reserved for a relatively small subset of patients with PDAC, ongoing research is uncovering additional markers, and targeted agents, that will hopefully translate to better outcomes for patients.
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Affiliation(s)
- Bayan Al-Share
- Department of Oncology, Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA
| | - Nour Hammad
- Department of Oncology, Ascension Providence Hospital and Medical Center/Michigan State University/Collage of Human Medicine, Southfield, MI, USA
| | - Maria Diab
- Department of Oncology, Emory University, Atlanta, GA, USA.
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17
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Wang Y, Lakoma A, Zogopoulos G. Building towards Precision Oncology for Pancreatic Cancer: Real-World Challenges and Opportunities. Genes (Basel) 2020; 11:E1098. [PMID: 32967105 PMCID: PMC7563487 DOI: 10.3390/genes11091098] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
The advent of next-generation sequencing (NGS) has provided unprecedented insight into the molecular complexity of pancreatic ductal adenocarcinoma (PDAC). This has led to the emergence of biomarker-driven treatment paradigms that challenge empiric treatment approaches. However, the growth of sequencing technologies is outpacing the development of the infrastructure required to implement precision oncology as routine clinical practice. Addressing these logistical barriers is imperative to maximize the clinical impact of molecular profiling initiatives. In this review, we examine the evolution of precision oncology in PDAC, spanning from germline testing for cancer susceptibility genes to multi-omic tumor profiling. Furthermore, we highlight real-world challenges to delivering precision oncology for PDAC, and propose strategies to improve the generation, interpretation, and clinical translation of molecular profiling data.
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Affiliation(s)
- Yifan Wang
- Department of Surgery, McGill University, Montreal, QC H4A 3J1, Canada; (Y.W.); (A.L.)
- Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H4A 3J1, Canada
- The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
| | - Anna Lakoma
- Department of Surgery, McGill University, Montreal, QC H4A 3J1, Canada; (Y.W.); (A.L.)
- Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H4A 3J1, Canada
- The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
| | - George Zogopoulos
- Department of Surgery, McGill University, Montreal, QC H4A 3J1, Canada; (Y.W.); (A.L.)
- Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H4A 3J1, Canada
- The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
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18
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Busch E, Kreutzfeldt S, Agaimy A, Mechtersheimer G, Horak P, Brors B, Hutter B, Fröhlich M, Uhrig S, Mayer P, Schröck E, Stenzinger A, Glimm H, Jäger D, Springfeld C, Fröhling S, Zschäbitz S. Successful BRAF/MEK inhibition in a patient with BRAF V600E-mutated extrapancreatic acinar cell carcinoma. Cold Spring Harb Mol Case Stud 2020; 6:mcs.a005553. [PMID: 32843432 PMCID: PMC7476408 DOI: 10.1101/mcs.a005553] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 06/09/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as BRAF fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with BRAFV600E-mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors. The patient presented to our clinic with abdominal pain and weight loss. Imaging showed extensive retroperitoneal disease as well as mediastinal lymphadenopathy. Because of elevated α-fetoprotein (AFP) levels and inconclusive histologic findings, a germ cell tumor was suspected; however, PEI chemotherapy was unsuccessful. A repeat biopsy yielded the diagnosis of PAC and treatment with FOLFIRINOX was initiated. Comprehensive molecular profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program revealed a somatic BRAFV600E mutation and a germline PALB2 stop-gain mutation. Therapy was therefore switched to BRAF/MEK inhibition, resulting in almost complete remission and disease control for 12 mo and a remarkable improvement in the patient's general condition. These results indicate that BRAF alterations are a valid therapeutic target in PAC that should be routinely assessed in this patient population.
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Affiliation(s)
- Elena Busch
- Department of Medical Oncology, University Hospital Heidelberg, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, 69120, Germany
| | - Simon Kreutzfeldt
- Department of Translational Medical Oncology, NCT Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
| | - Abbas Agaimy
- Institute of Pathology, University Hospital Erlangen, Erlangen, 91054, Germany
| | | | - Peter Horak
- Department of Translational Medical Oncology, NCT Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
| | - Benedikt Brors
- Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, 69120, Germany.,German Cancer Consortium
| | - Barbara Hutter
- Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, 69120, Germany.,Molecular Diagnostics Program, NCT Heidelberg and DKFZ, Heidelberg, 69120, Germany
| | - Martina Fröhlich
- Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, 69120, Germany.,Molecular Diagnostics Program, NCT Heidelberg and DKFZ, Heidelberg, 69120, Germany
| | - Sebastian Uhrig
- Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, 69120, Germany.,Molecular Diagnostics Program, NCT Heidelberg and DKFZ, Heidelberg, 69120, Germany
| | - Philipp Mayer
- Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | - Evelin Schröck
- NCT Partner Site Dresden, University Cancer Center (UCC) Dresden, Dresden, 01307, Germany.,Institute of Clinical Genetics, Technical University of Dresden, Dresden, 01307, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | - Hanno Glimm
- NCT Partner Site Dresden, University Cancer Center (UCC) Dresden, Dresden, 01307, Germany
| | - Dirk Jäger
- Department of Medical Oncology, University Hospital Heidelberg, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, 69120, Germany
| | - Christoph Springfeld
- Department of Medical Oncology, University Hospital Heidelberg, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, 69120, Germany
| | - Stefan Fröhling
- Department of Translational Medical Oncology, NCT Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.,German Cancer Consortium
| | - Stefanie Zschäbitz
- Department of Medical Oncology, University Hospital Heidelberg, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, 69120, Germany
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19
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, with systemic therapy being the mainstay of treatment. Survival continues to be limited, typically less than 1 year. The PDAC microenvironment is characterized by a paucity of malignant epithelial cells, abundant stroma with predominantly immunosuppressive T cells and myelosuppressive-type macrophages (M2), and hypovascularity. The current treatment options for metastatic PDAC are modified (m)FOLFIRINOX /FOLFIRINOX or nab-paclitaxel and gemcitabine in patients with good performance status (PS) (ECOG 0-1/KPS 70-100%) and gemcitabine with or without a second agent for those with ECOG PS 2-3. New therapies are emerging, and the current guidelines endorse both germline and somatic testing in PDAC to evaluate actionable findings. Important themes related to new therapeutic approaches include DNA damage repair strategies, immunotherapy, targeting the stroma, and cancer-cell metabolism. Targeted therapy alone (outside small genomically defined subsets) or in combination with standard cytotoxic therapy, thus far, has proven disappointing in PDAC; however, novel therapies are evolving with increased integration of genomic profiling along with a better understanding of the tumor microenvironment and immunology. A small but important sub-group of patients have some of these agents available in the clinics for use. Olaparib was recently approved by the US Food and Drug Administration for maintenance therapy in germline BRCA1/2 mutated PDAC following demonstration of survival benefit in a phase 3 trial. Pembrolizumab is approved for patients with defects in mismatch repair/microsatellite instability. PDAC with wild-type KRAS represents a unique subgroup who have enrichment of potentially targetable oncogenic drivers. Small-molecule inhibitors including ERBB inhibitors (e.g., afatinib, MCLA-128), TRK inhibitors (e.g., larotrectinib, entrectinib), ALK/ROS inhibitor (e.g., crizotinib), and BRAF/MEK inhibitors are in development. In a small subset of patients with the KRASG12C mutation, a KRASG12C inhibitor, AMG510, and other agents are being investigated. Major efforts are underway to effectively target the tumor microenvironment and to integrate immunotherapy into the treatment of PDAC, and although thus far the impact has been modest to ineffective, nonetheless, there is optimism that some of the challenges will be overcome.
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Affiliation(s)
- Ritu Raj Singh
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai St. Luke's and Mount Sinai West, New York, NY, 10019, USA
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
- Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
- David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
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20
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Pishvaian MJ, Blais EM, Brody JR, Lyons E, DeArbeloa P, Hendifar A, Mikhail S, Chung V, Sahai V, Sohal DPS, Bellakbira S, Thach D, Rahib L, Madhavan S, Matrisian LM, Petricoin EF. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol 2020; 21:508-518. [PMID: 32135080 PMCID: PMC7453743 DOI: 10.1016/s1470-2045(20)30074-7] [Citation(s) in RCA: 357] [Impact Index Per Article: 71.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND About 25% of pancreatic cancers harbour actionable molecular alterations, defined as molecular alterations for which there is clinical or strong preclinical evidence of a predictive benefit from a specific therapy. The Know Your Tumor (KYT) programme includes US patients with pancreatic cancer and enables patients to undergo commercially available multi-omic profiling to provide molecularly tailored therapy options and clinical trial recommendations. We sought to determine whether patients with pancreatic cancer whose tumours harboured such actionable molecular alterations and who received molecularly matched therapy had a longer median overall survival than similar patients who did not receive molecularly matched therapy. METHODS In this retrospective analysis, treatment history and longitudinal survival outcomes were analysed in patients aged 18 years or older with biopsy-confirmed pancreatic cancer of any stage, enrolled in the KYT programme and who received molecular testing results. Since the timing of KYT enrolment varied for each patient, the primary outcome measurement of median overall survival was calculated from the initial diagnosis of advanced disease until death. We compared median overall survival in patients with actionable mutations who were treated with a matched therapy versus those who were not treated with a matched therapy. FINDINGS Of 1856 patients with pancreatic cancer who were referred to the KYT programme between June 16, 2014, and March 31, 2019, 1082 (58%) patients received personalised reports based on their molecular testing results. Actionable molecular alterations were identified in 282 (26%) of 1082 samples. Among 677 patients for whom outcomes were available, 189 had actionable molecular alterations. With a median follow-up of 383 days (IQR 214-588), those patients with actionable molecular alterations who received a matched therapy (n=46) had significantly longer median overall survival than did those patients who only received unmatched therapies (n=143; 2·58 years [95% CI 2·39 to not reached] vs 1·51 years [1·33-1·87]; hazard ratio 0·42 [95% CI 0·26-0·68], p=0·0004). The 46 patients who received a matched therapy also had significantly longer overall survival than the 488 patients who did not have an actionable molecular alteration (2·58 years [95% CI 2·39 to not reached] vs 1·32 years [1·25-1·47]; HR 0·34 [95% CI 0·22-0·53], p<0·0001). However, median overall survival did not differ between the patients who received unmatched therapy and those without an actionable molecular alteration (HR 0·82 [95% CI 0·64-1·04], p=0·10). INTERPRETATION These real-world outcomes suggest that the adoption of precision medicine can have a substantial effect on survival in patients with pancreatic cancer, and that molecularly guided treatments targeting oncogenic drivers and the DNA damage response and repair pathway warrant further prospective evaluation. FUNDING Pancreatic Cancer Action Network and Perthera.
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Affiliation(s)
- Michael J Pishvaian
- Department of Gastrointestinal Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA; Perthera, McLean, VA, USA.
| | | | - Jonathan R Brody
- Perthera, McLean, VA, USA; The Jefferson Pancreatic, Biliary, and Related Cancer Center and the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Emily Lyons
- The Pancreatic Cancer Action Network, Manhattan Beach, CA, USA
| | | | | | - Sam Mikhail
- Mark Zangmeister Cancer Center, Columbus, OH, USA
| | | | - Vaibhav Sahai
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Davendra P S Sohal
- Department of Hematology/Oncology, University of Cincinnati, Cincinnati, OH, USA
| | | | | | - Lola Rahib
- The Pancreatic Cancer Action Network, Manhattan Beach, CA, USA
| | - Subha Madhavan
- Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA
| | | | - Emanuel F Petricoin
- Perthera, McLean, VA, USA; Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA
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21
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Wrzeszczynski KO, Rahman S, Frank MO, Arora K, Shah M, Geiger H, Felice V, Manaa D, Dikoglu E, Khaira D, Chimpiri AR, Michelini VV, Jobanputra V, Darnell RB, Powers S, Choi M. Identification of targetable BRAF ΔN486_P490 variant by whole-genome sequencing leading to dabrafenib-induced remission of a BRAF-mutant pancreatic adenocarcinoma. Cold Spring Harb Mol Case Stud 2019; 5:a004424. [PMID: 31519698 PMCID: PMC6913137 DOI: 10.1101/mcs.a004424] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 08/07/2019] [Indexed: 01/08/2023] Open
Abstract
The tumor genome of a patient with advanced pancreatic cancer was sequenced to identify potential therapeutic targetable mutations after standard of care failed to produce any significant overall response. Matched tumor-normal whole-genome sequencing revealed somatic mutations in BRAF, TP53, CDKN2A, and a focal deletion of SMAD4 The BRAF variant was an in-frame deletion mutation (ΔN486_P490), which had been previously demonstrated to be a kinase-activating alteration in the BRAF kinase domain. Working with the Novartis patient assistance program allowed us to treat the patient with the BRAF inhibitor, dabrafenib. The patient's overall clinical condition improved dramatically with dabrafenib. Levels of serum tumor marker dropped immediately after treatment, and a subsequent CT scan revealed a significant decrease in the size of both primary and metastatic lesions. The dabrafenib-induced remission lasted for 6 mo. Preclinical studies published concurrently with the patient's treatment showed that the BRAF in-frame mutation (ΔNVTAP) induces oncogenic activation by a mechanism distinct from that induced by V600E, and that this difference dictates the responsiveness to different BRAF inhibitors. This study describes a dramatic instance of how high-level genomic technology and analysis was necessary and sufficient to identify a clinically logical treatment option that was then utilized and shown to be of clinical value for this individual.
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Affiliation(s)
| | - Sadia Rahman
- New York Genome Center, New York, New York 10013, USA
| | - Mayu O Frank
- Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York 10065, USA
| | - Kanika Arora
- New York Genome Center, New York, New York 10013, USA
| | - Minita Shah
- New York Genome Center, New York, New York 10013, USA
| | | | | | - Dina Manaa
- New York Genome Center, New York, New York 10013, USA
| | - Esra Dikoglu
- New York Genome Center, New York, New York 10013, USA
| | | | - A Rao Chimpiri
- Renaissance School of Medicine, Department of Radiology, Stony Brook University, Stony Brook, New York 11794, USA
| | | | - Vaidehi Jobanputra
- New York Genome Center, New York, New York 10013, USA
- Columbia University Medical Center, New York, New York 10032, USA
| | - Robert B Darnell
- New York Genome Center, New York, New York 10013, USA
- Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York 10065, USA
- Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA
| | - Scott Powers
- Renaissance School of Medicine, Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA
| | - Minsig Choi
- Stony Brook Cancer Center, Stony Brook Medicine, Stony Brook, New York 11794, USA
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22
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Ormanns S. [Personalized cancer medicine : Biomarkers for molecular therapy stratification in pancreatic carcinoma]. DER PATHOLOGE 2018; 39:221-224. [PMID: 30361776 DOI: 10.1007/s00292-018-0539-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Ductal adenocarcinoma of the pancreas has a very poor prognosis and a rising incidence. Even after curative intent resection, which is possible in a minority of patients, most patients relapse, whereas the majority is diagnosed with inoperable or metastatic disease. That's why palliative systemic chemotherapy is the current therapeutic mainstay. Biomarker-based tumor characterization could identify potential therapy targets and enable a personalized cancer medicine. Although potentially targetable alterations occur at very low frequencies, the possible impact on patient outcome can be significant. This article summarizes some of the contributions to these aspects and gives an outlook on their clinical meaning.
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Affiliation(s)
- S Ormanns
- Pathologisches Institut, Medizinische Fakultät, Ludwig-Maximilians-Universität München, Thalkirchner Straße 36, 80337, München, Deutschland.
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