The authors would like to thank the patient and her family. We also gratefully acknowledge the assistance of Michelle Flores, Melodee Smith, Sherry Littlefield, Laura Connelly-Smith, James Riddle, Wayne Monsky, Ednus Warren, Stan Riddell, Daniel Flynn, Frank Bohmer, Alain Charest, David Baker, Brian Druker, Lance Stewart, Monika Davare, Julie Gralow, Bernie McLaughlin, Jennifer Specht, VK Gadi, Paul Martin, Corinne Fligner, David Yadock, Jennifer Spokely, Krystal Malhotra, Stephanie Parker, Daniel Campton, Josh Nordberg, Nick Drovetto, Zhijun Duan, Nicole Heying, Leila Ritter, and NW BioTrust.
Drs. Ramirez, Stilwell, and Kaldjian are employees of RareCyte; Drs. Madan, Austin, and Howard are employees of Covance/LabCorp Inc.; Drs. Komashko and Mecham are employees of Trialomics LLC; and Drs. Ronen and Dutkowski are employees of Data4Cure Inc. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. This publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000423. Funding for this work was provided by South Sound CARE, the Gary E. Milgard Family Foundation, the Pano Koumantaros Cancer Research Fund, the Washington Research Foundation, the University of Washington School of Medicine, NIDDK grant P30 DK56465 (S.H.), and private donors.
Scannell JW, Blanckley A, Boldon H, Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 2012;11:191–200.
Dexter DL, Kowalski HM, Blazar BA et al.. Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res 1978;38:3174–3181.
Stephens PJ, McBride DJ, Lin M et al.. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 2009;462:1005–1010.
Pleasance ED, Cheetham RK, Stephens PJ et al.. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 2010;463:191–196.
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:D945–950.
Stephens PJ, Tarpey PS, Davies H et al.. The landscape of cancer genes and mutational processes in breast cancer. Nature 2012;486:400–404.
Gerlinger M, Rowan AJ, Horswell S et al.. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883–892.
Shah SP, Roth A, Goya R et al.. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012;486:395–399.
Zare H, Wang J, Hu A et al.. Inferring clonal composition from multiple sections of a breast cancer. PLoS Comput Biol 2014;10:e1003703.
Eirew P, Steif A, Khattra J et al.. Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature 2015;518:422–426.
Wagle N, Grabiner BC, Van Allen E et al.. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med 2014;371:1426–1433.
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;4:546–553.
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;4:1014–1021.
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;33:1902–1909.
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.
Pusztai L, Viale G, Kelly CM, Hudis CA. Estrogen and HER-2 receptor discordance between primary breast cancer and metastasis. Oncologist 2010;15:1164–1268.
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.
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;16:56–67.
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;12:104–116.
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;11:690–699.
Chiarini F, Evangelisti C, McCubrey JA, Martelli AM. Current treatment strategies for inhibiting mTOR in cancer. Trends Pharmacol Sci 2015;36:124–135.
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;26:1048–1057.
Fidler IJ. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer 1973;9:223–227.
Liotta LA, Saidel MG, Kleinerman J. The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res 1976;36:889–894.
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;30:525–532.
Aceto N, Bardia A, Miyamoto DT et al.. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 2014;158:1110–1122.
Bergethon K, Shaw AT, Ou SI et al.. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863–870.
Micheel CM, Nass SJ, Omenn GS, eds. Evolution of Translational Omics: Lessons Learned and the Path Forward. Washington, DC: The National Academies Press; 2012.
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;3:1416–1429.
Tyner JW, Yang WF, Bankhead A et al.. Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening. Cancer Res 2013;73:285–296.
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;109:2766–2771.
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;345:216–220.