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.
Highlights
Capecitabine is an oral fluopyrimidine prodrug commonly used in treating breast and colorectal cancer patients
Using a Student T-test to evaluate sensitivity between the 2 cell models, we found that Lymphoblastoid cell lines (LCLs) in general were more sensitive to 5ʹ-DFUR than breast cancer cell lines (Figure 2B, p = 0.0004)
We showed that LCLs can be established from patient Peripheral blood mononuclear cells (PBMCs) isolated freshly or from whole blood preserved on ice and isolated with 48 hours
Summary
Capecitabine is an oral fluopyrimidine prodrug commonly used in treating breast and colorectal cancer patients. Capecitabine is approved for the treatment of taxane-resistant metastatic breast cancer either as monotherapy or in combination with other chemotherapeutic agents. In combination with other chemotherapies, clinical trials have shown that capecitabine treatment results in a median overall survival range from 11–19 months and a median progression free survival (PFS) ranging from 3–9 months [3,4,5,6]. Genetic variants that result in enzyme (e.g. thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DYPD)) activity deficiencies have been shown to independently predict toxicity and sensitivity to capecitabine [7, 8]. The role of germline genetic variants in capecitabine sensitivity has been explored using a human cellbased model: the International HapMap lymphoblastoid cell lines (LCLs) [9]
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