Testing chemotherapy efficacy in HER2 negative breast cancer using patient-derived spheroids

Journal of Translational Medicine

Research

Frank Arnold¹  Stefan Paepke²  Nina Ditsch³  Dieter Grab⁴  Ingo Bauerfeind⁵  Kathrin Halfter⁶  Oliver Hoffmann⁶  Mareike Ahne⁶  Barbara Mayer⁷ 

[1] Department of General, Visceral, and Transplantation Surgery, Hospital of the LMU Munich, Marchioninistr. 15, 81377, Munich, Germany;Department of Gynecology and Obstetrics, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany;Department of Obstetrics and Gynecology, Hospital of the University of Munich, Marchioninistr. 15, 81377, Munich, Germany;Klinikum Harlaching, Sanatoriumsplatz 2, 81545, Munich, Germany;Klinikum Landshut, Robert-Koch-Str. 1, 8434, Landshut, Germany;SpheroTec GmbH, Am Klopferspitz 19, 82152, Martinsried, Germany;SpheroTec GmbH, Am Klopferspitz 19, 82152, Martinsried, Germany;Department of General, Visceral, and Transplantation Surgery, Hospital of the LMU Munich, Marchioninistr. 15, 81377, Munich, Germany;

关键词: Breast cancer;    Personalized medicine;    Preclinical treatment selection;    In vitro diagnostics;    Spheroid cell culture;   

DOI  :  10.1186/s12967-016-0855-3

 received in 2015-12-22, accepted in 2016-04-06,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundTargeted 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.MethodsTumor 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.ResultsDifferences 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).ConclusionsThe 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.

【 授权许可】

CC BY   
© Halfter et al. 2016