title: Trabectedin as a chemotherapy option for patients with BRCA deficiency.
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.
authors.affiliation: University of Arizona at Saint Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA. Electronic address: Bradley.monk@usoncology.com.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Monk
authors.affiliation: Gynecologic Oncology Unit, Fondazione IRCCS National Cancer Institute of Milan, Via Venezian 1, 20133 Milan, Italy. Electronic address: domenica.lorusso@istitutotumori.mi.it.
authors.forename: Domenica
authors.initials: D
authors.lastname: Lorusso
authors.affiliation: Department of Medical Oncology, Bergonie Institute, Bordeaux, France. Electronic address: italiano@bergonie.org.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
authors.affiliation: 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.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: PharmaMar S.A., Avda. de los Reyes 1, 28770 Colmenar Viejo (Madrid), Spain. Electronic address: maracil@pharmamar.com.
authors.forename: Miguel
authors.initials: M
authors.lastname: Aracil
authors.affiliation: PharmaMar S.A., Avda. de los Reyes 1, 28770 Colmenar Viejo (Madrid), Spain. Electronic address: atanovic@pharmamar.com.
authors.forename: Adnan
authors.initials: A
authors.lastname: Tanović
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa, 19, 20156 Milan, Italy. Electronic address: maurizio.dincalci@marionegri.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000172:deficiency*; D024682:BRCA2 Protein / Q000172:deficiency*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004149:Dioxoles / Q000008:administration & dosage / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011092:Polyethylene Glycols / Q000008:administration & dosage; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000077606:Trabectedin
keywords: BRCA; Breast; Mutations; Ovarian cancer; Sarcoma; Trabectedin; Yondelis®