A New Model of Patient Tumor-Derived Breast Cancer Xenografts for Preclinical Assays

Abstract

Purpose:To establish a panel of human breast cancer (HBC) xenografts in immunodeficient mice suitable for pharmacologic preclinical assays. Experimental Design: 200 samples of HBCs were grafted into Swiss nude mice. Twenty-five transplantable xenografts were established (12.5%). Their characterization included histology, p53 status, genetic analysis by array comparative genomic hybridization, gene expression by Western blotting, and quantitative reverse transcription-PCR. Biological profiles of nine xenografts were compared with those of the corresponding patient's tumor. Chemosensitivities of 17 xenografts to a combination of Adriamycin and cyclophosphamide (AC), docetaxel, trastuzumab, and Degarelix were evaluated. Results: Almost all patient tumors established as xenografts displayed an aggressive phenotype, i.e., high-grade, triple-negative status. The histology of the xenografts recapitulated the features of the original tumors. Mutation of p53 and inactivation of Rb and PTEN proteins were found in 83%, 30%, and 42% of HBC xenografts, respectively. Two HBCx had an ERBB2 (HER2) amplification. Large variations were observed in the expression of HER family receptors and in genomic profiles. Genomic alterations were close to those of original samples in paired tumors. Three xenografts formed lung metastases. A total of 15 of the 17 HBCx (88%) responded to AC, and 8 (47%) responded to docetaxel. One ERBB2-amplified xenograft responded to trastuzumab, whereas the other did not. The drug response of HBC xenografts was concordant with that of the patient's tumor in five of seven analyzable cases. Breast cancer is one of the most frequently diagnosed types of cancer in women and a leading cause of cancer-related death in women. The incidence of breast cancer has increased by twothirds over the last 15 years. However, mortality has decreased by one-third due to the earlier detection of breast cancer and increasing use of systemic therapies. Recently, new chemotherapy agents and molecular targeted therapies, such as trastuzumab, have provided a real hope of decreasing breast cancer mortality. However, despite appropriate adjuvant systemic therapy, up to 30% of patients will relapse. The vast majority of deaths are caused by recurrent metastatic disease. To date, patients relapsing will frequently have received multiple therapies in the adjuvant setting (anthracycline-taxane -based chemotherapy, hormonotherapy, and trastuzumab in case of ERBB2 amplification). Therefore, it is clear that novel compounds are required in the metastatic setting. Considering the numerous compounds produced by pharmaceutical companies, we need new tools to speed up clinical development and to take into account the heterogeneity of the disease. Preclinical models are one potential solution. A preclinical screening step in drug development must predict not only the antitumoral activity of new compounds, but also in which tumor type or subtype the compound will be effective. The preclinical models presently used are not predictive enou...

Primary esophageal and gastro-esophageal junction cancer xenograft models: clinicopathological features and engraftment

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“…PTXGs are created by implanting tumor fragments from a patient into immunocompromised mice and using the resultant tumor for tissue expansion and subsequent experimentation. Similar models of lung, 9 breast, 10 pancreatic, 11 colon, 12 head and neck 13 and various other gastrointestinal and female genital cancers 14 have been shown to recapitulate the original tumor by having similar histology and cell morphology to the patient tumor. Though few studies have focused on the genomic similarities of patient tissue and primary xenografts, those published suggest that mutations are generally conserved.…”

CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts

“…Human breast cancer xenografts, HBCx-3, -8 and -10, were established as detailed (Marangoni et al, 2007). Treatments were done on groups of eight animals (HBCx-3 and HBCx-8) and 12 animals for the tumour recurrence experiment (HBCx-10).…”

Optimization of tumor xenograft dissociation for the profiling of cell surface markers and nutrient transporters

“…They were subsequently transplanted into secondary recipients and were considered to be established as of the third in vivo passage. 22 All experiments were performed in accordance with the UKCCCR animal ethics guidelines. 23 Well-established tumor models with a minimum tumor size of 600 mm 3 were used in this study.…”