title: Testing chemotherapy efficacy in HER2 negative breast cancer using patient-derived spheroids.
abstract: Targeted anti-HER2 therapy has greatly improved the prognosis for many breast cancer patients. However, treatment for HER2 negative disease is currently still selected from a multitude of untargeted chemotherapeutic treatment options. A predictive test was developed using patient-derived spheroids to identify the most effective therapy for patients with HER2 negative breast cancer of all stages, for clinically relevant subgroups, as well as individual patients.
  
  
  
  Tumor samples from 120 HER2 negative patients obtained through biopsy or surgical excision were tested in the breast cancer spheroid model using scaffold-free cell culture. Similarly, spheroids were also generated from established HER2 negative breast cancer cell lines T-47D, MCF7, HCC1143, and HCC1937 to compare treatment efficacy of heterogeneous cell populations from patient tumor tissue with homogeneous cell lines. Spheroids were treated in vitro with guideline-recommended compounds. Treatment mediated impact on cell survival was subsequently quantified using an ATP assay.
  
  
  
  Differences were observed in the metabolic activity of the untreated spheroids, whereby cell lines consistently achieved higher values compared to tissue spheroids (p < 0.001). A higher number of cells per spheroid correlated with a higher basal metabolic activity in tissue-derived spheroids (p < 0.01), while the opposite was observed for cell line spheroids (p < 0.01). Recurrent tumors showed a higher mean vitality (p < 0.01) compared to primary tumors. Except for taxanes, treatment efficacy for most tested compounds differed significantly between breast cancer tissue spheroids and breast cancer cell lines. Overall a high variability in treatment response in vitro was seen in the tissue spheroids regardless of the tested substances. A greater response to anthracycline/docetaxel was observed for hormone receptor negative samples (p < 0.01). A higher response to 5-FU (p < 0.01) and anthracycline (p < 0.05) was seen in high grade tumors. Smaller tumor size and negative lymph node status were both associated with a higher treatment efficacy to anthracycline treatment combined with 5-FU (cT1/2 vs cT3/4, p = 0.035, cN+ vs cN-, p < 0.05).
  
  
  
  The tissue spheroid model reflects current guideline treatment recommendations for HER2 negative breast cancer, whereas tested cell lines did not. This model represents a unique diagnostic method to select the most effective therapy out of several equivalent treatment options.
authors.affiliation: SpheroTec GmbH, Am Klopferspitz 19, 82152, Martinsried, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Halfter
authors.affiliation: SpheroTec GmbH, Am Klopferspitz 19, 82152, Martinsried, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hoffmann
authors.affiliation: Department of Obstetrics and Gynecology, Hospital of the University of Munich, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Ditsch
authors.affiliation: SpheroTec GmbH, Am Klopferspitz 19, 82152, Martinsried, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Ahne
authors.affiliation: Department of General, Visceral, and Transplantation Surgery, Hospital of the LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Arnold
authors.affiliation: Department of Gynecology and Obstetrics, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Paepke
authors.affiliation: Klinikum Harlaching, Sanatoriumsplatz 2, 81545, Munich, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Grab
authors.affiliation: Klinikum Landshut, Robert-Koch-Str. 1, 8434, Landshut, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Bauerfeind
authors.affiliation: SpheroTec GmbH, Am Klopferspitz 19, 82152, Martinsried, Germany. barbara.mayer@med.uni-muenchen.de.|Department of General, Visceral, and Transplantation Surgery, Hospital of the LMU Munich, Marchioninistr. 15, 81377, Munich, Germany. barbara.mayer@med.uni-muenchen.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mayer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: Breast cancer; In vitro diagnostics; Personalized medicine; Preclinical treatment selection; Spheroid cell culture