title: MRP1 expression in CTCs confers resistance to irinotecan-based chemotherapy in metastatic colorectal cancer.
abstract: Circulating tumor cells are important markers of tumor progression and can reflect tumor behavior in metastatic colorectal cancer (mCRC). Identification of proteins that confer resistance to treatment is an important step to predict response and better selection of treatment for patients. Multidrug resistance-associated protein 1 (MRP1) and Multidrug resistance-associated protein 4 (MRP4) play a role in irinotecan-resistance, and Excision Repair Cross-Complementation group 1 (ERCC1) expression can confer resistance to platinum compounds. Here, we included 34 patients with mCRC and most of them received FOLFIRI or FOLFOX chemotherapy (91.1%). CTCs were isolated by ISET(®) Technology and identified in 30 patients (88.2%), with a median of 2.0 CTCs/mL (0-31.0). We analyzed the immunocytochemical expression of MRP1, MRP4 and ERCC1 only in patients who had previously detectable CTCs, accordingly to treatment received (n = 19, 15 and 13 patients, respectively). Among patients treated with irinotecan-based chemotherapy, 4 out of 19 cases with MRP1 positive CTCs showed a worse progression free survival (PFS) in comparison to those with MRP1 negative CTCs (2.1 months vs. 9.1 months; p = 0.003). None of the other proteins studied in CTCs had significant association with PFS. We analyzed also histological sections of primary tumors and metastases by immunohistochemistry, and found no association with clinicopathological characteristics or with PFS. Our results show MRP1 as a potential biomarker of resistance to treatment with irinotecan when found in CTCs from mCRC patients. This is a small proof-of-principle study and these early findings need to be validated in a larger cohort of patients.
authors.affiliation: International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Emne Ali
authors.initials: EA
authors.lastname: Abdallah
authors.affiliation: Department of Medical Oncology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Marcello Ferretti
authors.initials: MF
authors.lastname: Fanelli
authors.affiliation: Department of Medical Oncology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Virgílio
authors.initials: V
authors.lastname: Souza E Silva
authors.affiliation: Department of Medical Oncology, A.C. Camargo Cancer Center, São Paulo, SP, 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, Brazil.
authors.forename: José Luiz
authors.initials: JL
authors.lastname: Gasparini Junior
authors.affiliation: Department of Medical Oncology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Daniel Vilarim
authors.initials: DV
authors.lastname: Araújo
authors.affiliation: International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, 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, Brazil.|Department of Health, Universidade Nove de Julho, São Paulo, Brazil.
authors.forename: Marcilei Eliza Cavicchioli
authors.initials: ME
authors.lastname: Buim
authors.affiliation: Department of Medical Oncology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Milena Shizue
authors.initials: MS
authors.lastname: Tariki
authors.affiliation: International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Vanessa da Silva
authors.initials: Vda S
authors.lastname: Alves
authors.affiliation: Department of Anatomical Pathology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Piana de Andrade
authors.affiliation: Department of Medical Oncology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Aldo Lourenço Abbade
authors.initials: AL
authors.lastname: Dettino
authors.affiliation: Department of Medical Oncology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Celso
authors.initials: C
authors.lastname: Abdon Lopes de Mello
authors.affiliation: International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Ludmilla Thomé Domingos
authors.initials: LT
authors.lastname: Chinen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D002166:Camptothecin; D000077146:Irinotecan; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1
keywords: ISET; chemoresistance; circulating tumor cells; metastatic colorectal cancer; multidrug resistance-associated protein 1