Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients
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Gladys Morrison1,2, Divya Lenkala1, Bonnie LaCroix1, Dana Ziliak1, Vandana Abramson3, Phuong Khanh Morrow4, Andres Forero5, Catherine Van Poznak6, Hope S Rugo7, Rita Nanda1, Peter H. O’Donnell1,2, R. Stephanie Huang1,2
1Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA
2Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA
3Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
4Department of Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
5Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA
6Department of Medical Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA
7University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
R. Stephanie Huang, email: [email protected]
Keywords: breast cancer, lymphoblastoid cell lines, patient-derived model, capecitabine, ex vivo model
Received: March 17, 2016 Accepted: April 27, 2016 Published: May 20, 2016
Capecitabine is commonly used in treating breast cancer; however, therapeutic response varies among patients and there is no clinically validated model to predict individual outcomes. Here, we investigated whether drug sensitivity quantified in ex vivo patients’ blood-derived cell lines can predict response to capecitabine in vivo. Lymphoblastoid cell lines (LCLs) were established from a cohort of metastatic breast cancer patients (n = 53) who were prospectively monitored during treatment with single agent capecitabine at 2000 mg/m2/day. LCLs were treated with increasing concentrations of 5’-DFUR, a major capecitabine metabolite, to assess patients’ ex vivo sensitivity to this drug. Subsequently, ex vivo phenotype was compared to observed patient disease response and drug induced-toxicities. We acquired an independent cohort of breast cancer cell lines and LCLs derived from the same donors from ATCC, compared their sensitivity to 5’-DFUR. As seen in the patient population, we observed large inter-individual variability in response to 5’-DFUR treatment in patient-derived LCLs. Patients whose LCLs were more sensitive to 5’-DFUR had a significantly longer median progression free survival (9-month vs 6-month, log rank p-value = 0.017). In addition, this significant positive correlation for 5’-DFUR sensitivity was replicated in an independent cohort of 8 breast cancer cell lines and LCLs derived from the same donor. Our data suggests that at least a portion of the individual sensitivity to capecitabine is shared between germline tissue and tumor tissue. It also supports the utility of patient-derived LCLs as a predictive model for capecitabine treatment efficacy in breast cancer patients.
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