title: Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility.
abstract: Circulating tumor cells (CTCs) are present at low concentrations in the peripheral blood of patients with solid tumors. It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations. In a proof-of-concept study, we established CTC cultures from six patients with estrogen receptor-positive breast cancer. Three of five CTC lines tested were tumorigenic in mice. Genome sequencing of the CTC lines revealed preexisting mutations in the PIK3CA gene and newly acquired mutations in the estrogen receptor gene (ESR1), PIK3CA gene, and fibroblast growth factor receptor gene (FGFR2), among others. Drug sensitivity testing of CTC lines with multiple mutations revealed potential new therapeutic targets. With optimization of CTC culture conditions, this strategy may help identify the best therapies for individual cancer patients over the course of their disease.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Bardia
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Aceto
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bersani
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Marissa W
authors.initials: MW
authors.lastname: Madden
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Donaldson
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Rushil
authors.initials: R
authors.lastname: Desai
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Huili
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Valentine
authors.initials: V
authors.lastname: Comaills
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medical Epidemiology and Biostatistics, Karolinska Insitutet, Stockholm, Sweden.
authors.forename: Zongli
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Ben S
authors.initials: BS
authors.lastname: Wittner
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.affiliation: Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Brachtel
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Sgroi
authors.affiliation: Center for Bioengineering in Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Shioda
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Cyril
authors.initials: C
authors.lastname: Benes
authors.affiliation: Center for Bioengineering in Medicine, Harvard Medical School, Charlestown, MA 02129, USA. Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Toner
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Surgery, Harvard Medical School, Charlestown, MA 02129, USA. maheswaran@helix.mgh.harvard.edu haber@helix.mgh.harvard.edu.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA. maheswaran@helix.mgh.harvard.edu haber@helix.mgh.harvard.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018929:Cell Culture Techniques; D002469:Cell Separation; D058534:Class I Phosphatidylinositol 3-Kinases; D003469:Culture; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006801:Humans; D051379:Mice; D044085:Microfluidics / Q000379:methods; D058990:Molecular Targeted Therapy; D009154:Mutation; D009360:Neoplastic Cells, Circulating / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D047628:Estrogen Receptor alpha; D019869:Phosphatidylinositol 3-Kinases; C506487:ESR1 protein, human; C484760:PIK3CA protein, human