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

Abstract

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.

Three-Dimensional Cell Cultures in Drug Discovery and Development

“…[109][110][111] For instance, patient-derived spheroids have been developed as a predictive test to identify the most effective therapy for 120 patients with HER2-negative breast cancer of all stages. 112 Results showed that the tissue spheroid model reflected current guideline treatment recommendations for HER2-negative breast cancer. Tissue spheroid showed greater responses to anthracycline/docetaxel for hormone receptor-negative samples, a higher response to fluorouracil and anthracycline in high-grade tumors, and a higher treatment efficacy to anthracycline treatment combined with fluorouracil for smaller tumor size and negative lymph node status.…”

Binding of galectin-1 to breast cancer cells MCF7 induces apoptosis and inhibition of proliferation in vitro in a 2D- and 3D- cell culture model

“…After 48 h of spheroid formation, chemotherapeutic agents, namely fluorouracil combined with epirubicin and cyclophosphamide (FEC) and docetaxel combined with doxorubicin and cyclophosphamide (TAC) were administered to the spheroids in clinically relevant combinations at the peak plasma concentrations as described previously [26]. Galectin-1 was applied in a concentration of 30 μg/ml.…”

Mass Spectrometry Analyses of Multicellular Tumor Spheroids

“…Cells grown as MCTS have been demonstrated to be more resistant to the majority of traditional chemotherapy treatments when compared to the same cells cultured as monolayers . The exact mechanism by which MCTS formation protects cells from chemotherapy has not been fully elucidated.…”