Skip to main content
Log in

MSI, RAS, BRAF und Co.

Personalisierte Therapie von gastrointestinalen Malignomen

  • fortbildung
  • Published:
InFo Onkologie Aims and scope

Für die Therapie gastrointestinaler Tumoren gibt es sowohl prognostische als auch prädiktive molekulare Marker. Manche sind nur bei ganz bestimmten Entitäten relevant, z. B. RAS-Mutationen bei Patienten mit Kolorektalkarzinom, andere sollten bei allen Patienten bestimmt werden, etwa Mikorsatelliteninstabilität oder Mismatch-Repair-Verlust.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

1
2
3

Literatur

  1. Pietrantonio F et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51 (5):587-94.

    Google Scholar 

  2. Rowland A et al. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer. 2015;112(12):1888–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jones JC et al. Non-V600 BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer. J Clin Oncol. 2017;35(23):2624–30.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Arnold D et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol. 2017;28(8):1713–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Van Cutsem E et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–422.

    Article  PubMed  Google Scholar 

  6. Douillard JY et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34.

    Article  CAS  PubMed  Google Scholar 

  7. Loupakis F et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371(17):1609–18.

    Article  CAS  PubMed  Google Scholar 

  8. Van Cutsem E et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33(7):692–700.

    Article  CAS  PubMed  Google Scholar 

  9. Van Cutsem E et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506.

    Article  CAS  PubMed  Google Scholar 

  10. Bennouna J et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37.

    Article  CAS  PubMed  Google Scholar 

  11. Tabernero J et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499–508.

    Article  CAS  PubMed  Google Scholar 

  12. Seymour MT et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013;14(8):749–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Peeters M et al. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. 2014;25(1):107–16.

    Article  CAS  PubMed  Google Scholar 

  14. Mayer RJ et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909–19.

    Article  PubMed  Google Scholar 

  15. Grothey A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12.

    Article  CAS  PubMed  Google Scholar 

  16. Le DT et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Venderbosch S et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014;20(20):5322–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kopetz S et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J Clin Oncol. 2017;35(4_Suppl):520.

    Article  Google Scholar 

  19. Huijberts S et al. BEACON CRC: safety lead-in (SLI) for the combination of binimetinib (BINI), encorafenib (ENCO), and cetuximab (CTX) in patients (pts) with BRAF-V600E metastatic colorectal cancer (mCRC). 2017;28(Suppl_5):517P.

    Google Scholar 

  20. Sartore-Bianchi A 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(6):738–746.

    Article  CAS  PubMed  Google Scholar 

  21. Hurwitz H et al. Pertuzumab + trastuzumab for HER2-amplified/overexpressed metastatic colorectal cancer (mCRC): Interim data from MyPathway. J Clin Oncol. 2017;35(4_Suppl):676.

    Article  Google Scholar 

  22. Al-Batran SE et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26(9):1435–42.

    Article  CAS  PubMed  Google Scholar 

  23. Cunningham D et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358(1):36–46.

    Article  CAS  PubMed  Google Scholar 

  24. Kang YK et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20(4):666–73.

    Article  PubMed  Google Scholar 

  25. Van Cutsem E et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24(31):4991–7.

    Article  CAS  PubMed  Google Scholar 

  26. Al-Batran SE et al. Effect of Neoadjuvant Chemotherapy Followed by Surgical Resection on Survival in Patients With Limited Metastatic Gastric or Gastroesophageal Junction Cancer: The AIO-FLOT3 Trial. JAMA Oncol. 2017;3(9):1237–1244.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Al-Batran SE et al. Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2008;19(11): 1882–7.

    Article  PubMed  Google Scholar 

  28. Van Cutsem E et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012;30(17):2119–27.

    Article  CAS  PubMed  Google Scholar 

  29. Lordick F et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):490–9.

    Article  CAS  PubMed  Google Scholar 

  30. Hecht JR et al. Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC—A Randomized Phase III Trial. J Clin Oncol. 2016;34(5):443–51.

    Article  CAS  PubMed  Google Scholar 

  31. Shah MA et al. Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial. JAMA Oncol. 2017;3(5):620–7.

    Article  PubMed  Google Scholar 

  32. Fuchs CS et al. RAINFALL: A randomized, double-blind, placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or without ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or gastroesophageal junction (G-GEJ) adenocarcinoma. J Clin Oncol. 2018;36(4_Suppl):5.

    Article  Google Scholar 

  33. Thuss-Patience PC et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer—a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011;47(15):2306–14.

    Article  CAS  PubMed  Google Scholar 

  34. Fuchs CS 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(9911):31–39.

    Article  CAS  PubMed  Google Scholar 

  35. Wilke H et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224–35.

    Article  CAS  PubMed  Google Scholar 

  36. Kang YK et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461–71.

    Article  CAS  PubMed  Google Scholar 

  37. Fuchs CS et al. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018;http://doi.org/cp8z

  38. Bang YJ 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(9742):687–97.

    Article  CAS  PubMed  Google Scholar 

  39. Tabernero J et al. Pertuzumab (P) + trastuzumab (H) + chemotherapy (CT) for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (mGC/GEJC): Final analysis of a Phase III study (JACOB). Ann Oncol. 2917;28(Suppl_5):6160.

    Google Scholar 

  40. Thuss-Patience PC et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017;18(5):640–53.

    Article  CAS  PubMed  Google Scholar 

  41. Zhu L et al. Microsatellite instability and survival in gastric cancer: A systematic review and meta-analysis. Mol Clin Oncol. 2015;3(3):699–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vincent A et al. Pancreatic cancer. Lancet. 2011;378(9791):607–20.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Quante AS et al. Projections of cancer incidence and cancer-related deaths in Germany by 2020 and 2030. Cancer Med. 2016;5(9):2649–56.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Gallego J et al. Biomarkers in pancreatic ductal adenocarcinoma. Clin Transl Oncol. 2017;19(12):1430–7.

    Article  CAS  PubMed  Google Scholar 

  45. Haas M et al. Efficacy of gemcitabine plus erlotinib in rash-positive patients with metastatic pancreatic cancer selected according to eligibility for FOLFIRINOX: A prospective phase II study of the ‚Arbeitsgemeinschaft Internistische Onkologie‘. Eur J Cancer. 2018; 94:95–103.

    Article  CAS  PubMed  Google Scholar 

  46. Moore MJ 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(15):1960–6.

    Article  CAS  PubMed  Google Scholar 

  47. Neoptolemos JP et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011–24.

    Article  CAS  PubMed  Google Scholar 

  48. Conroy T et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.

    Article  CAS  PubMed  Google Scholar 

  49. Von Hoff DD et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.

    Article  CAS  Google Scholar 

  50. Wang-Gillam A et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545–57.

    Article  CAS  PubMed  Google Scholar 

  51. Vonlaufen A et al. Pancreatic stellate cells and pancreatic cancer cells: an unholy alliance. Cancer Res. 2008;68(19):7707–10.

    Article  CAS  PubMed  Google Scholar 

  52. Hingorani SR et al. HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma. J Clin Oncol. 2018;36(4):359–66.

    Article  PubMed  Google Scholar 

  53. Hirakawa T et al. Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia. PLoS One. 2016;11(8):e0159912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ireland L et al. Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors. Cancer Res. 2016;76(23): 6851–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Banales JM et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13(5):261–80.

    Article  PubMed  Google Scholar 

  56. Primrose JN et al. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study. J Clin Oncol. 2017;35(15_Suppl):4006.

    Article  Google Scholar 

  57. Valle J et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–81.

    Article  CAS  PubMed  Google Scholar 

  58. Yoshikawa D et al. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008;98(2):418–25.

    Article  CAS  PubMed  Google Scholar 

  59. Malka D et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15(8):819–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chong DQ, Zhu AX. The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets. Oncotarget. 2016;7(29):46750–67.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Turcan S et al. Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nat Genet. 2018 Jan;50(1):62–72.

    Article  PubMed  Google Scholar 

  62. Javle M et al. Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma. J Clin Oncol. 2018;36(3):276–82.

    Article  PubMed  Google Scholar 

  63. DeLeon TT et al. Novel targeted therapy strategies for biliary tract cancers and hepatocellular carcinoma. Future Oncol. 2018;14(6):553–66.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marianne Sinn.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sinn, M., Stein, A. Personalisierte Therapie von gastrointestinalen Malignomen. Info Onkol. 21 (Suppl 1), 37–43 (2018). https://doi.org/10.1007/s15004-018-6136-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s15004-018-6136-y

Navigation