title: Activity of trabectedin in germline BRCA1/2-mutated metastatic breast cancer: results of an international first-in-class phase II study.
abstract: BACKGROUND
  Breast cancer is a heterogeneous disease defined by both germline and somatic abnormalities. In preclinical models, tumors carrying homologous recombination defects are highly sensitive to trabectedin. This phase II trial evaluated the efficacy and safety of trabectedin in BRCA1/2 germline mutation carriers with pretreated metastatic breast cancer (MBC).
  
  
  METHODS
  Trabectedin 1.3 mg/m(2) as a 3-h i.v. infusion was administered every 3 weeks until progression or intolerance. The primary efficacy end point was the objective response rate (ORR) as per RECIST. Secondary efficacy end points comprised time-to-event end points, and changes in tumor volume and expression of tumor marker CA15.3. Safety was evaluated using the NCI-CTCAE.
  
  
  RESULTS
  Forty BRCA1/2 germline mutation carriers with MBC were included. Confirmed partial response (PR) occurred in 6 of 35 assessable patients [ORR = 17%; 95% confidence interval (CI) 7% to 34%] and lasted 1.4-6.8 months. Median PFS was 3.9 months (95% CI 1.6-5.5 months). Eight patients (21%) showed changes in tumor volume, and 14 (40%) a clinical benefit. Trabectedin-related adverse events were generally mild/moderate, the most common being fatigue, nausea, constipation and anorexia. Severe laboratory abnormalities (neutropenia, transaminase increases) were mostly transient and noncumulative, and were managed by dose adjustments.
  
  
  CONCLUSIONS
  With the caveat of the limited patient number, trabectedin monotherapy showed activity and was well tolerated in heavily pretreated MBC patients selected for germline BRCA mutation. These results prompt further evaluation of trabectedin alone or combined with other specific drugs in this indication.
  
  
  BACKGROUND
  NCT00580112.
authors.affiliation: Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France suzette.delaloge@gustaveroussy.fr.
authors.forename: S
authors.initials: S
authors.lastname: Delaloge
authors.affiliation: Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
authors.forename: R
authors.initials: R
authors.lastname: Wolp-Diniz
authors.affiliation: Department of Medical Oncology, International Hereditary Cancer Center, Sczeczin, Poland.
authors.forename: T
authors.initials: T
authors.lastname: Byrski
authors.affiliation: Department of Oncology, Baylor-Charles A. Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Blum
authors.affiliation: Department of Medical Oncology, Institut Paoli Calmettes, Marseille.
authors.forename: A
authors.initials: A
authors.lastname: Gonçalves
authors.affiliation: Department of Medical Oncology, Institut de Cancérologie de l'OUEST, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Campone
authors.affiliation: Clinical R&D, PharmaMar, Colmenar Viejo, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Lardelli
authors.affiliation: Clinical R&D, PharmaMar, Colmenar Viejo, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Kahatt
authors.affiliation: Clinical R&D, PharmaMar, Colmenar Viejo, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Nieto
authors.affiliation: Clinical R&D, PharmaMar, Colmenar Viejo, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Cullell-Young
authors.affiliation: Department of Medical Oncology, International Hereditary Cancer Center, Sczeczin, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Lubinski
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D004149:Dioxoles / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use*; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
keywords: BRCA1/2; breast cancer; chemotherapy; trabectedin