abstract
Highlights
- •We sought if BRCA deficiencies are associated with clinical responses to trabectedin.
- •BRCA genes are an important predictive indicator of sensitivity to trabectedin.
- •Improved response to trabectedin is a hallmark of BRCA1/2-mutated carriers.
- •Stratification based on BRCA mutations should become standard in upcoming trials.
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.
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