Molekulare Testung des Prostatakarzinoms: wann, wie und mit welcher Konsequenz?

Zusammenfassung

Das metastasierte Prostatakarzinom ist eine heterogene Erkrankung. Bislang basiert die Behandlungsentscheidung meist auf der Tumorausdehnung und -symptomlast, Begleiterkrankungen und dem Patientenwunsch. Molekularpathologische Aspekte fließen nur selten ein.

Kostenrückgang und zunehmende Verbreitung des Next Generation Sequencing (NGS) haben zu einer Zunahme der molekularen Testung und einem besseren Verständnis der Bedeutung molekularer Alterationen für die Entstehung und Ausbreitung des Prostatakarzinoms geführt. Eine konsequentere Testung konstitutioneller Genveränderungen („Keimbahntestung“) deckt hereditäre Prädispositionen auf. Nach der Zulassung von Olaparib zur Therapie BRCA1/2 mutierter, kastrationsresistenter Prostatakarzinome befinden sich weitere zielgerichtete Therapieansätze in der Entwicklung.

In unserem Übersichtsartikel geben wir einen Überblick zur aktuellen molekularen Testung beim Prostatakarzinom und diskutieren mögliche Konsequenzen.

Abstract

Metastatic prostate cancer is a heterogeneous disease. To date, however, treatment decisions are often based on the extent and symptom burden of the tumour, concomitant diseases, and the patient’s wishes. Molecular pathology aspects are rarely taken into account.

Declining costs and the increasing use of next-generation sequencing (NGS) have led to an increase in molecular testing and a better understanding of the significance of molecular alterations for the development and spread of prostate cancer. More consistent germline testing reveals hereditary predispositions.

Following the approval of olaparib for the treatment of BRCA1/2 mutated, castration-resistant prostate cancer, further targeted therapeutic approaches are currently under development.

In our review article, we provide an overview of current molecular testing in prostate cancer and discuss possible consequences.

Fazit für die Praxis

• Das Prostatakarzinom ist eine heterogene Erkrankung.

• Eine Testung konstitutioneller Genalterationen (Keimbahntestung) soll allen Patienten angeboten werden, die die Kriterien der NCCN-Leitlinie erfüllen.

• Aktuell erfolgt die Behandlungsentscheidung in der metastasierten Situation häufig noch unabhängig von molekularen Markern.

• Aufgrund der schlechteren Prognose und dem geringeren Ansprechen der BRCA1/2+ Patienten auf Standardtherapien empfiehlt sich eine somatische Testung frühzeitig bei Progress unter dem ersten ARPI.

• Kombinationstherapien mit ARPI- und PARP-Inhibitoren können prinzipiell unabhängig vom HRR-Status eingesetzt werden, zeigen allerdings bei HRR+-Patienten, insbesondere BRCA1/2+-Patienten die höchste Effektivität.

• Genalterationen von TP53, PTEN, RB1 und FOXA1 gehen mit einem aggressiven Tumorverlauf und einem mutmaßlich schlechteren Ansprechen auf Standardtherapien einher.

• Eine umfassende molekularpathologische Analyse kann über die ZPM angeboten werden, wenn von einer baldigen Ausschöpfung der Standardtherapien auszugehen ist. Hier sollen potenziell targetierbare Läsionen identifiziert werden.

• Zielgerichtete Therapiestrategien für das Prostatakarzinom befinden sich in der klinischen Testung.

• Künftig dürften Therapieentscheidungen zunehmend auf dem individuellen molekularen Profil der Patienten beruhen.

Schlüsselwörter

Somatische Testung - Keimbahntestung - konstitutionelle Genveränderungen - zielgerichtete Therapie - PARP-Inhibitoren

Keywords

Somatic testing - germline testing - constitutional gene alterations - targeted therapy - PARP inhibitors

Publication History

Received: 05 February 2024

Accepted: 06 February 2024

Article published online:
27 March 2024

• Literatur

• 1 Merseburger AS, Krabbe LM, Krause BJ. et al. The Treatment of Metastatic, Hormone-Sensitive Prostatic Carcinoma. Dtsch Arztebl Int 2022; 119: 622-632 DOI: 10.3238/arztebl.m2022.0294. (PMID: 35912436)
• 2 Amsberg G von. Metastasiertes kastrationsresistentes Prostatakarzinom mit Therapiesequenz (mCRPC). 2023. https://link.springer.com/chapter/10.1007/978-3-662-67297-6_8
• 3 Tuffaha H, Edmunds K, Fairbairn D. et al. Guidelines for genetic testing in prostate cancer: a scoping review. Prostate Cancer Prostatic Dis 2023; DOI: 10.1038/s41391-023-00676-0. (PMID: 37202470)
• 4 Network NCC. NCCN Guidelines Version 4.2023 – Prostate cancer. 2023
• 5 Cheng HH, Sokolova AO, Schaeffer EM. et al. Germline and Somatic Mutations in Prostate Cancer for the Clinician. J Natl Compr Canc Netw 2019; 17: 515-521 DOI: 10.6004/jnccn.2019.7307. (PMID: 31085765)
• 6 Pauley K, Koptiuch C, Greenberg S. et al. Discrepancies between tumor genomic profiling and germline genetic testing. ESMO Open 2022; 7: 100526 DOI: 10.1016/j.esmoop.2022.100526.
• 7 Richards S, Aziz N, Bale S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-424 DOI: 10.1038/gim.2015.30. (PMID: 25741868)
• 8 Appelbaum PS, Berger SM, Brokamp E. et al. Practical considerations for reinterpretation of individual genetic variants. Genet Med 2023; 25: 100801 DOI: 10.1016/j.gim.2023.100801. (PMID: 36748709)
• 9 Kuzbari Z, Bandlamudi C, Loveday C. et al. Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations. Ann Oncol 2023; 34: 215-227 DOI: 10.1016/j.annonc.2022.12.003. (PMID: 36529447)
• 10 Jasin M, Rothstein R. Repair of strand breaks by homologous recombination. Cold Spring Harb Perspect Biol 2013; 5: a012740 DOI: 10.1101/cshperspect.a012740. (PMID: 24097900)
• 11 Chung JH, Dewal N, Sokol E. et al. Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors. JCO Precis Oncol 2019; 3 DOI: 10.1200/po.18.00283. (PMID: 31218271)
• 12 Castro E, Romero-Laorden N, Del Pozo A. et al. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 2019; 37: 490-503 DOI: 10.1200/jco.18.00358.
• 13 Annala M, Struss WJ, Warner EW. et al. Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer. Eur Urol 2017; 72: 34-42 DOI: 10.1016/j.eururo.2017.02.023. (PMID: 28259476)
• 14 Olmos D, Lorente D, Alameda D. et al. Presence of somatic/germline homologous recombination repair (HRR) mutations and outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) receiving first-line (1L) treatment stratified by BRCA status. Journal of Clinical Oncology 2023; 41: 5003-5003 DOI: 10.1200/JCO.2023.41.16_suppl.5003.
• 15 Bono J de, Mateo J, Fizazi K. et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2020; 382: 2091-2102 DOI: 10.1056/NEJMoa1911440. (PMID: 32343890)
• 16 Fizazi K, Piulats JM, Reaume MN. et al. Rucaparib or Physician's Choice in Metastatic Prostate Cancer. N Engl J Med 2023; 388: 719-732 DOI: 10.1056/NEJMoa2214676. (PMID: 36795891)
• 17 Nyberg T, Frost D, Barrowdale D. et al. Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study. Eur Urol 2020; 77: 24-35 DOI: 10.1016/j.eururo.2019.08.025. (PMID: 31495749)
• 18 Kaur H, Salles DC, Murali S. et al. Genomic and Clinicopathologic Characterization of ATM-deficient Prostate Cancer. Clin Cancer Res 2020; 26: 4869-4881 DOI: 10.1158/1078-0432.Ccr-20-0764. (PMID: 32694154)
• 19 Na R, Zheng SL, Han M. et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur Urol 2017; 71: 740-747 DOI: 10.1016/j.eururo.2016.11.033.
• 20 Chi KN, Sandhu S, Smith MR. et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol 2023; 34: 772-782 DOI: 10.1016/j.annonc.2023.06.009.
• 21 Clarke NW, Armstrong AJ, Thiery-Vuillemin A. et al. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. NEJM Evidence 2022; 1: EVIDoa2200043 DOI: 10.1056/EVIDoa2200043.
• 22 Rafiei S, Fitzpatrick K, Liu D. et al. ATM Loss Confers Greater Sensitivity to ATR Inhibition Than PARP Inhibition in Prostate Cancer. Cancer Res 2020; 80: 2094-2100 DOI: 10.1158/0008-5472.Can-19-3126.
• 23 Hall MJ, Bernhisel R, Hughes E. et al. Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers. Cancer Prev Res (Phila) 2021; 14: 433-440 DOI: 10.1158/1940-6207.Capr-20-0448.
• 24 Lu HM, Li S, Black MH. et al. Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing. JAMA Oncol 2019; 5: 51-57 DOI: 10.1001/jamaoncol.2018.2956.
• 25 Zhang F, Ma J, Wu J. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol 2009; 19: 524-529 DOI: 10.1016/j.cub.2009.02.018. (PMID: 19268590)
• 26 Carreira S, Porta N, Arce-Gallego S. et al. Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. Cancer Discov 2021; 11: 2812-2827 DOI: 10.1158/2159-8290.Cd-21-0007.
• 27 Yang X, Leslie G, Doroszuk A. et al. Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. J Clin Oncol 2020; 38: 674-685 DOI: 10.1200/jco.19.01907.
• 28 Pritchard CC, Mateo J, Walsh MF. et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 2016; 375: 443-453 DOI: 10.1056/NEJMoa1603144.
• 29 Fukui K. DNA mismatch repair in eukaryotes and bacteria. J Nucleic Acids 2010; 2010: 260512 DOI: 10.4061/2010/260512. (PMID: 20725617)
• 30 Abida W, Cheng ML, Armenia J. et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol 2019; 5: 471-478 DOI: 10.1001/jamaoncol.2018.5801. (PMID: 30589920)
• 31 Nava Rodrigues D, Rescigno P, Liu D. et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest 2018; 128: 4441-4453 DOI: 10.1172/jci121924.
• 32 Sedhom R, Antonarakis ES. Clinical implications of mismatch repair deficiency in prostate cancer. Future Oncol 2019; 15: 2395-2411 DOI: 10.2217/fon-2019-0068. (PMID: 31237441)
• 33 Raymond VM, Mukherjee B, Wang F. et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol 2013; 31: 1713-1718 DOI: 10.1200/jco.2012.44.1238.
• 34 Idos G, Valle L. Lynch Syndrome. et al. In: Adam MP, Feldman J, Mirzaa GM. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993
• 35 Boysen G, Rodrigues DN, Rescigno P. et al. SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity. Clin Cancer Res 2018; 24: 5585-5593 DOI: 10.1158/1078-0432.Ccr-18-0937.
• 36 Swami U, Isaacsson Velho P, Nussenzveig R. et al. Association of SPOP Mutations with Outcomes in Men with De Novo Metastatic Castration-sensitive Prostate Cancer. Eur Urol 2020; 78: 652-656 DOI: 10.1016/j.eururo.2020.06.033.
• 37 Jamaspishvili T, Berman DM, Ross AE. et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol 2018; 15: 222-234 DOI: 10.1038/nrurol.2018.9. (PMID: 29460925)
• 38 Turnham DJ, Bullock N, Dass MS. et al. The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer. Cells 2020; 9: 2342 DOI: 10.3390/cells9112342. (PMID: 33105713)
• 39 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 DOI: 10.1016/s0140-6736(21)00580-8. (PMID: 34246347)
• 40 Yehia L, Eng C. PTEN Hamartoma Tumor Syndrome. et al. In: Adam MP, Feldman J, Mirzaa GM. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993
• 41 Han W, Liu M, Han D. et al. RB1 loss in castration-resistant prostate cancer confers vulnerability to LSD1 inhibition. Oncogene 2022; 41: 852-864 DOI: 10.1038/s41388-021-02135-3. (PMID: 34975152)
• 42 Goel S, DeCristo MJ, McAllister SS. et al. CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest. Trends Cell Biol 2018; 28: 911-925 DOI: 10.1016/j.tcb.2018.07.002. (PMID: 30061045)
• 43 Hernández Borrero LJ, El-Deiry WS. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim Biophys Acta Rev Cancer 2021; 1876: 188556 DOI: 10.1016/j.bbcan.2021.188556. (PMID: 33932560)
• 44 Teroerde M, Nientiedt C, Duensing A. et al. Revisiting the Role of p53 in Prostate Cancer. In: Bott SRJ, Ng KL. Prostate Cancer. Brisbane (AU): Exon Publications; 2021. DOI: 10.36255/exonpublications.prostatecancer.p53.2021
• 45 Liu C, Zhu Y, Lou W. et al. Functional p53 determines docetaxel sensitivity in prostate cancer cells. Prostate 2013; 73: 418-427 DOI: 10.1002/pros.22583. (PMID: 22996738)
• 46 De Laere B, Oeyen S, Mayrhofer M. et al. TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res 2019; 25: 1766-1773 DOI: 10.1158/1078-0432.Ccr-18-1943. (PMID: 30209161)
• 47 Schneider K, Zelley K, Nichols KE. et al. Li-Fraumeni Syndrome. et al. In: Adam MP, Feldman J, Mirzaa GM. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993
• 48 Soundararajan R, Viscuse P, Pilie P. et al. Genotype-to-Phenotype Associations in the Aggressive Variant Prostate Cancer Molecular Profile (AVPC-m) Components. Cancers 2022; 14: 3233 DOI: 10.3390/cancers14133233. (PMID: 35805010)
• 49 Aparicio AM, Shen L, Tapia EL. et al. Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers. Clin Cancer Res 2016; 22: 1520-1530 DOI: 10.1158/1078-0432.Ccr-15-1259. (PMID: 26546618)
• 50 Shah N, Brown M. The Sly Oncogene: FOXA1 Mutations in Prostate Cancer. Cancer Cell 2019; 36: 119-121 DOI: 10.1016/j.ccell.2019.07.005. (PMID: 31408618)
• 51 Adams EJ, Karthaus WR, Hoover E. et al. FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes. Nature 2019; 571: 408-412 DOI: 10.1038/s41586-019-1318-9. (PMID: 31243370)
• 52 Ewing CM, Ray AM, Lange EM. et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 2012; 366: 141-149 DOI: 10.1056/NEJMoa1110000. (PMID: 22236224)
• 53 Nyberg T, Govindasami K, Leslie G. et al. Homeobox B13 G84E Mutation and Prostate Cancer Risk. Eur Urol 2019; 75: 834-845 DOI: 10.1016/j.eururo.2018.11.015. (PMID: 30527799)