A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer

View More View Less
  • a From the Center for Cancer Innovation, University of Washington, Seattle, Washington; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington; Department of Medicine/Hematology, University of Washington, Seattle, Washington; Seattle Cancer Care Alliance, Seattle, Washington; RareCyte Inc., Seattle, Washington; Northwest Medical Specialities, Puyallup and Tacoma, Washington; Department of Laboratory Medicine, University of Washington, Seattle, Washington; Department of Pathology, University of Washington, Seattle, Washington; Quellos High Throughput Screening Core, Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; Trialomics LLC, Seattle, Washington; University of California at Santa Cruz, Santa Cruz, California; Covance/LabCorp Inc., Seattle, Washington; Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Computer Science and Engineering, University of Washington, Seattle, Washington; and Data4Cure Inc., La Jolla, California.
Restricted access

Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient's evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs.

Correspondence: C. Anthony Blau, MD, University of Washington, 850 Republican Street, Box 358056, Seattle, WA 98109. E-mail: tblau@uw.edu
  • 1.

    Scannell JW, Blanckley A, Boldon H, Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 2012;11:191200.

  • 2.

    Blau CA, Liakopoulou E. Can we deconstruct cancer, one patient at a time? Trends Genet 2013;29:610.

  • 3.

    Nowell PC. The clonal evolution of tumor cell populations. Science 1976;194:2328.

  • 4.

    Dexter DL, Kowalski HM, Blazar BA et al. . Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res 1978;38:31743181.

  • 5.

    Stephens PJ, McBride DJ, Lin M et al. . Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 2009;462:10051010.

  • 6.

    Pleasance ED, Cheetham RK, Stephens PJ et al. . A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 2010;463:191196.

  • 7.

    Forbes SA, Bindal N, Bamford S et al. . COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 2010;39:D945950.

    • Search Google Scholar
    • Export Citation
  • 8.

    Stephens PJ, Tarpey PS, Davies H et al. . The landscape of cancer genes and mutational processes in breast cancer. Nature 2012;486:400404.

  • 9.

    Gerlinger M, Rowan AJ, Horswell S et al. . Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883892.

    • Search Google Scholar
    • Export Citation
  • 10.

    Shah SP, Roth A, Goya R et al. . The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012;486:395399.

  • 11.

    Zare H, Wang J, Hu A et al. . Inferring clonal composition from multiple sections of a breast cancer. PLoS Comput Biol 2014;10:e1003703.

  • 12.

    Marusyk A, Almendro V, Polyak K. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 2012;12:323334.

  • 13.

    Eirew P, Steif A, Khattra J et al. . Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature 2015;518:422426.

    • Search Google Scholar
    • Export Citation
  • 14.

    Gerlinger M, McGranahan N, Dewhurst SM et al. . Cancer: evolution within a lifetime. Annu Rev Genet 2014;48:215236.

  • 15.

    Iyer G, Hanrahan AJ, Milowsky MI et al. . Genome sequencing identifies a basis for everolimus sensitivity. Science 2012;338:221.

  • 16.

    Wagle N, Grabiner BC, Van Allen E et al. . Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med 2014;371:14261433.

    • Search Google Scholar
    • Export Citation
  • 17.

    Wagle N, Grabiner BC, Van Allen E et al. . Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov 2014;4:546553.

    • Search Google Scholar
    • Export Citation
  • 18.

    Al-Ahmadie H, Iyer G, Hohl M et al. . Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy. Cancer Discov 2014;4:10141021.

    • Search Google Scholar
    • Export Citation
  • 19.

    Isakoff SJ, Mayer EL, He L et al. . TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol 2015;33:19021909.

    • Search Google Scholar
    • Export Citation
  • 20.

    Campton DE, Ramirez AB, Nordberg JJ et al. . High-recovery visual identification and single-cell retrieval of circulating tumor cells for genomic analysis using a dual-technology platform integrated with automated immunofluorescence staining. BMC Cancer 2015;15:360.

    • Search Google Scholar
    • Export Citation
  • 21.

    Pusztai L, Viale G, Kelly CM, Hudis CA. Estrogen and HER-2 receptor discordance between primary breast cancer and metastasis. Oncologist 2010;15:11641268.

    • Search Google Scholar
    • Export Citation
  • 22.

    Criscitiello C, André F, Thompson AM et al. . Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives. Breast Cancer Res. 2014;16:205.

    • Search Google Scholar
    • Export Citation
  • 23.

    Pritchard CC, Salipante SJ, Koehler K et al. . Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens J Mol Diagn 2014;16:5667.

    • Search Google Scholar
    • Export Citation
  • 24.

    Craig DW, O'Shaughnessy JA, Kiefer JA et al. . Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities. Mol Cancer Ther 2013;12:104116.

    • Search Google Scholar
    • Export Citation
  • 25.

    Gozgit JM, Wong MJ, Moran L et al. . Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther 2012;11:690699.

    • Search Google Scholar
    • Export Citation
  • 26.

    Chiarini F, Evangelisti C, McCubrey JA, Martelli AM. Current treatment strategies for inhibiting mTOR in cancer. Trends Pharmacol Sci 2015;36:124135.

    • Search Google Scholar
    • Export Citation
  • 27.

    Woolf DK, Padhani AR, Makris A. Assessing response to treatment of bone metastases from breast cancer: what should be the standard of care? Ann Oncol 2015;26:10481057.

    • Search Google Scholar
    • Export Citation
  • 28.

    Fidler IJ. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer 1973;9:223227.

    • Search Google Scholar
    • Export Citation
  • 29.

    Liotta LA, Saidel MG, Kleinerman J. The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res 1976;36:889894.

    • Search Google Scholar
    • Export Citation
  • 30.

    Hou J, Krebs MG, Lancashire L et al. . Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol 2012;30:525532.

    • Search Google Scholar
    • Export Citation
  • 31.

    Aceto N, Bardia A, Miyamoto DT et al. . Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 2014;158:11101122.

    • Search Google Scholar
    • Export Citation
  • 32.

    Bergethon K, Shaw AT, Ou SI et al. . ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863870.

  • 33.

    Billard C. BH3 mimetics: status of the field and new developments. Mol Cancer Ther 2013;12:16911700.

  • 34.

    Micheel CM, Nass SJ, Omenn GS, eds. Evolution of Translational Omics: Lessons Learned and the Path Forward. Washington, DC: The National Academies Press; 2012.

    • Search Google Scholar
    • Export Citation
  • 35.

    Van Allen EM, Wagle N, Levy MA. Clinical analysis and interpretation of cancer genome data. J Clin Oncol 2013;31:18251833.

  • 36.

    Kurzrock R, Kantarjian H, Stewart DJ. A cancer trial scandal and its regulatory backlash. Nat Biotechnol 2014;32:2731.

  • 37.

    Pemovska T, Kontro M, Yadav B et al. . Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia. Cancer Discov 2013;3:14161429.

    • Search Google Scholar
    • Export Citation
  • 38.

    Tyner JW, Yang WF, Bankhead A et al. . Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening. Cancer Res 2013;73:285296.

    • Search Google Scholar
    • Export Citation
  • 39.

    Oakes SR, Vaillant F, Lim E et al. . Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737. Proc Natl Acad Sci USA 2012;109:27662771.

    • Search Google Scholar
    • Export Citation
  • 40.

    Yu M, Bardia A, Aceto N et al. . Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 2014;345:216220.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 640 164 5
PDF Downloads 170 97 3
EPUB Downloads 0 0 0