Subscribe to RSS
Download PDF
DOI: 10.1055/a-2549-7283
Zehn Jahre Molekulares Tumorboard: von der Genomsequenzierung zur personalisierten Krebstherapie
Ten Years of the Molecular Tumour Board: Genome Sequencing to Personalised Therapies
Zusammenfassung
Vor 20 Jahren wurde das menschliche Genom erstmals vollständig sequenziert. Das Human Genome Project wurde an 20 Zentren in den USA, Großbritannien, Deutschland, Frankreich, China und Japan durchgeführt, nahm 13 Jahre in Anspruch und war mit Kosten von 2,6 Mrd. € verbunden. Durch die Entwicklung des Next Generation Sequencing (NGS) kann nun, wenige Jahre später, im Gegensatz zur enzymatischen Sanger-Sequenzierung oder zum chemischen Maxam-Gilbert-Verfahren das gesamte humane Genom innerhalb weniger Stunden für unter 1000 € sequenziert werden. Die klinische Implementierung dieser molekularen Erkenntnisse stellt jedoch eine Herausforderung dar, denn eine präzise Interpretation der genetischen Daten ist zwingend erforderlich. Dies erfordert ein multidisziplinäres Team aus Medizinern, Molekularbiologen, Pathologen und Bioinformatikern, um die Relevanz der identifizierten genetischen Veränderungen in den klinischen Kontext einzuordnen. An dieser Stelle tritt das Molekulare Tumorboard in den Vordergrund. Es ermöglicht eine individualisierte Therapieentscheidung, indem es genetische und molekulare Befunde integriert und diese in Bezug auf verfügbare Therapien und klinische Studien bewertet.
Abstract
Twenty years ago, the human genome was first fully sequenced. The Human Genome Project was carried out at 20 centres in the USA, the UK, Germany, France, China, and Japan, took 13 years, and had costs amounting to 2.6 billion €. Thanks to the development of Next Generation Sequencing (NGS), however, just a few years later, the entire human genome can now be sequenced in just a few hours for under 1000 €. This is a stark contrast to the enzymatic Sanger sequencing or the chemical Maxam-Gilbert method. The clinical implementation of these molecular insights nonetheless presents a challenge, as precise interpretation of genetic data is absolutely essential. This requires a multidisciplinary team of clinicians, molecular biologists, pathologists, and bioinformaticians to place the relevance of identified genetic changes in the clinical context. At this point, the molecular tumour board comes to the forefront. It enables personalised treatment decisions by integrating genetic and molecular findings and evaluating them in relation to available therapies and clinical trials.
Publication History
Received: 28 January 2025
Accepted after revision: 28 February 2025
Article published online:
08 April 2025
© 2025. Thieme. All rights reserved.
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
-
Literatur
- 1 Lander ES, Linton LM, Birren B. et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860-921
- 2 Patel SJ, Sanjana NE, Kishton RJ. et al. Identification of essential genes for cancer immunotherapy. Nature 2017; 548: 537-542
- 3 Leichsenring J, Horak P, Kreutzfeldt S. et al. Variant classification in precision oncology. Int J Cancer 2019; 145: 2996-3010
- 4 Patel SP, Kurzrock R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol Cancer Ther 2015; 14: 847-856
- 5 Topalian SL, Taube JM, Anders RA. et al. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 2016; 16: 275-287
- 6 Boussiotis VA. Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N Engl J Med 2016; 375: 1767-1778
- 7 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
- 8 Wu YL, Lu S, Cheng Y. et al. Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial. J Thorac Oncol 2019; 14: 867-875
- 9 Cristescu R, Mogg R, Ayers M. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 2018; 362
- 10 Jardim DL, Goodman A, de Melo Gagliato D. et al. The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker. Cancer Cell 2021; 39: 154-173
- 11 Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330-337
- 12 Dudley JC, Lin MT, Le DT. et al. Microsatellite Instability as a Biomarker for PD-1 Blockade. Clin Cancer Res 2016; 22: 813-820
- 13 Lee V, Murphy A, Le DT. et al. Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade. Oncologist 2016; 21: 1200-1211
- 14 Keam SJ. Trastuzumab Deruxtecan: First Approval. Drugs 2020; 80: 501-508
- 15 Lee J, Park YH. Trastuzumab deruxtecan for HER2+ advanced breast cancer. Future Oncol 2022; 18: 7-19
- 16 Shitara K, Bang YJ, Iwasa S. et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med 2020; 382: 2419-2430
- 17 Li BT, Smit EF, Goto Y. et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med 2022; 386: 241-251
- 18 Bardia A, Tolaney SM, Punie K. et al. Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann Oncol 2021; 32: 1148-1156
- 19 Bardia A, Messersmith WA, Kio EA. et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132–01 basket trial. Ann Oncol 2021; 32: 746-756
- 20 Heist RS, Guarino MJ, Masters G. et al. Therapy of Advanced Non-Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan. J Clin Oncol 2017; 35: 2790-2797
- 21 Yu EY, Massard C, Retz M. et al. Keynote-365 cohort a: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol 2019; 37 (Suppl. 07) 145
- 22 Rempel E, Kluck K, Beck S. et al. Pan-cancer analysis of genomic scar patterns caused by homologous repair deficiency (HRD). NPJ Precis Oncol 2022; 6: 36
- 23 den Brok WD, Schrader KA, Sun S. et al. Homologous Recombination Deficiency in Breast Cancer: A Clinical Review. JCO Precis Oncol 2017; 1: 1-13
- 24 Knijnenburg TA, Wang L, Zimmermann MT. et al. Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 2018; 23: 239-254.e6
- 25 Abkevich V, Timms KM, Hennessy BT. et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 2012; 107: 1776-1782
- 26 Birkbak NJ, Wang ZC, Kim JY. et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2012; 2: 366-375
- 27 Popova T, Manié E, Rieunier G. et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 2012; 72: 5454-5462
- 28 Telli ML, Timms KM, Reid J. et al. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clin Cancer Res 2016; 22: 3764-3773
- 29 Ray-Coquard I, Pautier P, Pignata S. et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med 2019; 381: 2416-2428
- 30 Wang Y, Ung MH, Cantor S. et al. Computational Investigation of Homologous Recombination DNA Repair Deficiency in Sporadic Breast Cancer. Sci Rep 2017; 7: 15742
- 31 Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer 2016; 16: 110-120
- 32 Gröschel S, Hübschmann D, Raimondi F. et al. Defective homologous recombination DNA repair as therapeutic target in advanced chordoma. Nat Commun 2019; 10: 1635
- 33 Yates LR, Seoane J, Le Tourneau C. et al. The European Society for Medical Oncology (ESMO) Precision Medicine Glossary. Ann Oncol 2018; 29: 30-35
- 34 Prior IA, Hood FE, Hartley JL. The Frequency of Ras Mutations in Cancer. Cancer Res 2020; 80: 2969-2974
- 35 Weiss RA. A perspective on the early days of RAS research. Cancer Metastasis Rev 2020; 39: 1023-1028
- 36 Skoulidis F, Li BT, Dy GK. et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N Engl J Med 2021; 384: 2371-2381
- 37 Bekaii-Saab TS, Yaeger R, Spira AI. et al. Adagrasib in Advanced Solid Tumors Harboring a KRAS(G12C) Mutation. J Clin Oncol 2023; 41: 4097-4106
- 38 Hong DS, Fakih MG, Strickler JH. et al. KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med 2020; 383: 1207-1217
- 39 Shen H, Lundy J, Strickland AH. et al. KRAS G12D Mutation Subtype in Pancreatic Ductal Adenocarcinoma: Does It Influence Prognosis or Stage of Disease at Presentation?. Cells 2022; 11
- 40 Wang X, Allen S, Blake JF. et al. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS(G12D) Inhibitor. J Med Chem 2022; 65: 3123-3133
- 41 Zhou C, Li C, Luo L. et al. Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer. Cancer Cell 2024; 42: 1286-1300.e8
- 42 Leidner R, Sanjuan Silva N, Huang H. et al. Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer. N Engl J Med 2022; 386: 2112-2119
- 43 Kastenhuber ER, Lowe SW. Putting p53 in Context. Cell 2017; 170: 1062-1078
- 44 Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 1997; 420: 25-27
- 45 Oliner JD, Pietenpol JA, Thiagalingam S. et al. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature 1993; 362: 857-860
- 46 Saleh MN, Patel MR, Bauer TM. et al. Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-type TP53. Clin Cancer Res 2021; 27: 5236-5247
- 47 Wang W, Albadari N, Du Y. et al. MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future. Pharmacol Rev 2024; 76: 414-453
- 48 Catalanotti F, Cheng DT, Shoushtari AN. et al. PTEN Loss-of-Function Alterations Are Associated With Intrinsic Resistance to BRAF Inhibitors in Metastatic Melanoma. JCO Precis Oncol 2017; 1: PO.16.00054
- 49 Sweeney C, Bracarda S, Sternberg CN. et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2021; 398: 131-142
- 50 Mateo J, Ganji G, Lemech C. et al. A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res 2017; 23: 5981-5992
- 51 Heinrich K, Miller-Phillips L, Ziemann F. et al. Lessons learned: the first consecutive 1000 patients of the CCCMunich(LMU) Molecular Tumor Board. J Cancer Res Clin Oncol 2023; 149: 1905-1915
- 52 Frost H, Graham DM, Carter L. et al. Patient attrition in Molecular Tumour Boards: a systematic review. Br J Cancer 2022; 127: 1557-1564
- 53 Hoefflin R, Lazarou A, Hess ME. et al. Transitioning the Molecular Tumor Board from Proof of Concept to Clinical Routine: A German Single-Center Analysis. Cancers (Basel) 2021; 13: 1151
- 54 Hoefflin R, Geissler AL, Fritsch R. et al. Personalized Clinical Decision Making Through Implementation of a Molecular Tumor Board: A German Single-Center Experience. JCO Precis Oncol 2018; 2: PO.18.00105
- 55 Oelschläger L, Künstner A, Frey F. et al. Whole-Exome Sequencing, Mutational Signature Analysis, and Outcome in Multiple Myeloma-A Pilot Study. Int J Mol Sci 2024; 25: 13418
- 56 Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Medizinische Onkologie, 11. bis 14. Oktober 2024, Basel. Oncol Res Treat [Anonym]. 2024; 47 (Suppl. 2) 11-354