Langzeitremission bei einem Patienten mit metastasiertem Adenokarzinom des Pankreas: Aktuelle Therapiemöglichkeiten und neue Therapiealgorithmen mit Hilfe des Molekularen Tumorboards

Zusammenfassung

Hintergrund Das Adenokarzinom des Pankreas geht trotz verbesserter diagnostischer Möglichkeiten und neuer teilweise multimodaler Therapien mit einer sehr schlechten Prognose einher. Eine Heilung kann nur in lokalisierten Stadien mittels vollständiger Resektion erreicht werden. Da bei Diagnosestellung jedoch bereits in 45–70% der Fälle eine Fernmetastasierung vorliegt, gelten die meisten Fälle als primär inoperabel. Aufgrund neuer molekularer Erkenntnisse haben sich zielgerichtete Therapiemöglichkeiten eröffnet. Wir berichten von einem Patienten mit metastasiertem Adenokarzinom des Pankreas mit Nachweis verschiedener Mutationen, die Angriffspunkte für gezielte Therapien darstellen und erläutern mögliche Therapieansätze.

Fallbericht Bei einem Mitte 50-jährigen Patienten wurde bei abdominellen Schmerzen ein metastasiertes Adenokarzinom des Pankreas diagnostiziert. Unter einer palliativen platinhaltigen Chemotherapie mit FOLFIRINOX konnte bildgebend ein fast komplettes Ansprechen erreicht werden. Nach Nachweis einer BRCA-2-Mutation erfolgte der Einschluss in die POLO-Studie mit einer Erhaltungstherapie mit dem Poly(ADP-ribose)-Polymerase (PARP)- Inhibitor Olaparib, unter dem es nach 8 Monaten zu einem Progress kam. Es folgten Zweit- und Drittlinientherapien mit Gemcitabin in Kombination mit Nab-Paclitaxel und im Verlauf mit Erlotinib. Zudem konnte eine aktivierende Mutation im KRAS-Gen festgestellt werden. Auf eine weitere experimentelle gezielte Therapie bezüglich dieser Mutation wurde von Seiten des Patienten verzichtet.

Schlussfolgerung Die Identifizierung prädiktiver Faktoren und spezifischer therapierbarer Mutationen bei Patient*innen mit fortgeschrittenem Adenokarzinom des Pankreas scheint bei aktuell noch sehr schlechter Prognose dieser Erkrankung von großer Bedeutung, um individualisierte Therapien zu ermöglichen.

Abstract

Background Pancreatic cancer is still considered one of the most aggressive types of cancer and is associated with a very poor prognosis although there have been improvements in diagnostics and chemotherapy regimes in recent years. A cure can only be achieved through complete resection which is only possible when diagnosed at a very early stage, though this is rarely the case. We report on a patient with stage IV adenocarcinoma of the pancreas in which several therapeutically actionable mutations could be detected and discuss new options of targeted therapies.

Case Report A patient in his 50s was diagnosed with metastatic adenocarcinoma of the pancreas. The patient showed an excellent response to platinum-based chemotherapy with FOLFIRINOX. When a germline mutation in the BRCA-2 gene could be identified, he took part in the POLO-study receiving a maintenance therapy with the PARP-Inhibitor Olaparib. Due to a relapse, 2nd and 3rd line chemotherapy regimens were applied with Gemcitabine combined with Nab-Paclitaxel and later with Erlotinib. Although an activating mutation in the KRAS-gene could be detected as well, the patient rejected further experimental treatment.

Conclusion Identifying predictive factors and specific targetable mutations in patients with advanced pancreatic cancer is needed to be able to apply more individual and specific therapies in order to improve outcomes.

Schlüsselwörter

Adenokarzinom des Pankreas - Molekulare Therapie - Langzeitremission - BRCA-Mutation

Keywords

adenocarcinoma of the pancreas - molecular guided therapy - long time remission - BRCA-mutation

Publication History

Received: 09 July 2021

Accepted after revision: 07 November 2021

Article published online:
14 December 2021

• Literatur

• 1 Robert Koch-Institut. Der Epidemiologischen Krebsregister In Deutschland E.V. Krebs in Deutschland 2015/2016. 2019 DOI: 10.25646/5977
• 2 Pourshams A, Sepanlou SG, Ikuta KS. et al. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet Gastroenterology & Hepatology 2019; 4: 934-947 DOI: 10.1016/S2468-1253(19)30347-4. (PMID: 31648972)
• 3 Robert Koch-Institut. Berichts zum Krebsgeschehen in Deutschland 2016. RKI-Bib1 (Robert Koch-Institut). 2016 DOI: 10.17886/rkipubl-2016-014
• 4 Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006; 20: 197-209 DOI: 10.1016/j.bpg.2005.10.001. (PMID: 16549324)
• 5 Shindo K, Yu J, Suenaga M. et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol 2017; 35: 3382-3390 DOI: 10.1200/JCO.2017.72.3502. (PMID: 28767289)
• 6 Salo-Mullen EE, O'Reilly EM, Kelsen DP. et al. Identification of germline genetic mutations in patients with pancreatic cancer. Cancer 2015; 121: 4382-4388 DOI: 10.1002/cncr.29664. (PMID: 26440929)
• 7 DaVee T, Coronel E, Papafragkakis C. et al. Pancreatic cancer screening in high-risk individuals with germline genetic mutations. Gastrointest Endosc 2018; 87: 1443-1450 DOI: 10.1016/j.gie.2017.12.019. (PMID: 29309780)
• 8 Conroy T, Desseigne F, Ychou M. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817-1825 DOI: 10.1056/NEJMoa1011923. (PMID: 21561347)
• 9 Pishvaian MJ, Blais EM, Brody JR. et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. The Lancet Oncology 2020; 21: 508-518 DOI: 10.1016/S1470-2045(20)30074-7. (PMID: 32135080)
• 10 Mosele F, Remon J, Mateo J. et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol 2020; 31: 1491-1505 DOI: 10.1016/j.annonc.2020.07.014. (PMID: 32853681)
• 11 Pflüger M, Tillack A, Schneider C. et al. Jahresbericht 2019, Klinisches Krebsregister Brandenburg Berlin, Berichtsjahre 2009–2018.
• 12 Rawla P, Sunkara T, Gaduputi V. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol 2019; 10: 10-27 DOI: 10.14740/wjon1166. (PMID: 30834048)
• 13 Rahib L, Smith BD, Aizenberg R. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014; 74: 2913-2921 DOI: 10.1158/0008-5472.CAN-14-0155. (PMID: 24840647)
• 14 McGuigan A, Kelly P, Turkington RC. et al. Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol 2018; 24: 4846-4861 DOI: 10.3748/wjg.v24.i43.4846. (PMID: 30487695)
• 15 von Hoff DD, Ervin T, Arena FP. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691-1703 DOI: 10.1056/NEJMoa1304369. (PMID: 24131140)
• 16 Shi S, Yu X. Selecting chemotherapy for pancreatic cancer: Far away or so close?. Semin Oncol 2019; 46: 39-47 DOI: 10.1053/j.seminoncol.2018.12.004. (PMID: 30611527)
• 17 Fernández A, Salgado M, García A. et al. Prognostic factors for survival with nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer in real-life practice: the ANICE-PaC study. BMC Cancer 2018; 18: 1185 DOI: 10.1186/s12885-018-5101-3. (PMID: 30497432)
• 18 O'Kane GM, Grünwald BT, Jang G-H. et al. GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer. Clin Cancer Res 2020; 26: 4901-4910 DOI: 10.1158/1078-0432.CCR-19-3724. (PMID: 32156747)
• 19 Moffitt RA, Marayati R, Flate EL. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet 2015; 47: 1168-1178 DOI: 10.1038/ng.3398. (PMID: 26343385)
• 20 Sinn M, Sinn BV, Treue D. et al. TP53 Mutations Predict Sensitivity to Adjuvant Gemcitabine in Patients with Pancreatic Ductal Adenocarcinoma: Next-Generation Sequencing Results from the CONKO-001 Trial. Clin Cancer Res 2020; 26: 3732-3739 DOI: 10.1158/1078-0432.CCR-19-3034. (PMID: 32234756)
• 21 Ducreux M, Cuhna AS, Caramella C. et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26 (05) v56-v68 DOI: 10.1093/annonc/mdv295.. (PMID: 26314780)
• 22 Oken MM, Creech RH, Tormey DC. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655 (PMID: 7165009)
• 23 Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell [Anonym]. 2017; 32: 185-203.e13 DOI: 10.1016/j.ccell.2017.07.007.
• 24 Bailey P, Chang DK, Nones K. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016; 531: 47-52 DOI: 10.1038/nature16965. (PMID: 26909576)
• 25 Waddell N, Pajic M, Patch A-M. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518: 495-501 DOI: 10.1038/nature14169. (PMID: 25719666)
• 26 Golan T, Hammel P, Reni M. et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med 2019; 381: 317-327 DOI: 10.1056/NEJMoa1903387. (PMID: 31157963)
• 27 Wattenberg MM, Asch D, Yu S. et al. Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br J Cancer 2020; 122: 333-339 DOI: 10.1038/s41416-019-0582-7. (PMID: 31787751)
• 28 Pihlak R, Weaver JMJ, Valle JW. et al. Advances in Molecular Profiling and Categorisation of Pancreatic Adenocarcinoma and the Implications for Therapy. Cancers (Basel) 2018; 10 DOI: 10.3390/cancers10010017. (PMID: 29329208)
• 29 Kastrinos F, Mukherjee B, Tayob N. et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA 2009; 302: 1790-1795 DOI: 10.1001/jama.2009.1529. (PMID: 19861671)
• 30 Marabelle A, Le DT, Ascierto PA. et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol 2020; 38: 1-10 DOI: 10.1200/JCO.19.02105. (PMID: 31682550)
• 31 Ko AH, Bekaii-Saab T, van Ziffle J. et al. A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma. Clin Cancer Res 2016; 22: 61-68 DOI: 10.1158/1078-0432.CCR-15-0979. (PMID: 26251290)
• 32 Sinn BV, Striefler JK, Rudl MA. et al. KRAS mutations in codon 12 or 13 are associated with worse prognosis in pancreatic ductal adenocarcinoma. Pancreas 2014; 43: 578-583 DOI: 10.1097/MPA.0000000000000077.. (PMID: 24681874)
• 33 Philip PA, Benedetti J, Corless CL. et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol 2010; 28: 3605-3610 DOI: 10.1200/JCO.2009.25.7550. (PMID: 20606093)
• 34 Aung KL, Fischer SE, Denroche RE. et al. Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial. Clin Cancer Res 2018; 24: 1344-1354 DOI: 10.1158/1078-0432.CCR-17-2994. (PMID: 29288237)
• 35 Moore MJ, Goldstein D, Hamm J. et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960-1966 DOI: 10.1200/JCO.2006.07.9525.
• 36 Govindan R, Fakih M, Price T. et al. OA02.02 Phase 1 Study of Safety, Tolerability, PK and Efficacy of AMG 510, a Novel KRASG12C Inhibitor, Evaluated in NSCLC. Journal of Thoracic Oncology 2019; 14: S208 DOI: 10.1016/j.jtho.2019.08.412.
• 37 McCarthy MJ, Pagba CV, Prakash P. et al. Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding. ACS Omega 2019; 4: 2921-2930 DOI: 10.1021/acsomega.8b03308. (PMID: 30842983)
• 38 Gillson J, Ramaswamy Y, Singh G. et al. Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?. Cancers (Basel) 2020; 12 DOI: 10.3390/cancers12051341. (PMID: 32456277)
• 39 Jones MR, Williamson LM, Topham JT. et al. NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2019; 25: 4674-4681 DOI: 10.1158/1078-0432.CCR-19-0191. (PMID: 31068372)
• 40 Drilon A, Laetsch TW, Kummar S. et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 2018; 378: 731-739 DOI: 10.1056/NEJMoa1714448. (PMID: 29466156)
• 41 O'Reilly EM, Lee JW, Zalupski M. et al. Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. J Clin Oncol 2020; 38: 1378-1388 DOI: 10.1200/JCO.19.02931. (PMID: 31976786)