Therapeutic advances in metastatic pancreatic cancer: a focus on targeted therapies DOI Creative Commons
Anthony Turpin, Cindy Neuzillet,

Elise Colle

et al.

Therapeutic Advances in Medical Oncology, Journal Year: 2022, Volume and Issue: 14

Published: Jan. 1, 2022

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 based on two chemotherapy combinations (FOLFIRINOX gemcitabine plus nab-paclitaxel) which were validated more than 8 years ago. Although almost all targeting specific molecular alterations have failed so far when administered to unselected patients, encouraging results observed the small subpopulations with germline BRCA 1/2 mutations, somatic gene fusions ( neurotrophic tyrosine receptor kinase, Neuregulin 1, enriched KRAS wild-type PDAC), G12C or microsatellite instability. While targeted tumor metabolism therapies immunotherapy been disappointing, they still under investigation combination other drugs. Optimizing pharmacokinetics adapting available chemotherapies signatures promising avenues research. This review evaluates expectations limits analyses existing trials. A permanent search for actionable vulnerabilities cells microenvironments will probably result a personalized therapeutic approach, keeping mind that supportive care must also play major role if real clinical efficacy be achieved these patients.

Language: Английский

Pancreatic cancer: Advances and challenges DOI Creative Commons
Christopher J. Halbrook, Costas A. Lyssiotis, Marina Pasca di Magliano

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1729 - 1754

Published: April 1, 2023

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. tumors are characterized by a complex microenvironment that orchestrates metabolic alterations supports milieu interactions among various cell types within this niche. In review, we highlight foundational studies driven our understanding these processes. We further discuss recent technological advances continue to expand complexity. posit clinical translation research endeavors will enhance currently dismal survival rate recalcitrant disease.

Language: Английский

Citations

554
Neoadjuvant therapy for pancreatic cancer DOI
Christoph Springfeld, Cristina R. Ferrone, Matthew H. G. Katz

et al.

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(5), P. 318 - 337

Published: March 17, 2023

Language: Английский

Citations

211
Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up DOI Creative Commons
Thierry Conroy, Per Pfeiffer, Valérie Vilgrain

et al.

Annals of Oncology, Journal Year: 2023, Volume and Issue: 34(11), P. 987 - 1002

Published: Sept. 9, 2023

Language: Английский

Citations

190
Therapeutic developments in pancreatic cancer DOI
Zilun Hu, Eileen M. O’Reilly

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 21(1), P. 7 - 24

Published: Oct. 5, 2023

Language: Английский

Citations

135
The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma DOI Creative Commons
Daniel J. Renouf, Jonathan M. Loree, Jennifer J. Knox

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 26, 2022

Immunotherapy-based monotherapy treatment in metastatic pancreatic ductal adenocarcinoma (mPDAC) has shown limited benefit outside of the mismatch repair deficiency setting, while safety and efficacy combining dual-checkpoint inhibitor immunotherapy with chemotherapy remains uncertain. Here, we present results from CCTG PA.7 study (NCT02879318), a randomized phase II trial comparing gemcitabine nab-paclitaxel without immune checkpoint inhibitors durvalumab tremelimumab 180 patients mPDAC. The primary endpoint was overall survival. Secondary endpoints included progression-free survival objective response rate. Results were negative as combination did not improve among unselected patient population (p = 0.72) toxicity to elevation lymphocytes group 0.02). Exploratory baseline circulating tumor DNA (ctDNA) sequencing revealed increased for KRAS wildtype tumors both 0.001) 0.004) groups. These data support utility ctDNA analysis PDAC prognostic value ctDNA-based mutation status.

Language: Английский

Citations

73
Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer DOI Creative Commons
Dimitrios Stefanoudakis, Maximos Frountzas, Dimitriοs Schizas

et al.

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(4), P. 2827 - 2844

Published: March 23, 2024

The present review demonstrates the major tumor suppressor genes, including TP53, CDKN2A and SMAD4, associated with pancreatic cancer. Each gene’s role, prevalence impact on development progression are analyzed, focusing intricate molecular landscape of In addition, this underscores prognostic significance specific mutations, such as loss explores some potential targeted therapies tailored to these signatures. findings highlight importance genomic analyses for risk assessment, early detection design personalized treatment approaches in Overall, provides a comprehensive analysis intricacies tumors, paving way more effective therapeutic interventions.

Language: Английский

Citations

23
Efficacy of Zenocutuzumab in NRG1 Fusion–Positive Cancer DOI
Alison M. Schram, Kōichi Goto,

Dong-Wan Kim

et al.

New England Journal of Medicine, Journal Year: 2025, Volume and Issue: 392(6), P. 566 - 576

Published: Feb. 5, 2025

Neuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors. NRG1 binds to human epidermal growth factor receptor 3 (HER3), leading heterodimerization with HER2 and activation of downstream proliferation pathways. The efficacy safety zenocutuzumab, a bispecific antibody against HER3, patients fusion-positive tumors unclear. In this registrational, phase 2 clinical study, we assigned advanced cancer involving any tumor type receive zenocutuzumab at dose 750 mg intravenously every weeks. primary end point was overall response (complete or partial response) according investigator assessment. Secondary points included duration response, progression-free survival, safety. A total 204 12 types were enrolled treated. Among 158 who had measurable disease least 24 weeks before the data-cutoff date, occurred 30% (95% confidence interval [CI], 23 37). median 11.1 months CI, 7.4 12.9); 19% responses ongoing date. Responses observed - including 27 93 (29%; 95% 20 39) non-small-cell lung (NSCLC) 15 36 (42%; 25 59) pancreatic across fusion partners. survival 6.8 5.5 9.1). Adverse events primarily grade 2. most common adverse that considered by be related diarrhea (in 18% patients), fatigue 12%), nausea 11%). Infusion-related reactions (composite term) 14% patients. One patient discontinued owing treatment-related event. Zenocutuzumab showed cancer, notably NSCLC mainly low-grade events. (Funded Merus; eNRGy ClinicalTrials.gov number, NCT02912949.).

Language: Английский

Citations

8
Clinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall survival DOI Creative Commons
Anna M. Varghese, Maria Perry, Joanne F. Chou

et al.

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Nearly all pancreatic adenocarcinomas (PDAC) are genomically characterized by KRAS exon 2 mutations. Most patients with PDAC present advanced disease and treated cytotoxic therapy. Genomic biomarkers prognostic of outcomes have been challenging to identify. Herein leveraging a cohort 2,336 spanning stages, we characterize the genomic clinical correlates in PDAC. We show that subtype wild-type tumors is associated early onset, distinct somatic germline features, significantly better overall survival. Allelic imbalances at locus widespread. mutant allele dosage gains, observed one five (20%) KRAS-mutated diploid tumors, correlated demonstrate potential across stages. With rapidly expanding landscape targeting, our findings implications for practice understanding de novo acquired resistance RAS therapeutics. Analyses data from adenocarcinoma find gains hallmark progression predictive poor different

Language: Английский

Citations

3
Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer DOI
Harshabad Singh,

Rachel B. Keller,

Kevin S. Kapner

et al.

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 29(22), P. 4627 - 4643

Published: July 18, 2023

Abstract Purpose: Approximately 8% to 10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features this subset cancer is important guide patient stratification for trials molecularly targeted agents. Experimental Design: We analyzed a single-institution cohort 795 exocrine cases (including 785 PDAC cases) with multigene sequencing panel identified 73 patients (9.2%) KRAS wild-type (WT) cancer. Results: Overall, 43.8% (32/73) WT had evidence an alternative driver MAPK pathway, including BRAF in-frame deletions receptor tyrosine kinase fusions. Conversely, 56.2% did clear alteration, but 29.3% these MAPK-negative (12/41) demonstrated activating alterations other oncogenic drivers, such as GNAS, MYC, PIK3CA, CTNNB1. demonstrate potent efficacy pan-RAF MEK inhibition patient-derived organoid models carrying deletions. Moreover, we durable benefit therapy harboring tumor ROS1 fusion. Clinically, tumors were significantly younger age onset (median age: 62.6 vs. 65.7 years; P = 0.037). SMAD4 associated particularly poor prognosis cases. Conclusions: This study defines genomic underpinnings highlights potential therapeutic avenues future investigation directed trials. See related commentary by Kato et al., p. 4527

Language: Английский

Citations

27
Next-generation therapies for pancreatic cancer DOI Creative Commons
Conor Buckley, Eileen M. O’Reilly

Expert Review of Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 18(1-3), P. 55 - 72

Published: Feb. 28, 2024

Introduction Pancreas ductal adenocarcinoma (PDAC) is a frequently lethal malignancy that poses unique therapeutic challenges. The current mainstay of therapy for metastatic PDAC (mPDAC) cytotoxic chemotherapy. NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, oxaliplatin) an emerging standard care in the setting. An evolving understanding pathogenesis driving shift toward targeted therapy. Olaparib, poly-ADP-ribose polymerase (PARP) inhibitor, has regulatory approval maintenance BRCA-mutated mPDAC along with other agents receiving disease-agnostic approvals including rare fusions and mismatch repair deficiency. Ongoing research continues to identify evaluate expanding array therapies PDAC.

Language: Английский

Citations

15