title: MRP1 overexpression determines poor prognosis in prospectively treated patients with localized high-risk soft tissue sarcoma of limbs and trunk wall: an ISG/GEIS study.
abstract: Patients with localized high-risk soft tissue sarcomas (STS) of the limbs and trunk wall still have a considerable metastatic recurrence rate of more than 50%, in spite of adjuvant chemotherapy. This drug-ceiling effect of chemotherapy in sarcoma setting could be explained, at least partially, by multidrug resistance (MDR) mechanisms. The aim of this study was to ascertain whether mRNA and protein expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and GSTA1 (glutathione S-transferase pi) was prognostic in localized high-risk STS. Immunohistochemistry and reverse transcriptase-PCR studies were performed from biopsies at the time of diagnosis. Patients of this series were prospectively enrolled into a phase III trial that compared three versus five cycles of epirubicin plus ifosfamide. The series of 102 patients found 41 events of recurrence and 37 of death with a median follow-up of 68 months. In univariate analysis, variables with a statistically significant relationship with relapse-free survival (RFS) were: MRP1 expression (5-year RFS rate of 23% in positive cases and 63% in negative cases, P = 0.029), histology (5-year RFS rate of 74% in undifferentiated pleomorphic sarcoma and 43% in synovial sarcoma, P = 0.028), and ABCC1 expression (5-year RFS rate of 33% in overexpression and 65% in downregulation, P = 0.012). Combined ABCC1/MRP1 was the only independent prognostic factor for both RFS (HR = 2.704, P = 0.005) and overall survival (HR = 2.208, P = 0.029). ABCC1/MRP1 expression shows robust prognostic relevance in patients with localized high-risk STS treated with anthracycline-based chemotherapy, which is the standard front line treatment in STS. This finding deserves attention as it points to a new targetable protein in STS.
authors.affiliation: Corresponding Author: Javier Martin-Broto, Department of Oncology, University Hospital Son Espases, Cra Valdemosa 79, 07010 (Office 144, 1H), Palma de Mallorca, Spain. javier.martin@ssib.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin-Broto
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Gutierrez
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Ramos
authors.forename: José A
authors.initials: JA
authors.lastname: Lopez-Guerrero
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
authors.forename: Silvia
authors.initials: S
authors.lastname: Stacchiotti
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Silvia
authors.initials: S
authors.lastname: Calabuig
authors.forename: Paola
authors.initials: P
authors.lastname: Collini
authors.forename: Marco
authors.initials: M
authors.lastname: Gambarotti
authors.forename: Silvia
authors.initials: S
authors.lastname: Bague
authors.forename: Angelo P
authors.initials: AP
authors.lastname: Dei Tos
authors.forename: Elena
authors.initials: E
authors.lastname: Palassini
authors.forename: Pablo
authors.initials: P
authors.lastname: Luna
authors.forename: Josefina
authors.initials: J
authors.lastname: Cruz
authors.forename: Ricardo
authors.initials: R
authors.lastname: Cubedo
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Trufero
authors.forename: Andres
authors.initials: A
authors.lastname: Poveda
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernandez-Serra
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopez-Pousa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gronchi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple / Q000235:genetics; D005121:Extremities / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018943:Anthracyclines; D005982:Glutathione Transferase; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C484555:GSTA1 protein, human; C421109:multidrug resistance-associated protein 1