title: Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients.
abstract: 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.
authors.affiliation: Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.|Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: Morrison
authors.affiliation: Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Lenkala
authors.affiliation: Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: LaCroix
authors.affiliation: Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Ziliak
authors.affiliation: Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Vandana
authors.initials: V
authors.lastname: Abramson
authors.affiliation: Department of Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Phuong Khanh
authors.initials: PK
authors.lastname: Morrow
authors.affiliation: Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero
authors.affiliation: Department of Medical Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Van Poznak
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Nanda
authors.affiliation: Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.|Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: O'Donnell
authors.affiliation: Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.|Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA.
authors.forename: R Stephanie
authors.initials: RS
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000069287:Capecitabine / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008875:Middle Aged; D011237:Predictive Value of Tests
chemical_list: D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine
keywords: breast cancer; capecitabine; ex vivo model; lymphoblastoid cell lines; patient-derived model