title: Thymidylate synthase expression in circulating tumor cells: a new tool to predict 5-fluorouracil resistance in metastatic colorectal cancer patients.
abstract: Thymidylate synthase (TYMS) is an important enzyme for 5-fluorouracil (5-FU) metabolism in metastatic colorectal cancer (mCRC) patients. The search for this enzyme in circulating tumor cells (CTCs) can be a powerful tool to follow-up cancer patients. mCRC patients were enrolled before the beginning of 5-FU-based chemotherapy. The blood was filtered on Isolation by Size of Epithelial Tumor Cells (ISET), and the analysis of TYMS expression in CTCs was made by immunocytochemistry. Additionally, we verified TYMS staining in primary tumors and metastases from the same patients. There were included 54 mCRC patients and 47 of them received 5-FU-based chemotherapy. The median CTCs number was 2 per mL. We were not able to analyze immunocytochemistry in 13 samples (9 patients with absence of CTCs and 4 samples due to technical reasons). Therefore, TYMS expression on CTCs was analyzed in 34 samples and was found positive in 9 (26.5%). Six of these patients had tumor progression after treatment with 5-FU. We found an association between CTC TYMS staining and disease progression (DP), although without statistical significance (P = 0.07). TYMS staining in primary tumors and metastases tissues did not have any correlation with disease progression (P = 0.67 and P = 0.42 respectively). Patients who had CTC count above the median (2 CTCs/mL) showed more TYMS expression (P = 0.02) correlating with worse prognosis. Our results searching for TYMS staining in CTCs, primary tumors and metastases suggest that the analysis of TYMS can be useful tool as a 5-FU resistance predictor biomarker if analyzed in CTCs from mCRC patients.
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, São Paulo, SP 01508 010, Brazil.
authors.forename: Emne Ali
authors.initials: EA
authors.lastname: Abdallah
authors.affiliation: Department of Clinical Oncology, A. C. Camargo Cancer Center, São Paulo, SP 01509 010, Brazil.
authors.forename: Marcello Ferretti
authors.initials: MF
authors.lastname: Fanelli
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, São Paulo, SP 01508 010, Brazil.|Department of Health, Universidade Nove De Julho, São Paulo, SP 01156 050, Brazil.
authors.forename: Marcilei Eliza Cavicchioli
authors.initials: ME
authors.lastname: Buim
authors.affiliation: Department of Clinical Oncology, A. C. Camargo Cancer Center, São Paulo, SP 01509 010, Brazil.
authors.forename: Marcelo Calil
authors.initials: MC
authors.lastname: Machado Netto
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, São Paulo, SP 01508 010, Brazil.
authors.forename: José Luiz
authors.initials: JL
authors.lastname: Gasparini Junior
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, São Paulo, SP 01508 010, Brazil.
authors.forename: Virgílio
authors.initials: V
authors.lastname: Souza E Silva
authors.affiliation: Department of Clinical Oncology, A. C. Camargo Cancer Center, São Paulo, SP 01509 010, Brazil.
authors.forename: Aldo Lourenço Abbade
authors.initials: AL
authors.lastname: Dettino
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, São Paulo, SP 01508 010, Brazil.
authors.forename: Natalia Breve
authors.initials: NB
authors.lastname: Mingues
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, São Paulo, SP 01508 010, Brazil.
authors.forename: Juliana Valim
authors.initials: JV
authors.lastname: Romero
authors.affiliation: Department of Clinical Oncology, A. C. Camargo Cancer Center, São Paulo, SP 01509 010, Brazil.
authors.forename: Luciana Menezes Mendonça
authors.initials: LM
authors.lastname: Ocea
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, São Paulo, SP 01508 010, Brazil.
authors.forename: Bruna Maria Malagoli
authors.initials: BM
authors.lastname: Rocha
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, São Paulo, SP 01508 010, Brazil.
authors.forename: Vanessa Silva
authors.initials: VS
authors.lastname: Alves
authors.affiliation: Department of Clinical Oncology, A. C. Camargo Cancer Center, São Paulo, SP 01509 010, Brazil.
authors.forename: Daniel Vilarim
authors.initials: DV
authors.lastname: Araújo
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, São Paulo, SP 01508 010, Brazil.
authors.forename: Ludmilla Thomé Domingos
authors.initials: LT
authors.lastname: Chinen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000175:diagnosis / Q000188:drug therapy*; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D011379:Prognosis; D013940:Thymidylate Synthase / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; C000600377:TYMS protein, human; D013940:Thymidylate Synthase; D005472:Fluorouracil
keywords: chemotherapy resistance; circulating tumor cells; isolation by size of epithelial tumor cells; metastatic colorectal cancer; thymidylate synthase