Molekularpathologische Aspekte in der Viszeralchirurgie

Zusammenfassung

Der Erkenntnisgewinn im Bereich der molekularen Medizin hat zu fundamentalen Erweiterungen in der Diagnostik und in der Behandlung von Krebspatienten geführt. Einen unverzichtbaren Beitrag zu dieser individualisierten Therapie leistet die molekulare Diagnostik in der Pathologie, die durch die Identifikation und Interpretation von charakteristischen genetischen Veränderungen (Biomarker) in einzelnen Zellen und Geweben spezifische Informationen zur Diagnosesicherung und Therapie zahlreicher Erkrankungen beitragen kann. Besonders im Hinblick auf den Einsatz neuer zielgerichteter Medikamente, deren Ansprechen in vielen Fällen vom Vorliegen oder Fehlen bestimmter Zielstrukturen oder genetischer Veränderungen abhängig ist, erlangen die molekularpathologischen Bestimmungen prädiktiver Biomarker einen zunehmenden Stellenwert und unterstützen die klinischen Kollegen in der Wahl der optimalen Therapie für den einzelnen Patienten. Ziel dieser Übersichtsarbeit ist es, allgemeine Aspekte der molekularen Tumorpathologie relevanter Tumorentitäten zu erläutern und hinsichtlich verfügbarer zielgerichteter Therapien vorzustellen.

Abstract

New insights gained in the field of molecular medicine have led to fundamental progress in the diagnosis and treatment of tumour patients. Individualised treatment has been essentially facilitated by molecular diagnostics, which, by identifying and interpreting characteristic genetic alterations (biomarkers) in single cells and tissues, provide specific information to confirm the diagnosis and support the treatment of numerous diseases. Particularly with regard to the use of new targeted drugs, which often require the presence or absence of specific target structures or genetic alterations to induce response, the molecular pathological determination of predictive biomarkers plays an increasing role and helps clinicians to decide on optimal therapies for individual patients. The aim of this review is to highlight general aspects of molecular tumour pathology for relevant tumour entities and to present available targeted therapies.

Schlüsselwörter

Molekularpathologie - zielgerichtete Therapien - Viszeralchirurgie - Mutationen

Key words

molecular pathology - targeted therapies - visceral surgery - mutations

• Literatur

• 1 Werner M. Allgemeine Onkogenese und Tumorpathologie. In: Siewert JR, Rothmund M, Schumpelick V, Hrsg. Praxis der Viszeralchirurgie. Onkologische Chirurgie. 3. Aufl. Berlin Heidelberg: Springer; 2010: 4-12
• 2 Wittekind C. Klassifikation von Tumoren. In: Siewert JR, Stein HJ, Hrsg. Chirurgie. 9. Aufl. Berlin Heidelberg: Springer; 2012: 160-178
• 3 Chin L, Andersen JN, Futreal PA. Cancer genomics: from discovery science to personalized medicine. Nat Med 2011; 17: 297-303
• 4 Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer 2005; 5: 845-856
• 5 Dietel M. Prädiktive Biomarker. Die Schlüsselrolle der Molekularpathologie. Onkologe 2007; 13: 56-66
• 6 Stenzinger A, Penzel R, Endris V et al. Molekulare Diagnostik in der Pathologie. Dtsch Med Wochenschr 2013; 138: 1061-1068
• 7 Hentschel J, Sändig I, Unger T et al. Molekulargenetische und molekularpathologische Analysen. Forum 2015; 30: 118-121
• 8 Schmid KW. Pathologie der malignen Schilddrüsentumoren. In: Siewert JR, Rothmund M, Schumpelick V, Hrsg. Praxis der Viszeralchirurgie: Endokrine Chirurgie. 3. Aufl. Berlin Heidelberg: Springer; 2013: 139-152
• 9 DeLellis RA, Lloyd RV, Heitz PU, Eng C. WHO Histological Classification of Thyroid and Parathyroid Tumours. In: World Health Organization Classification of Tumours Pathology & Genetics. Tumours of Endocrine Organs. Lyon: IARC Press; 2004
• 10 Rosai J, Carcangiu M, DeLellis RA. Tumors of the Thyroid Gland. In: Atlas of Tumor Pathology. Vol 5. Washington/DC: AFIP; 1992
• 11 Schmid KW, Führer D. Rolle der Molekularpathologie beim Schilddrüsenkarzinom. Onkologe 2015; 21: 584-596
• 12 Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 2013; 13: 184-199
• 13 Adeniran AJ, Zhu Z, Gandhi M et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol 2006; 30: 216-222
• 14 Nikiforov YE. Molecular analysis of thyroid tumors. Mod Pathol 2011; 2: 34-43
• 15 Soares P, Trovisco V, Rocha AS et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 2003; 22: 4578-4580
• 16 Dralle H, Musholt TJ, Schabram J et al. German Association of Endocrine Surgeons practice guideline for the surgical management of malignant thyroid tumors. Langenbecks Arch Surg 2013; 398: 347-375
• 17 Soares P, Lima J, Preto A et al. Genetic alterations in poorly differentiated and undifferentiated thyroid carcinomas. Curr Genomics 2011; 12: 609-617
• 18 Liu X, Bishop J, Shan Y et al. Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer 2013; 20: 603-610
• 19 Tiedje V, Schmid KW, Weber F et al. Differenzierte Schilddrüsenkarzinome. Internist 2015; 56: 153-168
• 20 Spitzweg C, Bible KC, Hofbauer LC et al. Advanced radioiodine-refractory differentiated thyroid cancer: the sodium iodide symporter and other emerging therapeutic targets. Lancet Diabetes Endocrinol 2014; 2: 830-842
• 21 Ho AL, Grewal RK, Leboeuf R et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013; 368: 623-632
• 22 Alonso-Gordoa T, Díez JJ, Durán M et al. Advances in thyroid cancer treatment: latest evidence and clinical potential. Ther Adv Med Oncol 2015; 7: 22-38
• 23 Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of Tumours of the Digestive System. Lyon: IARC Press; 2010
• 24 Aust DE, Barreton GB. Sporadische Tumoren des Kolorektums. In: Stolte M, Rüschoff J, Klöppel G, Hrsg. Pathologie. Verdauungstrakt und Peritoneum. 3. Aufl. Berlin, Heidelberg: Springer; 2013: 611-661
• 25 Benatti P, Gafa R, Barana D et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 2005; 11: 8332-8340
• 26 Malesci A, Laghi L, Bianchi P et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res 2007; 13: 3831-3839
• 27 Samowitz WS, Sweeney C, Herrick J et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 2005; 65: 6063-6069
• 28 De Roock W, De Vriendt V, Normanno N et al. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 2011; 12: 594-603
• 29 Neumann JHL, Jung A, Kirchner T. Molekulare Pathologie des kolorektalen Karzinoms. Pathologe 2015; 36: 137-144
• 30 Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010; 138: 2073-2087
• 31 Mangold E, Pagenstecher C, Friedl W et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1.721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer 2005; 116: 692-702
• 32 Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 1626-1634
• 33 De Roock W, Piessevaux H, De Schutter J et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008; 19: 508-515
• 34 Robert Koch-Institut, Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. Hrsg. Krebs in Deutschland 2009/2010. 9. Ausgabe. Berlin: 2013
• 35 Stadler ZK, Salo-Mullen E, Patil SM et al. Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer. Cancer 2012; 118: 493-499
• 36 Moynahan ME, Chiu JW, Koller BH et al. Brca1 controls homology-directed DNA repair. Mol Cell 1999; 4: 511-518
• 37 Murai J, Huang SY, Das BB et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 2012; 72: 5588-5599
• 38 Kaufman B, Shapira-Frommer R, Schmutzler RK et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33: 244-250
• 39 Lowery M, Kelsen DP, Smith SC et al. Phase II trial of veliparib (V) in patients (pts) with previously treated BRCA or PALB2-mutated (mut) pancreas adenocarcinoma (PC). J Clin Oncol 2015; 33 (Suppl. 03) S358
• 40 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
• 41 Dal Molin M, Matthaei H, Wu J et al. Clinicopathological correlates of activating GNAS mutations in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann Surg Oncol 2013; 20: 3802-3808
• 42 Bioulac-Sage P, Rebouissou S, Thomas C et al. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology 2007; 46: 740-748
• 43 Bioulac-Sag P, Balabaud C, Wanless IR. Focal Nodular Hyperplasia and Hepatocellular Adenoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: IARC Press; 2010: 198-204
• 44 Micchelli ST, Vivekanandan P, Boitnott JK et al. Malignant transformation of hepatic adenomas. Mod Pathol 2008; 21: 491-497
• 45 Kondo F, Fukusato T, Kudo M. Pathological Diagnosis of Benign Hepatocellular Nodular Lesions Based on the New World Health Organization Classification. Oncology 2014; 87 (Suppl. 01) S37-S49
• 46 Bioulac-Sage P, Cubel G, Balabaud C. Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers. Semin Liver Dis 2011; 31: 91-103
• 47 Fuccio L, Zagari RM, Eusebi LH et al. Meta-analysis: can Helicobacter pylori eradication treatment reduce the risk for gastric cancer?. Ann Intern Med 2009; 151: 121-128
• 48 Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014; 513: 202-209
• 49 Rubin I, Yarden Y. The basic biology of HER2. Ann Oncol 2001; 12 (Suppl. 01) S3-S8
• 50 Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177-182
• 51 Jorgensen JT, Hersom M. HER2 as a prognostic marker in gastric cancer – a systematic analysis of data from the literature. J Cancer 2012; 3: 137-144
• 52 Terashima M, Ochiai A, Kitada K et al. Impact of human epidermal growth factor receptor (EGFR) and ERBB2 (HER2) expressions on survival in patients with stage II/III gastric cancer, enrolled in the ACTS-GC study. J Clin Oncol 2011; 29: 4013
• 53 Bang YJ, Van Cutsem E, 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
• 54 Hamamoto Y. Evaluation of the appropriate use of trastuzumab for advanced or metastatic HER2-positive gastric cancer. In: Ohtsu A, ed. 9th Annual Meeting of the Japanese Society of Medical Oncology. July 21 – 23, 2011; Yokohama, Japan.
• 55 Nishina T, Kajiwara T, Hori S et al. A long-term survival case of HER2-positive unresectable advanced gastric cancer that markedly responded to trastuzumab + capecitabine + cisplatin combination therapy. 83rd Annual Meeting of the Japanese Gastric Cancer Association, March 3 – 5, 2011; Misawa, Japan.
• 56 Hegewisch-Becker S, Moorahrend E, Kröning H et al. Trastuzumab (TRA) in combination with different first-line chemotherapies for treatment of HER2-positive metastatic gastric or gastroesophageal junction cancer (MGC): findings from the German noninterventional observational study HerMES. J Clin Oncol 2012; 30: 4065
• 57 Miettinen M, Lasota J. Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics. Pol J Pathol 2003; 54: 3-24
• 58 DeMatteo RP, Lewis JJ, Leung D et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231: 51-58
• 59 Duensing S, Duensing A. Targeted therapies of gastrointestinal stromal tumors (GIST)-the next frontiers. Biochem Pharmacol 2010; 80: 575-583
• 60 Tornillo L. Gastrointestinal stromal tumor – an evolving concept. Front Med 2014; 1: 43
• 61 Blanke CD, Rankin C, Demetri GD et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008; 26: 626-632
• 62 Joensuu H, Eriksson M, Sundby Hall K et al. One vs. three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 2012; 307: 1265-1272
• 63 The ESMO-Group. GIST: ESMO CLINICAL Practice Guidelines for Diagnosis, Treatment und Follow up. Ann Oncol 2014; 25 (Suppl. 03) S23-S26