Molekulare Prognosefaktoren in der onkologischen Viszeralchirurgie

Einleitung

Die moderne onkologische Viszeralchirurgie ist ein wichtiger Grundstein der multimodalen onkologischen Therapie und bildet zusammen mit der Strahlentherapie und internistischen Onkologie die effektivste Allianz zur Behandlung von Krebs. Die hier zur Verfügung stehenden Instrumente sinnvoll zu koordinieren und für jeden einzelnen Patienten sicher einzusetzen, ist eine Herausforderung. Außer den konventionellen bildgebenden Verfahren und der histologischen Aufarbeitung der Gewebe ist es daher umso wichtiger, dass Instrumente zur Verfügung stehen, welche die Entscheidungen zum Einsatz der vielfältigen Methoden weiter lenken. Hier kommt den molekularen Prognosefaktoren eine immer stärkere Bedeutung zu.

Das Verständnis molekularer Prozesse innerhalb von Tumoren hat in den letzten Jahren einen enormen Wissenszuwachs erfahren. Einige der bislang eher experimentellen Faktoren finden mehr und mehr Einzug in die klinische Routine, sodass es heute in der onkologischen Chirurgie unabdingbar ist, exakte Kenntnisse über derartige Prozesse zu haben. Aufgrund der Umfänglichkeit dieses Themenkomplexes soll sich im Folgenden auf ausgewählte molekulare Prognosefaktoren für Tumoren des Magens, Pankreas sowie Kolorektum beschränkt werden, die zukünftig eine stärkere Rolle in der klinischen Versorgung spielen werden, da hier gezielt Substanzen für individualisierte Therapien entwickelt werden.

Publication History

Article published online:
16 August 2022

• Literatur

• 1 Hutter C, Zenklusen JC. The Cancer Genome Atlas: Creating Lasting Value beyond Its Data. Cell 2018; 173: 283-285 DOI: 10.1016/j.cell.2018.03.042. (PMID: 29625045)
• 2 Camargo MC, Kim WH, Chiaravalli AM. et al. Improved survival of gastric cancer with tumour Epstein–Barr virus positivity: an international pooled analysis. Gut 2014; 63: 236-243 DOI: 10.1136/gutjnl-2013-304531. (PMID: 23580779)
• 3 Oki E, Oda S, Maehara Y. et al. Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair. Oncogene 1999; 18: 2143-2147 DOI: 10.1038/sj.onc.1202583. (PMID: 10321739)
• 4 Vilar E, Gruber SB. Microsatellite instability in colorectal cancer—the stable evidence. Nat Rev Clin Oncol 2010; 7: 153-162 DOI: 10.1038/nrclinonc.2009.237. (PMID: 20142816)
• 5 Ma C, Patel K, Singhi AD. et al. Programmed Death-Ligand 1 Expression Is Common in Gastric Cancer Associated With Epstein-Barr Virus or Microsatellite Instability. Am J Surg Pathology 2016; 40: 1496-1506 DOI: 10.1097/pas.0000000000000698. (PMID: 27465786)
• 6 Akiyama T, Sudo C, Ogawara H. et al. The Product of the Human c-erbB-2 Gene: a 185-Kilodalton Glycoprotein with Tyrosine Kinase Activity. Science 1986; 232: 1644-1646 DOI: 10.1126/science.3012781. (PMID: 3012781)
• 7 Thompson SK, Sullivan TR, Davies R. et al. HER-2/neu Gene Amplification in Esophageal Adenocarcinoma and Its Influence on Survival. Ann Surg Oncol 2011; 18: 2010-2017 DOI: 10.1245/s10434-011-1554-1. (PMID: 21267790)
• 8 Plum PS, Gebauer F, Krämer M. et al. HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma. BMC Cancer 2019; 19: 38 DOI: 10.1186/s12885-018-5242-4. (PMID: 30621632)
• 9 Bang YJ, Cutsem EV, Feyereislova A. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687-697 DOI: 10.1016/s0140-6736(10)61121-x.
• 10 Janjigian YY, Werner D, Pauligk C. et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis. Ann Oncol 2012; 23: 2656-2662 DOI: 10.1093/annonc/mds104. (PMID: 22689179)
• 11 Bozzetti C, Negri FV, Lagrasta CA. et al. Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma. Brit J Cancer 2011; 104: 1372-1376 DOI: 10.1038/bjc.2011.121. (PMID: 21487407)
• 12 Ylä-Herttuala S, Rissanen TT, Vajanto I. et al. Vascular Endothelial Growth Factors Biology and Current Status of Clinical Applications in Cardiovascular Medicine. J Am Coll Cardiol 2007; 49: 1015-1026 DOI: 10.1016/j.jacc.2006.09.053. (PMID: 17349880)
• 13 Fuchs CS, Tomasek J, Yong CJ. et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383: 31-39 DOI: 10.1016/s0140-6736(13)61719-5. (PMID: 24094768)
• 14 Levine AJ. p53, the Cellular Gatekeeper for Growth and Division. Cell 1997; 88: 323-331 DOI: 10.1016/s0092-8674(00)81871-1. (PMID: 9039259)
• 15 Lee J, van Hummelen P, Go C. et al. High-Throughput Mutation Profiling Identifies Frequent Somatic Mutations in Advanced Gastric Adenocarcinoma. Plos One 2012; 7: e38892 DOI: 10.1371/journal.pone.0038892. (PMID: 22723903)
• 16 Endoh Y, Sakata K, Tamura G. et al. Cellular phenotypes of differentiated-type adenocarcinomas and precancerous lesions of the stomach are dependent on the genetic pathways. J Pathology 2000; 191: 257-263 DOI: 10.1002/1096-9896(2000)9999:9999<::AID-PATH631>3.0.CO;2-2.
• 17 Li QF, Yao RY, Liu K. et al. Genetic Polymorphism of GSTP1: Prediction of Clinical Outcome to Oxaliplatin/5-FU-based Chemotherapy in Advanced Gastric Cancer. J Korean Med Sci 2010; 25: 846-852 DOI: 10.3346/jkms.2010.25.6.846. (PMID: 20514304)
• 18 Seufferlein T, Porzner M, Becker T. et al. S3-Leitlinie zum exokrinen Pankreaskarzinom. Z Gastroenterol 2013; 51: 1395-1440 DOI: 10.1055/s-0033-1356220.
• 19 Mateos RS, Conlon KC. Pancreatic cancer. Surg Oxf 2016; 34: 282-291 DOI: 10.1016/j.mpsur.2016.03.011.
• 20 Jones S, Zhang X, Parsons DW. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801-1806 DOI: 10.1126/science.1164368. (PMID: 18772397)
• 21 Kamisawa T, Wood LD, Itoi T. et al. Pancreatic cancer. Lancet 2016; 388: 73-85 DOI: 10.1016/s0140-6736(16)00141-0. (PMID: 26830752)
• 22 Hayashi A, Hong J, Iacobuzio-Donahue CA. The pancreatic cancer genome revisited. Nat Rev Gastroenterol Hepatol 2021; 18: 469-481 DOI: 10.1038/s41575-021-00463-z. (PMID: 34089011)
• 23 Shain AH, Giacomini CP, Matsukuma K. et al. Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proc Natl Acad Sci U S A 2012; 109: E252-E259 DOI: 10.1073/pnas.1114817109. (PMID: 22233809)
• 24 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)
• 25 Waddell N, Pajic M, Patch AM. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518: 495-501 DOI: 10.1038/nature14169. (PMID: 25719666)
• 26 Connor AA, Denroche RE, Jang GH. et al. Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. JAMA Oncol 2017; 3: 774-783 DOI: 10.1001/jamaoncol.2016.3916. (PMID: 27768182)
• 27 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)
• 28 Collisson EA, Sadanandam A, Olson P. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 2011; 17: 500-503 DOI: 10.1038/nm.2344. (PMID: 21460848)
• 29 Iacobuzio-Donahue CA, Velculescu VE, Wolfgang CL. et al. Genetic Basis of Pancreas Cancer Development and Progression: Insights from Whole-Exome and Whole-Genome Sequencing. Clin Cancer Res 2012; 18: 4257-4265 DOI: 10.1158/1078-0432.ccr-12-0315. (PMID: 22896692)
• 30 Grant RC, Denroche RE, Borgida A. et al. Exome-Wide Association Study of Pancreatic Cancer Risk. Gastroenterology 2018; 154: 719-722.e3 DOI: 10.1053/j.gastro.2017.10.015. (PMID: 29074453)
• 31 Lowery MA, Wong W, Jordan EJ. et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst 2018; 110: 1067-1074 DOI: 10.1093/jnci/djy024. (PMID: 29506128)
• 32 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)
• 33 Perkhofer L, Gout J, Roger E. et al. DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives. Gut 2021; 70: 606-617 DOI: 10.1136/gutjnl-2019-319984. (PMID: 32855305)
• 34 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)
• 35 Javle M, Shacham-Shmueli E, Xiao L. et al. Olaparib Monotherapy for Previously Treated Pancreatic Cancer With DNA Damage Repair Genetic Alterations Other Than Germline BRCA Variants. JAMA Oncol 2021; 7: 693-699 DOI: 10.1001/jamaoncol.2021.0006. (PMID: 33662100)
• 36 Humphris JL, Patch AM, Nones K. et al. Hypermutation In Pancreatic Cancer. Gastroenterology 2017; 152: 68-74.e2 DOI: 10.1053/j.gastro.2016.09.060. (PMID: 27856273)
• 37 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)
• 38 Le DT, Durham JN, Smith KN. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357: 409-413 DOI: 10.1126/science.aan6733. (PMID: 28596308)
• 39 Boyiadzis MM, Kirkwood JM, Marshall JL. et al. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J Immunother Cancer 2018; 6: 35 DOI: 10.1186/s40425-018-0342-x. (PMID: 29754585)
• 40 Romero JM, Grünwald B, Jang GH. et al. A Four-Chemokine Signature Is Associated with a T-cell–Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer. Clin Cancer Res 2020; 26: 1997-2010 DOI: 10.1158/1078-0432.ccr-19-2803. (PMID: 31964786)
• 41 Dekker E, Tanis PJ, Vleugels JLA. et al. Colorectal cancer. Lancet 2019; 394: 1467-1480 DOI: 10.1016/s0140-6736(19)32319-0. (PMID: 31631858)
• 42 Venook AP, Niedzwiecki D, Innocenti F. et al. Impact of primary (1o) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol 2016; 34: 3504 DOI: 10.1200/jco.2016.34.15_suppl.3504.
• 43 Hurwitz H, Fehrenbacher L, Novotny W. et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N Engl J Med 2004; 350: 2335-2342 DOI: 10.1056/nejmoa032691. (PMID: 15175435)
• 44 Roth AD, Tejpar S, Delorenzi M. et al. Prognostic Role of KRAS and BRAF in Stage II and III Resected Colon Cancer: Results of the Translational Study on the PETACC-3, EORTC 40993, SAKK 60–00 Trial. J Clin Oncol 2009; 28: 466-474 DOI: 10.1200/jco.2009.23.3452. (PMID: 20008640)
• 45 Kopetz S, Grothey A, Yaeger R. et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N Engl J Med 2019; 381: 1632-1643 DOI: 10.1056/nejmoa1908075. (PMID: 31566309)
• 46 Cutsem EV, Huijberts S, Grothey A. et al. Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E–Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study. J Clin Oncol 2019; 37: 1460-1469 DOI: 10.1200/jco.18.02459. (PMID: 30892987)
• 47 Overman MJ, McDermott R, Leach JL. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18: 1182-1191 DOI: 10.1016/s1470-2045(17)30422-9. (PMID: 28734759)
• 48 Le DT, Uram JN, Wang H. et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015; 372: 2509-2520 DOI: 10.1056/nejmoa1500596. (PMID: 26028255)
• 49 Chalabi M, Fanchi LF, Van den Berg JG. et al. LBA37_PRNeoadjuvant ipilimumab plus nivolumab in early stage colon cancer. Ann Oncol 2018; 29 (Suppl. 08) viii731 DOI: 10.1093/annonc/mdy424.047.
• 50 Ganesh K, Stadler ZK, Cercek A. et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol 2019; 16: 361-375 DOI: 10.1038/s41575-019-0126-x. (PMID: 30886395)
• 51 Sinicrope FA, Ou FS, Shi Q. et al. Randomized trial of FOLFOX alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient DNA mismatch repair or microsatellite instability (ATOMIC, Alliance A021502). J Clin Oncol 2017; 35: TPS3630 DOI: 10.1200/jco.2017.35.15_suppl.tps3630.
• 52 Sartore-Bianchi A, Trusolino L, Martino C. et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 2016; 17: 738-746 DOI: 10.1016/s1470-2045(16)00150-9. (PMID: 27108243)