Role of trabectedin in BRCA-mutated patients

Abstract

Trabectedin, approved for the treatment of adult patients with advanced soft tissue sarcoma (STS), after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents, and in combination with pegylated liposomal doxorubicin (PLD) for the treatment of patients with relapsed platinum-sensitive ovarian cancer (ROC), has a complex multi-targeted mechanism of action. Not only does trabectedin interact with DNA binding proteins and modulate transcription leading to cell-cycle arrest, growth inhibition and cancer cell death, it also has activity in the tumour microenvironment and may inhibit epithelial-mesenchymal transition, thus preventing epithelial cancer cells becoming more aggressive and thus reducing their metastatic potential and preventing development of resistance to chemotherapy. Differences in the cancer cell DNA repair mechanism appear to affect sensitivity to trabectedin, with those deficient in homologous recombination (HR) being highly sensitive to trabectedin and nucleotide excision repair-deficient cells being less sensitive to trabectedin. As trabectedin-induced damage requires repair of DNA-double-stranded breaks, this pathway appears to be pivotal for drug-induced cytotoxicity and response to trabectedin. It was hypothesized that differential expression of factors involved in DNA repair, such as the protein nibrin, may affect clinical outcomes of patients with ROC. Indeed low nibrin expression seems to be associated with significantly better clinical outcome in patients with platinum-sensitive disease treated with the combination of trabectedin plus PLD, but not in with PLD alone. The accumulating evidence of the existence of a sub-set of tumours with defects in the HR-DNA repair pathway, – the BRCAness phenotype – suggests that these patients should benefit more from trabectedin-based therapy. Early data show that this may be true for patients with STS and metastatic breast cancer (MBC) suggesting a potential role for trabectedin monotherapy in the management of these conditions. This may also be the case in high-grade serous ovarian carcinomas for which improved outcomes have been seen in patients with germline BRCA mutations. The BRCAness phenotype is expected to identify tumour cells likely to be more vulnerable to trabectedin on the basis of its mechanism of action and we await further data from ongoing evaluations of response to trabectedin according to BRCA mutation status and DNA polymorphism of other genes involved in DNA repair with interest. Expression levels of DNA repair genes could be used as molecular biomarkers to select patients who will obtain greater benefit from trabectedin.