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

Javier Martin-Broto, Antonio M. Gutierrez, Rafael F. Ramos, José A. Lopez-Guerrero, Stefano Ferrari, Silvia Stacchiotti, Piero Picci, Silvia Calabuig, Paola Collini, Marco Gambarotti, Silvia Bague, Angelo P. Dei Tos, Elena Palassini, Pablo Luna, Josefina Cruz, Ricardo Cubedo, Javier Martinez-Trufero, Andres Poveda, Paolo G. Casali, Antonio Fernandez-SerraAntonio Lopez-Pousa, Alessandro Gronchi

Research output: Contribution to journalArticle

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 drugceiling 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.

Original languageEnglish
Pages (from-to)249-259
Number of pages11
JournalMolecular Cancer Therapeutics
Volume13
Issue number1
DOIs
Publication statusPublished - Jan 2013

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Sarcoma
Extremities
Recurrence
Survival Rate
P-Glycoprotein
Survival
Glutathione S-Transferase pi
Synovial Sarcoma
Drug Therapy
Epirubicin
Ifosfamide
Anthracyclines
Multiple Drug Resistance
Adjuvant Chemotherapy
Reverse Transcriptase Polymerase Chain Reaction
Histology
Down-Regulation
Immunohistochemistry
Biopsy
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / 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.

In: Molecular Cancer Therapeutics, Vol. 13, No. 1, 01.2013, p. 249-259.

Research output: Contribution to journalArticle

Martin-Broto, J, Gutierrez, AM, Ramos, RF, Lopez-Guerrero, JA, Ferrari, S, Stacchiotti, S, Picci, P, Calabuig, S, Collini, P, Gambarotti, M, Bague, S, Dei Tos, AP, Palassini, E, Luna, P, Cruz, J, Cubedo, R, Martinez-Trufero, J, Poveda, A, Casali, PG, Fernandez-Serra, A, Lopez-Pousa, A & Gronchi, A 2013, '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', Molecular Cancer Therapeutics, vol. 13, no. 1, pp. 249-259. https://doi.org/10.1158/1535-7163.MCT-13-0406
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. / 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. In: Molecular Cancer Therapeutics. 2013 ; Vol. 13, No. 1. pp. 249-259.
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T2 - An ISG/GEIS study

AU - Martin-Broto, Javier

AU - Gutierrez, Antonio M.

AU - Ramos, Rafael F.

AU - Lopez-Guerrero, José A.

AU - Ferrari, Stefano

AU - Stacchiotti, Silvia

AU - Picci, Piero

AU - Calabuig, Silvia

AU - Collini, Paola

AU - Gambarotti, Marco

AU - Bague, Silvia

AU - Dei Tos, Angelo P.

AU - Palassini, Elena

AU - Luna, Pablo

AU - Cruz, Josefina

AU - Cubedo, Ricardo

AU - Martinez-Trufero, Javier

AU - Poveda, Andres

AU - Casali, Paolo G.

AU - Fernandez-Serra, Antonio

AU - Lopez-Pousa, Antonio

AU - Gronchi, Alessandro

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