Background: Treatment of osteosarcoma of the extremities consists of surgical resection preceded and followed by chemotherapy, including high-dose methotrexate or adriamycin-based protocols. When distant relapse occurs, therapeutic options are scarce. Trabectedin, a DNA-binding agent, is indicated for the treatment of patients with advanced soft tissue sarcomas after failure of anthracyclines and ifosfamide. In this indication, the 6-month progression-free survival is about 35-40%. Recent reports showed that some specific single nucleotide polymorphisms (SNPs) from DNA repair genes could be associated with sensitivity to trabectedin in soft tissue sarcomas. Case Reports: We report our experience of 2 metastatic, heavily pre-treated osteosarcoma patients who were treated with trabectedin. Pyrosequencing analyses of tumors from both patients for several SNPs of the ERCC1, ERCC5 and BRAC1 genes were performed. Both patients showed major response to trabectedin, which was interestingly related with homozygoty of the common guanine allele of ERCC5 (G/G genotype; Asp/Asp) after pyrosenquencing analysis of tumors from both patients. This polymorphism was previously shown to be associated with better outcome in soft tissue sarcoma patients treated with trabectedin. Conclusion: Homozygoty for the wild-type Asp1104 SNP of the ERCC5 gene was found in 2 cases of relapsed osteosarcoma, who responded to trabectedin.

Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, Marcove RC, Lane JM, Mehta B, Urban C: Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 1982;49:1221-1230.
Hogendoorn PC, Athanasou N, Bielack S, De Alava E, Dei Tos AP, Ferrari S, Gelderblom H, Grimer R, Hall KS, Hassan B, Jurgens H, Paulussen M, Rozeman L, Taminiau AH, Whelan J, Vanel D: Bone sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(suppl 5):v204-213.
Bacci G, Briccoli A, Mercuri M, Ferrari S, Bertoni F, Gasbarrini A, Fabbri N, Cesari M, Forni C, Campanacci M: Osteosarcoma of the extremities with synchronous lung metastases: long-term results in 44 patients treated with neo-adjuvant chemotherapy. J Chemother 1998;10:69-76.
Blay JY, Le Cesne A, Verweij J, Scurr M, Seynaeve C, Bonvalot S, Hogendoorn P, Jimeno J, Evrard V, van Glabbeke M, Judson I: A phase II study of ET-743/trabectedin (‘Yondelis') for patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2004;40:1327-1331.
Laverdiere C, Kolb EA, Supko JG, Gorlick R, Meyers PA, Maki RG, Wexler L, Demetri GD, Healey JH, Huvos AG, Goorin AM, Bagatell R, Ruiz-Casado A, Guzman C, Jimeno J, Harmon D: Phase II study of ecteinascidin 743 in heavily pre-treated patients with recurrent osteosarcoma. Cancer 2003;98:832-840.
Ruiz-Casado A, Lopez-Martin J, Nieto A, Blay J-Y, Delaloge S, Van Oosterom A, Millan S, Martin C, Guzman C, Jimeno J: Ecteinascidin in heavily pre-treated advanced sarcoma patients as a compassionate basis. Proc Am Soc Clin Oncol 2002;21:abstr 1631.
Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, Hande KR, Keohan ML, Samuels BL, Schuetze S, Lebedinsky C, Elsayed YA, Izquierdo MA, Gomez J, Park YC, Le Cesne A: Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyo-sarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase ii study of two different schedules. J Clin Oncol 2009; 27:4188-4196.
Le Cesne A, Blay JY, Judson I, Van Oosterom A, Verweij J, Radford J, Lorigan P, Rodenhuis S, Ray-Coquard I, Bonvalot S, Collin F, Jimeno J, Di Paola E, Van Glabbeke M, Nielsen OS: Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group trial. J Clin Oncol 2005; 23:576-584.
Garcia-Carbonero R, Supko JG, Manola J, Seiden MV, Harmon D, Ryan DP, Quigley MT, Merriam P, Canniff J, Goss G, Matulonis U, Maki RG, Lopez T, Puchalski TA, Sancho MA, Gomez J, Guzman C, Jimeno J, Demetri GD: Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol 2004;22:1480-1490.
Yovine A, Riofrio M, Blay JY, Brain E, Alexandre J, Kahatt C, Taamma A, Jimeno J, Martin C, Salhi Y, Cvitkovic E, Misset JL: Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol 2004; 22:890-899.
Italiano A, Laurand A, Laroche A, Casali P, Sanfilippo R, Le Cesne A, Judson I, Blay JY, Ray-Coquard I, Bui B, Coindre JM, Nieto A, Tercero JC, Jimeno J, Robert J, Pourquier P: ERCC5/XPG, ERCC1, and BRCA1 gene status and clinical benefit of trabectedin in patients with soft tissue sarcoma. Cancer 2011;117:3445-3456.
Huygh G, Clement PM, Dumez H, Schoffski P, Wildiers H, Selleslach J, Jimeno JM, Wever ID, Sciot R, Duck L, Van Oosterom AT: Ecteinascidin-743: evidence of activity in advanced, pre-treated soft tissue and bone sarcoma patients. Sarcoma 2006;2006:56282.
Dileo P, Bacci G, Aglietta M, Ferrari S, Gignani G, Sessa C, Jimeno J, Marsoni S, Casali P: Final results of a phase II trial of 3 hr infusion trabectidin in patients with recurrent sarcoma. 31st Esmo Congress, Istanbul, Turkey, 2006, abstr. 524 P.
Takebayashi Y, Pourquier P, Zimonjic DB, Nakayama K, Emmert S, Ueda T, Urasaki Y, Kanzaki A, Akiyama SI, Popescu N, Kraemer KH, Pommier Y: Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 2001;7:961-966.
Biason P, Hattinger CM, Innocenti F, Talamini R, Alberghini M, Scotlandi K, Zanusso C, Serra M, Toffoli G: Nucleotide excision repair gene variants and association with survival in osteosarcoma patients treated with neoadjuvant chemotherapy; Pharmacogenomics J 2012;12:476-483.
Caronia D, Patino-Garcia A, Milne RL, Zalacain-Diez M, Pita G, Alonso MR, Moreno LT, Sierrasesumaga-Ariznabarreta L, Benitez J, Gonzalez-Neira A: Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients. Pharmacogenomics J 2009;9:347-353.
Herrero AB, Martin-Castellanos C, Marco E, Gago F, Moreno S: Cross-talk between nucleotide excision and homologous recombination DNA repair pathways in the mechanism of action of antitumor trabectedin. Cancer Res 2006;66:8155-8162.
Mirabello L, Yu K, Berndt SI, Burdett L, Wang Z, Chowdhury S, Teshome K, Uzoka A, Hutchinson A, Grotmol T, Douglass C, Hayes RB, Hoover RN, Savage SA: A comprehensive candidate gene approach identifies genetic variation associated with osteosarcoma; BMC Cancer 2011;11:209.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.