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Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients

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Abstract

Genomic research of high grade glioma (HGG) has revealed complex biology with potential for therapeutic impact. However, the utilization of this information and impact upon patient outcome has yet to be assessed. We performed capture-based next generation sequencing (NGS) genomic analysis assay of 236/315 cancer-associated genes, with average depth of over 1000 fold, to guide treatment in HGG patients. We reviewed clinical utility and response rates in correlation to NGS results. Forty-three patients were profiled: 34 glioblastomas, 8 anaplastic astrocytomas, and one patient with anaplastic oligodendroglioma. Twenty-five patients were profiled with the 315 gene panel. The median number of identified genomic alterations (GAs) per patient was 4.5 (range 1–23). In 41 patients (95 %) at least one therapeutically-actionable GA was detected, most commonly in EGFR [17 (40 %)]. Genotype-directed treatments were prescribed in 13 patients, representing a 30 % treatment decision impact. Treatment with targeted agents included everolimus as a single agent and in combination with erlotinib; erlotinib; afatinib; palbociclib; trametinib and BGJ398. Treatments targeted various genomic findings including EGFR alterations, mTOR activation, cell cycle targets and FGFR1 mutations. None of the patients showed response to respective biologic treatments. In this group of patients with HGG, NGS revealed a high frequency of GAs that lead to targeted treatment in 30 % of the patients. The lack of response suggests that further study of mechanisms of resistance in HGG is warranted before routine use of biologically-targeted agents based on NGS results.

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References

  1. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29

    Article  PubMed  Google Scholar 

  2. Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA 310:1842–1850

    Article  CAS  PubMed  Google Scholar 

  3. Thomas AA, Brennan CW, DeAngelis LM, Omuro AM (2014) Emerging therapies for glioblastoma. JAMA Neurol 71:1437–1444

    Article  PubMed  Google Scholar 

  4. Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003

    Article  CAS  PubMed  Google Scholar 

  5. Eckel-Passow JE, Lachance DH, Molinaro AM et al (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:2499–2508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481–2498

    Article  Google Scholar 

  7. Sandmann T, Bourgon R, Garcia J et al (2015) Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first-line radiotherapy and temozolomide: retrospective analysis of the avaglio trial. J Clin Oncol 33:2735–2744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  Google Scholar 

  9. TC Network (2013) Corrigendum: comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 494:506

    Article  Google Scholar 

  10. Brennan CW, Verhaak RG, McKenna A et al (2013) The somatic genomic landscape of glioblastoma. Cell 155:462–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Verhaak RG, Hoadley KA, Purdom E et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Frampton GM, Fichtenholtz A, Otto GA et al (2013) Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31:1023–1031

    Article  CAS  PubMed  Google Scholar 

  13. Gao J, Aksoy BA, Dogrusoz U et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6:pl1

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cerami E, Gao J, Dogrusoz U et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404

    Article  PubMed  Google Scholar 

  15. Le DT, Uram JN, Wang H et al (2015) PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kaufman B, Shapira-Frommer R, Schmutzler RK et al (2015) Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33:244–250

    Article  CAS  PubMed  Google Scholar 

  17. Nobusawa S, Stawski R, Kim YH, Nakazato Y, Ohgaki H (2011) Amplification of the PDGFRA, KIT and KDR genes in glioblastoma: a population-based study. Neuropathology 31:583–588

    Article  PubMed  Google Scholar 

  18. Vivanco I, Robins HI, Rohle D et al (2012) Differential sensitivity of glioma-versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov 2:458–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Beau-Faller M, Prim N, Ruppert AM et al (2014) Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol 25:126–131

    Article  CAS  PubMed  Google Scholar 

  20. Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181

    Article  CAS  PubMed  Google Scholar 

  21. Janne PA, Yang JC, Kim DW et al (2015) AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372:1689–1699

    Article  PubMed  Google Scholar 

  22. van den Bent MJ, Brandes AA, Rampling R et al (2009) Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 27:1268–1274

    Article  PubMed  PubMed Central  Google Scholar 

  23. Mellinghoff IK, Wang MY, Vivanco I et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024

    Article  CAS  PubMed  Google Scholar 

  24. Mantripragada KC, Olszewski AJ, Schumacher A et al (2016) Clinical trial accrual targeting genomic alterations after next-generation sequencing at a non-national cancer institute-designated cancer program. J Oncol Pract 12:e396–e404

    Article  PubMed  Google Scholar 

  25. Rich JN, Reardon DA, Peery T et al (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133–142

    Article  CAS  PubMed  Google Scholar 

  26. Tsimberidou AM, Wen S, Hong DS et al (2014) Personalized medicine for patients with advanced cancer in the phase I program at MD Anderson: validation and landmark analyses. Clin Cancer Res 20:4827–4836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kris MG, Johnson BE, Berry LD et al (2014) Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998–2006

    Article  PubMed  PubMed Central  Google Scholar 

  28. Johnson BE, Mazor T, Hong C et al (2014) Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:189–193

    Article  CAS  PubMed  Google Scholar 

  29. Francis JM, Zhang CZ, Maire CL et al (2014) EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov 4:956–971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nathanson DA, Gini B, Mottahedeh J et al (2014) Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 343:72–76

    Article  CAS  PubMed  Google Scholar 

  31. Lass U, Numann A, von Eckardstein K et al (2012) Clonal analysis in recurrent astrocytic, oligoastrocytic and oligodendroglial tumors implicates IDH1-mutation as common tumor initiating event. PLoS One 7:e41298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hodges TR, Choi BD, Bigner DD, Yan H, Sampson JH (2013) Isocitrate dehydrogenase 1: what it means to the neurosurgeon: a review. J Neurosurg 118:1176–1180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Huszthy PC, Daphu I, Niclou SP et al (2012) In vivo models of primary brain tumors: pitfalls and perspectives. Neuro Oncol 14:979–993

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yasuda H, Park E, Yun CH et al (2013) Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 5:216ra177

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lee JC, Vivanco I, Beroukhim R et al (2006) Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 3:e485

    Article  PubMed  PubMed Central  Google Scholar 

  36. Locker GY, Kaul K, Weinberg DS et al (2006) The I1307K APC polymorphism in Ashkenazi Jews with colorectal cancer: clinical and pathologic features. Cancer Genet Cytogenet 169:33–38

    Article  CAS  PubMed  Google Scholar 

  37. Yablonski-Peretz T, Paluch-Shimon S, Gutman LS et al (2016) Screening for germline mutations in breast/ovarian cancer susceptibility genes in high-risk families in Israel. Breast Cancer Res Treat. 155:133–138

    Article  CAS  PubMed  Google Scholar 

  38. Wen PY, Chang SM, Lamborn KR et al (2014) Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04–02. Neuro Oncol 16:567–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Disclosures

Lior Soussan-Gutman, Addie Dvir and Roi Yair are employed by Oncotest-Teva, formerly the distributor of Foundation Medicine in Israel. Jeffrey Ross and Siraj M. Ali are employed by Foundation Medicine in Cambridge, MA.

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    Authors and Affiliations

    1. Division of Oncology, Neuro-Oncology Service, Tel Aviv Sourasky Medical Center, 6 Weizman Street, 64239, Tel Aviv, Israel

      Deborah T. Blumenthal & Felix Bokstein

    2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

      Deborah T. Blumenthal, Shlomit Yust-Katz, Zvi Ram & Felix Bokstein

    3. Oncotest-Teva Pharmaceuticals, Petah Tikva, Israel

      Addie Dvir, Roi Yair & Lior Soussan-Gutman

    4. Department of Oncology, Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

      Alexander Lossos

    5. Department of Oncology, Rambam Health Care Campus, Haifa, Israel

      Tzahala Tzuk-Shina & Alejandro Lokiec

    6. Oncology Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel

      Tzach Lior

    7. Oncology Institute, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel

      Dror Limon & Shlomit Yust-Katz

    8. Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

      Zvi Ram

    9. Foundation Medicine, Cambridge, MA, USA

      Jeffrey S. Ross & Siraj M. Ali

    10. Albany Medical College, Albany, NY, USA

      Jeffrey S. Ross

    Authors
    1. Deborah T. Blumenthal
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    2. Addie Dvir
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    13. Lior Soussan-Gutman
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    Correspondence to Deborah T. Blumenthal.

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    Deborah T. Blumenthal and Addie Dvir have contributed equally to this work.

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    Blumenthal, D.T., Dvir, A., Lossos, A. et al. Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients. J Neurooncol 130, 211–219 (2016). https://doi.org/10.1007/s11060-016-2237-3

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    • DOI: https://doi.org/10.1007/s11060-016-2237-3

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