ABSTRACT
We investigated the prognostic significance of circulating tumor cells (CTCs) determined immediately before the second cycle of chemotherapy in patients with metastatic breast cancer (MBC). The CTC counts were taken at baseline, before the first cycle of chemotherapy (CTC-0), and on day 21 before commencing the second cycle of chemotherapy (CTC-21) in consecutive MBC patients. The study's primary objectives were to analyze relationships between CTC-21 count and overall survival (OS). Based on the current literature, the CTC measurements were dichotomized as 0-4 versus ≥ 5 CTCs. Of 117 patients recruited, 99 were evaluable. Patients with 0-4 CTCs on day 21 had a significantly better OS than those with ≥ 5 CTCs (median OS: 38.5 months vs. 8.7 months). They also had a significantly better progression-free survival (PFS; median: 9.4 months vs. 3.0 months) and clinical benefit rate (77% vs. 44%). The OS of patients whose baseline CTCs were ≥ 5 but dropped to <5 on day 21 was apparently similar to those who had <5 CTCs at baseline. In a Cox regression analysis, CTC-21 was the only independent variable significantly predicting OS and PFS. Our data indicate that CTCs determined immediately before the second cycle of chemotherapy is an early and strong predictor of treatment outcome in MBC patients.
Subject(s)
Breast Neoplasms/drug therapy , Neoplastic Cells, Circulating/pathology , Prognosis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Survival Analysis , Treatment OutcomeABSTRACT
PURPOSE: Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism. EXPERIMENTAL DESIGN: We genotyped a total of 13 polymorphisms in the carboxylesterase 2 (CES2) gene, the cytidine deaminase (CDD) gene, the thymidine phosphorylase (TP) gene, the thymidylate synthase (TS) gene, and the dihydropyrimidine dehydrogenase (DPD) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS. RESULTS: We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR = 2.02, 95% CI = 1.02-3.99, P = 0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional genetic variations across the CDD promoter. We found an insertion, rs3215400, in linkage disequilibrium with rs532545 (D' = 0.92), which was more clearly associated with HFS (OR = 0.51, 95% CI = 0.27-0.95, P = 0.028) in patients and with total CDD gene expression (P = 0.004) in lymphoblastoid cells. In silico analysis suggested that this insertion might create a binding site for the transcriptional regulator E2F. Using a SNaPshot assay in lymphoblastoid cells, we observed a 5.7-fold increased allele-specific mRNA expression from the deleted allele. CONCLUSIONS: The deleted allele of rs3215400 shows an increased allele-specific expression and is significantly associated with an increased risk of capecitabine-induced HFS.
Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Cytidine Deaminase/genetics , Deoxycytidine/analogs & derivatives , Erythema/chemically induced , Fluorouracil/analogs & derivatives , Foot Dermatoses/chemically induced , Hand Dermatoses/chemically induced , Prodrugs/adverse effects , Adult , Aged , Aged, 80 and over , Base Sequence , Binding Sites , Breast Neoplasms/drug therapy , Capecitabine , Cell Line, Tumor , Colorectal Neoplasms/drug therapy , Deoxycytidine/adverse effects , E2F Transcription Factors/metabolism , Erythema/genetics , Female , Fluorouracil/adverse effects , Foot Dermatoses/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Hand Dermatoses/genetics , Haplotypes , Humans , Logistic Models , Male , Middle Aged , Pain/chemically induced , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Sequence Analysis, DNA , Syndrome , Transcription, GeneticABSTRACT
PURPOSE: Circulating tumor cells (CTCs) can be detected in the peripheral blood of around 50% of patients with metastatic breast cancer. Their numbers are an independent predictor of the patient's progression-free survival (PFS) and of overall survival (OS). However, to date, none of the studies carried out with the most commonly used system of CTC determination (the CellSearch System, approved by the US Food and Drug Administration) has examined the intra-patient variation in CTC numbers, a variation that could impact on prognosis assessment. EXPERIMENTAL DESIGN: To evaluate possible circadian variations in the number of CTCs in patients with breast cancer a pilot study was conducted in which these cells were quantified 12 h apart (at 8:00 a.m. and 8:00 p.m. of the same day) in a cohort of hospitalized patients with metastatic breast cancer. RESULTS: Out of the 58 patients included in the study, 51 were evaluable. No statistically significant differences between day-time and night-time CTC numbers were observed (p=0.8427, Wilcoxon matched pair test). Only two of the patients were classified in different prognostic categories in the morning and night determinations (5 or more CTCs=poor prognosis group; <5 CTCs=good prognosis group). The prognostic classification of the remaining 49 patients was the same at 8:00 a.m. and 8:00 p.m. CONCLUSION: The number of peripheral blood CTCs in metastatic breast cancer patients is not significantly different at 8:00 a.m. from that at 8:00 p.m. and, as such, indicates a lack of circadian rhythm with respect to CTC numbers in these patients.
