Abstract
BackgroundMetastatic breast cancer (mBC) is a complex and life-threatening disease and although it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy. The patient-derived xenograft (PDX) model is suggested as a practical tool to predict the clinical outcome of this disease as well as to screen novel drugs. This study aimed to establish PDX models in Korean patients and analyze their genomic profiles and utility for translational research.MethodsPercutaneous core needle biopsy or punch biopsy samples were used for xenotransplantation. Whole exome sequencing and transcriptome analysis were performed to assess the genomic and RNA expression profiles, respectively. Copy number variation and mutational burden were analyzed and compared with other metastatic breast cancer genomic results. Mutational signatures were also analyzed. The antitumor effect of an ATR inhibitor was tested in the relevant PDX model.ResultsOf the 151 cases studied, 40 (26%) PDX models were established. Notably, the take rate of all subtypes, including the hormone receptor-positive (HR +) subtype, exceeded 20%. The PDX model had genomic fidelity and copy number variation that represented the pattern of its donor sample. TP53, PIK3CA, ESR1, and GATA3 mutations were frequently found in our samples, with TP53 being the most frequently mutated, and the somatic mutations in these genes strengthened their frequency in the PDX model. The ESR1 mutation, CCND1 amplification, and the APOBEC signature were significant features in our HR + HER2- PDX model. Fulvestrant in combination with palbociclib showed a partial response to the relevant patient’s tumor harboring the ESR1 mutation, and CCND1 amplification was found in the PDX model. AZD6738, an ATR inhibitor, delayed tumor growth in a relevant PDX model.ConclusionsOur PDX model was established using core needle biopsy samples from primary and metastatic tissues. Genomic profiles of the samples reflected their original tissue characteristics and could be used for the interpretation of clinical outcomes.
Highlights
Metastatic breast cancer is a complex and life-threatening disease and it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy
We report 40 patient-derived xenograft (PDX) models established using percutaneous core needle biopsy or punch biopsy samples of Korean patients with Metastatic breast cancer (mBC)
Patient characteristics In total, 151 core needle biopsy tissues were obtained from 130 patients between 2014 and 2017 for the establishment of PDXs
Summary
Metastatic breast cancer (mBC) is a complex and life-threatening disease and it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy. The patient-derived xenograft (PDX) model is suggested as a practical tool to predict the clinical outcome of this disease as well as to screen novel drugs. Clinical molecular subtyping is insufficient when patients fail to respond to standard case therapies, and precise molecular markers are needed to select targeted drugs for each patient and to implement precision medicine [2]. Due to insufficient molecular markers and drug resistance, various chemotherapeutic drug combinations used for the treatment of mBC have been unsuccessful [4]. There is an eager need to identify novel molecular markers using better techniques and understand the characteristics of the individual tumor
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