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

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 mu...

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Published in:Molecular cancer therapeutics 2014-01, Vol.13 (1), p.249-259
Main Authors: Martin-Broto, Javier, Gutierrez, Antonio M, Ramos, Rafael F, Lopez-Guerrero, José A, Ferrari, Stefano, Stacchiotti, Silvia, Picci, Piero, Calabuig, Silvia, Collini, Paola, Gambarotti, Marco, Bague, Silvia, Dei Tos, Angelo P, Palassini, Elena, Luna, Pablo, Cruz, Josefina, Cubedo, Ricardo, Martinez-Trufero, Javier, Poveda, Andres, Casali, Paolo G, Fernandez-Serra, Antonio, Lopez-Pousa, Antonio, Gronchi, Alessandro
Format: Article
Language:English
Subjects:
Aged
Anthracyclines - administration & dosage
ATP Binding Cassette Transporter, Sub-Family B
ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis
ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
Disease-Free Survival
Drug Resistance, Multiple - genetics
Extremities - pathology
Female
Gene Expression Regulation, Neoplastic
Glutathione Transferase - biosynthesis
Glutathione Transferase - genetics
Humans
Male
Middle Aged
Multidrug Resistance-Associated Proteins - biosynthesis
Multidrug Resistance-Associated Proteins - genetics
Neoplasm Recurrence, Local - genetics
Neoplasm Recurrence, Local - mortality
Neoplasm Recurrence, Local - pathology
Prognosis
Sarcoma - drug therapy
Sarcoma - genetics
Sarcoma - mortality
Sarcoma - pathology
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Summary: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.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-13-0406