Ability to generate patient-derived Breast cancer xenografts is enhanced in chemoresistant disease and predicts poor patient outcomes

Priscilla F. McAuliffe, Kurt W. Evans, Argun Akcakanat, Ken Chen, Xiaofeng Zheng, Hao Zhao, Agda Karina Eterovic, Takafumi Sangai, Ashley M. Holder, Chandeshwar Sharma, Huiqin Chen, Kim Anh Do, Emily Tarco, Mihai Gagea, Katherine A. Naff, Aysegul Sahin, Asha S. Multani, Dalliah M. Black, Elizabeth A. Mittendorf, Isabelle BedrosianGordon B. Mills, Ana Maria Gonzalez-Angulo, Funda Meric-Bernstam

    Research output: Contribution to journalArticle

    22 Scopus citations

    Abstract

    Background: Breast cancer patients who are resistant to neoadjuvant chemotherapy (NeoCT) have a poor prognosis. There is a pressing need to develop in vivo models of chemo resistant tumors to test novel therapeutics. We hypothesized that patient-derived breast cancer xenografts (BCXs) from chemo-naïve and chemotherapy-exposed tumors can provide high fidelity in vivo models for chemoresistant breast cancers. Methods: Patient tumors and BCXs were characterized with short tandem repeat DNA fingerprinting, reverse phase protein arrays, molecular inversion probe arrays, and next generation sequencing. Results: Forty-eight breast cancers (24 post-chemotherapy, 24 chemo-naïve) were implanted and 13 BCXs were established (27%). BCX engraftment was higher in TNBC compared to hormonereceptor positive cancer (53.8% vs. 15.6%, p = 0.02), in tumors from patients who received NeoCT (41.7% vs. 8.3%, p = 0.02), and in patients who had progressive disease on NeoCT (85.7% vs. 29.4%, p = 0.02). Twelve patients developed metastases after surgery; in five, BCXs developed before distant relapse. Patients whose tumors developed BCXs had a lower recurrence-free survival (p = 0.015) and overall survival (p<0.001). Genomic losses and gains could be detected in the BCX, and three models demonstrated a transformation to induce mouse tumors. However, overall, somatic mutation profiles including potential drivers were maintained upon implantation and serial passaging. One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile. Conclusions: BCXs can be established from clinically aggressive breast cancers, especially in TNBC patients with poor response to NeoCT. Future studies will determine the potential of in vivo models for identification of genotype-phenotype correlations and individualization of treatment.

    Original languageEnglish (US)
    Article numbere0136851
    JournalPloS one
    Volume10
    Issue number9
    DOIs
    StatePublished - Sep 1 2015

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Agricultural and Biological Sciences(all)
    • General

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    McAuliffe, P. F., Evans, K. W., Akcakanat, A., Chen, K., Zheng, X., Zhao, H., Eterovic, A. K., Sangai, T., Holder, A. M., Sharma, C., Chen, H., Do, K. A., Tarco, E., Gagea, M., Naff, K. A., Sahin, A., Multani, A. S., Black, D. M., Mittendorf, E. A., ... Meric-Bernstam, F. (2015). Ability to generate patient-derived Breast cancer xenografts is enhanced in chemoresistant disease and predicts poor patient outcomes. PloS one, 10(9), [e0136851]. https://doi.org/10.1371/journal.pone.0136851