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.
Highlights
Patient-derived xenografts (PDXs) are increasingly used in cancer research as a tool to inform cancer biology and drug response
The generation of PDX models both sensitive and resistant to standard neoadjuvant chemotherapy (NAC) is feasible and these models exhibit similar biological and drug response characteristics as the patients’ primary tumors. These models may be useful for biomarker discovery and future drug development
Ultrasound-guided baseline percutaneous core-needle biopsies of the primary breast tumor were obtained after study enrollment at Mayo Clinic Rochester (MCR) or Mayo Clinic Florida (MCF)
Summary
Patient-derived xenografts (PDXs) are increasingly used in cancer research as a tool to inform cancer biology and drug response. 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. Breast cancer can be classified into five subtypes based on clinical and IHC criteria, namely, triple negative (ER-/PR-/ HER2-), ER+/HER2+, ER-/HER2+, luminal A and luminal B subtypes which differ in clinical outcomes and optimal treatment strategies [4]. A deeper understanding of the mechanisms involved in drug response is necessary to achieve the goal of individualized drug therapy. This knowledge would guide future drug development and help make it possible to overcome resistance to “standard” chemotherapy [8, 10]
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