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Cancer Treat Rev. 2016 Nov;50:175-182. doi: 10.1016/j.ctrv.2016.09.009. Epub 2016 Sep 15.

Trabectedin as a chemotherapy option for patients with BRCA deficiency.

Author information

1
University of Arizona at Saint Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA. Electronic address: Bradley.monk@usoncology.com.
2
Gynecologic Oncology Unit, Fondazione IRCCS National Cancer Institute of Milan, Via Venezian 1, 20133 Milan, Italy. Electronic address: domenica.lorusso@istitutotumori.mi.it.
3
Department of Medical Oncology, Bergonie Institute, Bordeaux, France. Electronic address: italiano@bergonie.org.
4
Drug Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, SM2 5PT Sutton, United Kingdom. Electronic address: Stan.Kaye@icr.ac.uk.
5
PharmaMar S.A., Avda. de los Reyes 1, 28770 Colmenar Viejo (Madrid), Spain. Electronic address: maracil@pharmamar.com.
6
PharmaMar S.A., Avda. de los Reyes 1, 28770 Colmenar Viejo (Madrid), Spain. Electronic address: atanovic@pharmamar.com.
7
Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa, 19, 20156 Milan, Italy. Electronic address: maurizio.dincalci@marionegri.it.

Abstract

Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity. In addition, trabectedin has shown the ability to modulate the tumor microenvironment. Indeed, the activity of trabectedin is related to altered function and expression of DNA repair genes, such as BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2. The particular sensitivity of sarcoma, ovarian and breast cancer cells deficient in HRR, previously observed in preclinical models, now has been confirmed in the clinical setting as well, suggesting that BRCA mutations are associated with improved clinical responses to trabectedin. Current efforts are focused on the evaluation of these unique features of trabectedin and on the identification of predictive factors for patients with an objective to determine whether a deficiency of HRR DNA repair pathway could impact the clinical benefit achieved from trabectedin.

KEYWORDS:

BRCA; Breast; Mutations; Ovarian cancer; Sarcoma; Trabectedin; Yondelis®

PMID:
27710871
DOI:
10.1016/j.ctrv.2016.09.009
[Indexed for MEDLINE]
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