Markery odpovědi pro inhibitor angiogeneze bevacizumab
SOUHRN
Bevacizumab je první inhibitor angiogeneze, který prokazatelně zpomaluje progresi metastatického onemocnění pacientů s karcinomem. Třebaže jeho používání změnilo klinickou praxi, není u všech pacientů dosaženo odpovědi nebo se u nich postupně rozvíjí rezistence, což se projeví poměrně nevelkým prodloužením přežití. Aktuálně je důležité vyvinout robustní biomakery, které umožní informované rozhodování při výběru pacientů, u nichž má terapie bevacizumabem největší přínos. V tomto článku popisujeme nedávný pokrok dosažený při hledání těchto markerů, včetně prvních výsledků randomizovaných klinických studií fáze III, které hodnotily účinnost bevacizumabu v kombinaci s ucelenými analýzami biomarkerů. Tyto studie naznačují, že silnými kandidátními biomarkery jsou zejména koncentrace cirkulujících krátkých izoforem vaskulárního endoteliálního růstového faktoru A (vascular endothelial growth factor A, VEGF‑A), exprese neuropilinu‑1 a receptoru 1 VEGF v nádorech nebo plazmě, a genetické varianty VEGFA nebo jeho receptorů. Aktuálně je na pořadu dne rozšíření tohoto prvního souboru biomarkerů a jeho validace, s následným uvedením do klinické praxe. Je naplánováno provedení první prospektivní studie biomarkerů s názvem MERiDiAN, v níž budou léčeni pacienti stratifikovaní podle koncentrace cirkulujících krátkých izoforem VEGF‑A bevacizumabem a paclitaxelem, která nám v optimálním případě ukáže nová vodítka pro účinnější léčbu pacientů.
J Clin Oncol 31:1219‑1230. © 2013 by American Society of Clinical Oncology
Celý článek naleznete v časopise Journal of Clinical Oncology číslo 2/2013 na straně 101-112
LITERATURA
1. Carmeliet P, Jain RK: Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298‑307, 2011
2. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335‑2342, 2004
3. Sandler A, Gray R, Perry MC, et al: Paclitaxel‑carboplatin alone or with bevacizumab for non‑small‑cell lung cancer. N Engl J Med 355: 2542‑2550, 2006
4. Escudier B, Bellmunt J, Négrier S, et al: Phase III trial of bevacizumab plus interferon alfa‑2a in patients with metastatic renal cell carcinoma (AVOREN): Final analysis of overall survival. J Clin Oncol 28:2144‑2150, 2010
5. Escudier B, Pluzanska A, Koralewski P, et al: Bevacizumab plus interferon alfa‑2a for treatment of metastatic renal cell carcinoma: A randomised, doubleblind phase III trial. Lancet 370:2103‑2111, 2007
6. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti‑vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427‑434, 2003
7. Burger RA, Brady MF, Bookman MA, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473‑2483, 2011
8. Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:2484‑2496, 2011
9. Kreisl TN, Kim L, Moore K, et al: Phase II trial of single‑agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740‑745, 2009
10. Miller K, Wang M, Gralow J, et al: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666‑2676, 2007
11. Robert NJ, Diéras V, Glaspy J, et al: RIBBON‑1: Randomized, double‑blind, placebo‑controlled, phase III trial of chemotherapy with or without bevacizumab for first‑line treatment of human epidermal growth factor receptor 2‑negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29:1252‑1260, 2011
12. Miles DW, Chan A, Dirix LY, et al: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first‑line treatment of human epidermal growth factor receptor 2‑negative metastatic breast cancer. J Clin Oncol 28:3239‑3247, 2010
13. Rugo HS: Inhibiting angiogenesis in breast cancer: The beginning of the end or the end of the beginning? J Clin Oncol 30:898‑901, 2012
14. Potti A, Schilsky RL, Nevins JR: Refocusing the war on cancer: The critical role of personalized treatment. Sci Transl Med 2:28cm13, 2010
15. Potente M, Gerhardt H, Carmeliet P: Basic and therapeutic aspects of angiogenesis. Cell 146: 873‑887, 2011
16. Ellis LM, Hicklin DJ: VEGF‑targeted therapy: Mechanisms of anti‑tumour activity. Nat Rev Cancer 8:579‑591, 2008
17. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF‑specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145‑147, 2004
18. Muggia F, Safra T, Borgato L, et al: Pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD) given alone and with bevacizumab (B) in patients with recurrent epithelial ovarian cancer (rEOC). J Clin Oncol 28:406s, 2010 (suppl; abstr 5064)
19. Jain RK: Normalizing tumor vasculature with anti‑angiogenic therapy: A new paradigm for combination therapy. Nat Med 7:987‑989, 2001
20. Batchelor TT, Sorensen AG, di Tomaso E, et al: AZD2171, a pan‑VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83‑95, 2007
21. Fischer I, Cunliffe CH, Bollo RJ, et al: Highgrade glioma before and after treatment with radiation and Avastin: Initial observations. Neuro Oncol 10:700‑708, 2008
22. Goel S, Duda DG, Xu L, et al: Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91:1071‑1121, 2011
23. Van Cutsem E, Lambrechts D, Prenen H, et al: Lessons from the adjuvant bevacizumab trial on colon cancer: What next? J Clin Oncol 29:1‑4, 2011
24. Carmeliet P, Jain RK: Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10:417‑427, 2011
25. Grothey A, Hedrick EE, Mass RD, et al: Response‑independent survival benefit in metastatic colorectal cancer: A comparative analysis of N9741 and AVF2107. J Clin Oncol 26:183‑189, 2008
26. Chun YS, Vauthey JN, Boonsirikamchai P, et al: Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. JAMA 302:2338‑2344, 2009
27. Saltz LB, Clarke S, Díaz‑Rubio E, et al: Bevacizumab in combination with oxaliplatin‑based chemotherapy as first‑line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol 26:2013‑2019, 2008
28. Bottsford‑Miller JN, Coleman RL, Sood AK: Resistance and escape from antiangiogenesis therapy: Clinical implications and future strategies. J Clin Oncol 30:4026‑4034, 2012
29. Goede V, Coutelle O, Neuneier J, et al: Identification of serum angiopoietin‑2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab‑containing therapy. Br J Cancer 103:1407‑1414, 2010
30. Dowlati A, Gray R, Sandler AB, et al: Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non‑small cell lung cancer treated with chemotherapy with or without bevacizumab: An Eastern Cooperative Oncology Group Study. Clin Cancer Res 14:1407‑1412, 2008
31. Hegde PS, Jubb AM, Chen D, et al: Predictive impact of circulating vascular endothelial growth factor in 4 phase III trials evaluating bevacizumab. Clin Cancer Res [epub ahead of print on November 20, 2012]
32. Willett CG, Duda DG, di Tomaso E, et al: Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: A multidisciplinary phase II study. J Clin Oncol 27:3020‑3026, 2009
33. Tolaney SM, Duda DG, Boucher Y, et al: A phase II study of preoperative (preop) bevacizumab (bev) followed by dose‑dense (dd) doxorubicin (A)/ cyclophosphamide (C)/paclitaxel (T) in combination with bev in HER2‑negative operable breast cancer (BC). J Clin Oncol 30:55s, 2012 (suppl; abstr 1026)
34. Leighl N, Reck M, de Haas S, et al: Analysis of biomarkers (BMs) in the AVAiL phase III randomised study of first‑line Bevacizumab (Bv) with cisplatingemcitabine (CG) in patients (pts) with non‑small cell lung cancer (NSCLC). Eur J Cancer 7:558, 2009 (abstr 9172)
35. Mok T, Gorbunova V, Juhasz E, et al: Biomarker analysis in BO21015, a phase II randomised study of first‑line bevacizumab (BEV) combined with carboplatin‑gemcitabine (CG) or carboplatin‑paclitaxel (CP) in patients (pts) with advanced or recurrent nonsquamous non‑small cell lung cancer (NSCLC). Eur J Cancer 47:S592, 2011 (suppl 1; abstr 9003)
36. Van Cutsem E, Jayson G, Dive C, et al: Analysis of blood plasma factors in the AVITA phase III randomized study of bevacizumab (bev) with gemcitabine‑erlotinib (GE) in patients (pts) with metastatic pancreatic cancer (mPC). Eur J Cancer 47: S95‑S96, 2011 (suppl 1; abstr 803)
37. Miles DW, de Haas SL, Dirix L, et al: Plasma biomarker analyses in the AVADO phase III randomized study of first‑line bevacizumab + docetaxel in patients with human epidermal growth factor receptor (HER) 2‑negative metastatic breast cancer. Cancer Res 70, 2010 (suppl 2; abstr P2‑16‑04)
38. Jayson GC, de Haas S, Delmar P, et al: Evaluation of plasma VEGF‑A as a potential predictive pan‑tumour biomarker for bevacizumab. Proceedings of the 2011 European Multidisciplinary Cancer Congress, Stockholm, Sweden, September 23‑27, 2011 (abstr 804)
39. Van Cutsem E, de Haas S, Kang YK, 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 30:2119‑2127, 2012
40. Boige V, Malka D, Bourredjem A, et al: Efficacy, safety, and biomarkers of single‑agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist 17:1063‑1072, 2012
41. Kaseb AO, Garrett‑Mayer E, Morris JS, et al: Efficacy of bevacizumab plus erlotinib for advanced hepatocellular carcinoma and predictors of outcome: Final results of a phase II trial. Oncology 82:67‑74, 2012
42. Kopetz S, Hoff PM, Morris JS, et al: Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: Efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28:453‑459, 2010
43. Zhu AX, Ancukiewicz M, Supko JG, et al: Clinical, pharmacodynamic (PD), and pharmacokinetic (PK) evaluation of cediranib in advanced hepatocellular carcinoma (HCC): A phase II study (CTEP 7147). J Clin Oncol 30:266s, 2012 (suppl; abstr 4112)
44. Meyerhardt JA, Ancukiewicz M, Abrams TA, et al: Phase I study of cetuximab, irinotecan, and vandetanib (ZD6474) as therapy for patients with previously treated metastastic colorectal cancer. PLoS One 7:e38231, 2012
45. Ruiz de Almodovar C, Lambrechts D, Mazzone M, et al: Role and therapeutic potential of VEGF in the nervous system. Physiol Rev 89:607‑648, 2009
46. Baar J, Silverman P, Lyons J, et al: A vasculature‑targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: Impact on angiogenic biomarkers. Clin Cancer Res 15:3583‑3590, 2009
47. Horn L, Dahlberg SE, Sandler AB, et al: Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensive‑stage small‑cell lung cancer: Eastern Cooperative Oncology Group Study E3501. J Clin Oncol 27:6006‑6011, 2009
48. Buysschaert I, Schmidt T, Roncal C, et al: Genetics, epigenetics and pharmaco‑(epi)genomics in angiogenesis. J Cell Mol Med 12:2533‑2551, 2008
49. Fuerstenberger G, Boneberg E, Simcock M, et al: Predictive and prognostic potential of angiogenic serum factors and circulating endothelial cells in metastatic melanoma patients receiving temozolamide plus bevacizumab (SAKK 50/07). J Clin Oncol 28:632s, 2010 (suppl; abstr 8585)
50. Smerdel MP, Steffensen KD, Waldstrøm M, et al: The predictive value of serum VEGF in multiresistant ovarian cancer patients treated with bevacizumab. Gynecol Oncol 118:167‑171, 2010
51. Lieu CH, Tran HT, Jiang Z, et al: The association of alternate VEGF ligands with resistance to anti‑VEGF therapy in metastatic colorectal cancer. J Clin Oncol 29:229s, 2011 (suppl; abstr 3533)
52. Loupakis F, Cremolini C, Fioravanti A, et al: Pharmacodynamic and pharmacogenetic angiogenesis- related markers of first‑line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer 104:1262‑1269, 2011
53. Batchelor TT, Duda DG, di Tomaso E, et al: Phase II study of cediranib, an oral pan‑vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 28:2817‑2823, 2010
54. Nikolinakos PG, Altorki N, Yankelevitz D, et al: Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early‑stage non‑small cell lung cancer patients treated with pazopanib. Cancer Res 70:2171‑2179, 2010
55. Bertolini F, Shaked Y, Mancuso P, et al: The multifaceted circulating endothelial cell in cancer: Towards marker and target identification. Nat Rev Cancer 6:835‑845, 2006
56. Pohl A, El‑Khoueiry A, Yang D, et al: Pharmacogenetic profiling of CD133 is associated with response rate (RR) and progression‑free survival (PFS) in patients with metastatic colorectal cancer (mCRC), treated with bevacizumab‑based chemotherapy. Phar
macogenomics J 10.1038/tpj.2011.61 [epub ahead of print on January 10, 2012]
57. Weickhardt AJ, Williams D, Lee C, et al: Vascular endothelial growth factors (VEGF) and VEGF receptor expression as predictive biomarkers for benefit with bevacizumab in metastatic colorectal cancer (mCRC): Analysis of the phase III MAX study. J Clin Oncol 29: 228s, 2011 (suppl; abstr 3531)
58. Jubb AM, Miller KD, Rugo HS, et al: Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer. Clin Cancer Res 17:372‑381, 2011
59. Foernzler D, Delmar P, Kockx M, et al: Tumor tissue based biomarker analysis in NO16966: A randomized phase III study of first‑line bevacizumab in combination with oxaliplatin‑based chemotherapy in patients with mCRC. 2010 Gastrointestinal Cancers Symposium, January 22‑24, 2010 (abstr 374)
60. Shah M, Kang Y, Ohtsu A, et al: Tumor and blood plasma biomarker analyses in the AVAGAST phase III randomized study of first‑line bevacizumab + capecitabine/cisplatin in patients with advanced gastric cancer. Ann Oncol 21:S176, 2010 (suppl 8)
61. Shojaei F, Wu X, Malik AK, et al: Tumor refractoriness to anti‑VEGF treatment is mediated by CD11b_Gr1_ myeloid cells. Nat Biotechnol 25:911‑920, 2007
62. Carmeliet P: Angiogenesis in life, disease and medicine. Nature 438:932‑936, 2005
63. Loges S, Schmidt T, Carmeliet P: Mechanisms of resistance to anti‑angiogenic therapy and development of third‑generation anti‑angiogenic drug candidates. Genes Cancer 1:12‑25, 2010
64. Crawford Y, Kasman I, Yu L, et al: PDGF‑C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti‑VEGF treatment. Cancer Cell 15:21‑34, 2009
65. Cascone T, Herynk MH, Xu L, et al: Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitorresistant human lung adenocarcinoma. J Clin Invest 121:1313‑1328, 2011
66. Xu L, Duda DG, di Tomaso E, et al: Direct evidence that bevacizumab, an anti‑VEGF antibody, up‑regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res 69:7905‑7910, 2009
67. Zhu AX, Sahani DV, Duda DG, et al: Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: A phase II study. J Clin Oncol 27:3027‑3035, 2009
68. O’Connor JP, Jackson A, Parker GJ, et al: Dynamic contrast‑enhanced MRI in clinical trials of antivascular therapies. Nat Rev Clin Oncol 9:167‑177, 2012
69. Lambrechts D, Storkebaum E, Morimoto M, et al: VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 34:383‑394, 2003
70. Schneider BP, Wang M, Radovich M, et al: Association of vascular endothelial growth factor and vascular endothelial growth factor receptor‑2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26:4672‑4678, 2008
71. Miles DW, De Haas SL, Romieu G, et al: Polymorphism analysis in the AVADO randomised phase III trial of first‑line bevacizumab (BEV) combined with docetaxel in HER2‑negative metastatic breast cancer (mBC). Eur J Cancer 47:S176, 2011 (suppl 1; abstr 1423)
72. Koutras AK, Antonacopoulou AG, Eleftheraki AG, et al: Vascular endothelial growth factor polymorphisms and clinical outcome in colorectal cancer patients treated with irinotecan‑based chemotherapy and bevacizumab. Pharmacogenomics J 12:468‑475, 2012
73. Lambrechts D, Delmar P, Miles DW, et al: Single nucleotide polymorphism analysis and outcome in advanced‑stage cancer patients treated with bevacizumab. Eur J Cancer 47:S173, 2011 (suppl 1; abstr 1414)
74. Loupakis F, Ruzzo A, Salvatore L, et al: Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first‑line FOLFIRI plus bevacizumab in metastatic colorectal cancer. BMC Cancer 11:247, 2011
75. Wang Y, Zheng Y, Zhang W, et al: Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol 50:760‑767, 2007
76. Gerger A, El‑Khoueiry A, Zhang W, et al: Pharmacogenetic angiogenesis profiling for first‑line bevacizumab plus oxaliplatin‑based chemotherapy in patients with metastatic colorectal cancer. Clin Cancer Res 17:5783‑5792, 2011
77. Hull J, Thomson A, Kwiatkowski D: Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax 55:1023‑1027, 2000
78. lo Giudice L, Di Salvatore M, Astone A, et al: Polymorphisms in VEGF, eNOS, COX‑2, and IL‑8 as predictive markers of response to bevacizumab. J Clin Oncol 28:97e, 2010 (suppl; abstr e13502)
79. Schultheis AM, Lurje G, Rhodes KE, et al: Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab. Clin Cancer Res 14:7554‑7563, 2008
80. Xu CF, Bing NX, Ball HA, et al: Pazopanib efficacy in renal cell carcinoma: Evidence for predictive genetic markers in angiogenesis‑related and exposure‑related genes. J Clin Oncol 29:2557‑2564, 2011
81. Zhang W, Dahlberg SE, Yang D, et al: Genetic variants in angiogenesis pathway associated with clinical outcome in NSCLC patients (pts) treated with bevacizumab in combination with carboplatin and paclitaxel: Subset pharmacogenetic analysis of ECOG 4599. J Clin Oncol 27:414s, 2009 (suppl; abstr 8032)
82. Lambrechts D, Claes B, Delmar P, et al: VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: An analysis of data from the AViTA and AVOREN randomised trials. Lancet Oncol 13:724‑733, 2012
83. Hansen TF, Christensen RD, Andersen RF, et al: The predictive value of single nucleotide polymorphisms in the VEGF system to the efficacy of first‑line treatment with bevacizumab plus chemotherapy in patients with metastatic colorectal cancer: Results from the Nordic ACT trial. Int J Colorectal Dis 27:715‑720, 2012
84. Rosenfeld PJ, Brown DM, Heier JS, et al: Ranibizumab for neovascular age‑related macular degeneration. N Engl J Med 355:1419‑1431, 2006
85. Price TJ, Hardingham JE, Lee CK, et al: Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol 29:2675‑2682, 2011
86. Rudge JS, Holash J, Hylton D, et al: VEGF trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S A 104:18363‑18370, 2007
87. Autiero M, Waltenberger J, Communi D, et al: Role of PlGF in the intra‑ and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9:936‑943, 2003
88. Fischer C, Mazzone M, Jonckx B, et al: FLT1 and its ligands VEGFB and PlGF: Drug targets for antiangiogenic therapy? Nat Rev Cancer 8:942‑956, 2008
89. Mazzone M, Dettori D, Leite de Oliveira R, et al: Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136:839‑851, 2009
90. Van Cutsem E, Tabernero J, Lakomy R, 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 30:3499‑3506, 2012
91. Bagri A, Tessier‑Lavigne M, Watts RJ: Neuropilins in tumor biology. Clin Cancer Res 15:1860‑1864, 2009
92. Pan Q, Chanthery Y, Liang WC, et al: Blocking neuropilin‑1 function has an additive effect with anti‑VEGF to inhibit tumor growth. Cancer Cell 11:53‑67, 2007
93. Beck B, Driessens G, Goossens S, et al: A vascular niche and a VEGF‑Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478:399‑403, 2011
Zdroj: Journal od Clinical Oncology
