Establishing and characterizing patient-derived xenografts using pre-chemotherapy percutaneous biopsy and post-chemotherapy surgical samples from a prospective neoadjuvant breast cancer study

Abstract

BackgroundPatient-derived xenografts (PDXs) are increasingly used in cancer research as a tool to inform cancer biology and drug response. Most available breast cancer PDXs have been generated in the metastatic setting. However, in the setting of operable breast cancer, PDX models both sensitive and resistant to chemotherapy are needed for drug development and prospective data are lacking regarding the clinical and molecular characteristics associated with PDX take rate in this setting.MethodsThe Breast Cancer Genome Guided Therapy Study (BEAUTY) is a prospective neoadjuvant chemotherapy (NAC) trial of stage I-III breast cancer patients treated with neoadjuvant weekly taxane+/-trastuzumab followed by anthracycline-based chemotherapy. Using percutaneous tumor biopsies (PTB), we established and characterized PDXs from both primary (untreated) and residual (treated) tumors. Tumor take rate was defined as percent of patients with the development of at least one stably transplantable (passed at least for four generations) xenograft that was pathologically confirmed as breast cancer.ResultsBaseline PTB samples from 113 women were implanted with an overall take rate of 27.4% (31/113). By clinical subtype, the take rate was 51.3% (20/39) in triple negative (TN) breast cancer, 26.5% (9/34) in HER2+, 5.0% (2/40) in luminal B and 0% (0/3) in luminal A. The take rate for those with pCR did not differ from those with residual disease in TN (p = 0.999) and HER2+ (p = 0.2401) tumors. The xenografts from 28 of these 31 patients were such that at least one of the xenografts generated had the same molecular subtype as the patient. Among the 35 patients with residual tumor after NAC adequate for implantation, the take rate was 17.1%. PDX response to paclitaxel mirrored the patients’ clinical response in all eight PDX tested.ConclusionsThe generation of PDX models both sensitive and resistant to standard NAC is feasible and these models exhibit similar biological and drug response characteristics as the patients’ primary tumors. Taken together, these models may be useful for biomarker discovery and future drug development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0920-8) contains supplementary material, which is available to authorized users.

PANOPLY:Omics-guided drug prioritization method tailored to an individual patient

“…We have validated PANOPLY’s predictions in a single patient at present using PDXs, in future, we plan to validate PANOPLY-predicted drugs in PDXs derived from additional patients. Like several other groups and we have shown, PDX models faithfully represent tumor biology 23,37 , so these results should provide insight into PANOPLY’s reliability. In conclusion, our results indicate that combining multiple sources of -omics and clinical data to predict promising agents for a patient or groups of patients with cancer is feasible.…”

“…To validate PANOPLY’s drug predictions, we tested PDX models 23 obtained from BEAUTY 24 study (BC_051_1_1) for a TNBC patient whose tumor did not respond to neoadjuvant paclitaxel and anthracycline/cyclophosphamide treatment (Supplementary Methods).…”

DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine

“…3D organoid cultures recapitulate in vivo tissue structural organization and more closely resemble the actual tumor biology than 2D cultures of primary or immortalized cells (31), thereby providing an attractive platform for testing cancer cell response to drugs (32). As previously described, we generated a panel of PDX models from patients with primary breast cancer recruited in a prospective neoadjuvant study of anthracycline-and taxane-based chemotherapy, with PDX models derived from both baseline percutaneous biopsy prior to chemotherapy and postchemotherapy surgical samples (33,34). In addition to in vivo PDX studies, we also successfully grew organoids using the PDX tumors to test response to therapies and to identify molecular markers that might be associated with response ( Figure 1A).…”

Precision medicine, agriculture, and genome editing: science and ethics

“…The BEAUTY (Breast Cancer Genome Guided Therapy) study (NCT ID: NCT02022202) is an example of such a precision medicine study. It is a prospective neoadjuvant chemotherapy trial of stage I to III patients with invasive breast cancer, using percutaneous tumor biopsies (PTBs) to establish stably propagated, patient‐derived xenografts (PDXs) into immunodeficient NOD/SCID or NOD/SCID/IL2γ ‐receptor null (NSG) mice . These PDXs provide opportunities to assess dose–response relationships and pharmacogenomic data to accurately predict drug responses in patients.…”