Efficacy Of Trabectedin In Patients Research Articles

A Growth Modulation Index-Based GEISTRA Score as a New Prognostic Tool for Trabectedin Efficacy in Patients with Advanced Soft Tissue Sarcomas: A Spanish Group for Sarcoma Research (GEIS) Retrospective Study.

Simple SummarySoft tissue sarcomas (STS) are an uncommon and heterogeneous group of tumors, with scarce options for treatment in advanced cases. There is no consensus regarding which is the best treatment sequence for these patients. Although trabectedin is an approved drug for STS treatment, after progression to anthracyclines, the clinical profile of the patients that most benefit from this drug it is not defined. We have retrospectively analyzed a sample of 357 nonselected sarcoma patients from real-world experience, treated homogeneously with trabectedin, confirming and validating results from previous clinical trials and other retrospective studies. After analyzing clinical prognostic factors, we selected those which predicted a better growth modulation index (GMI > 1.33), and we defined the GEISTRA score, an easy to obtain and reproducible clinical tool, that can help us to optimize the use of trabectedin in advanced sarcoma patients.The aim of this study was to identify an easily reliable prognostic score that selects the subset of advanced soft tissue sarcoma (ASTS) patients with a higher benefit with trabectedin in terms of time to progression and overall survival. A retrospective series of 357 patients with ASTS treated with trabectedin as second- or further-line in 19 centers across Spain was analyzed. First, it was confirmed that patients with high growth modulation index (GMI > 1.33) were associated with the better clinical outcome. Univariate and multivariate analyses were performed to identify factors associated with a GMI > 1.33. Thus, GEISTRA score was based on metastasis free-interval (MFI ≤ 9.7 months), Karnofsky < 80%, Non L-sarcomas and better response in the previous systemic line. The median GMI was 0.82 (0–69), with 198 patients (55%) with a GMI < 1, 41 (11.5%) with a GMI 1–1.33 and 118 (33.1%) with a GMI > 1.33. The lowest GEISTRA score showed a median of time-to-progression (TTP) and overall survival (OS) of 5.7 and 19.5 months, respectively, whereas it was 1.8 and 3.1 months for TTP and OS, respectively, for the GEISTRA 4 score. This prognostic tool can contribute to better selecting candidates for trabectedin treatment in ASTS.

The Danish experience with trabectedin treatment for metastatic sarcoma: Importance of hyponatremia

Background. Trabectedin was in Europe approved for treatment of metastatic soft tissue sarcoma (STS) in 2007 based on results of a phase II study with relatively few patients. The purpose of this nationwide retrospective study was to assess efficacy and safety of using trabectedin in the entire unselected cohort of patients with metastatic sarcoma and to test known, as well as new prognostic factors that may affect overall survival (OS).Patients and methods. Between January 2008 and April 2013, 117 patients were treated with trabectedin for metastatic sarcoma in the three specialized sarcoma centers in Denmark. Known prognostic factors such as age, gender and performance status, the histopathology as well as other new factors such as response to previous chemotherapy and hyponatremia were tested.Results. Median age was 59 years. Lipo- and leiomysosarcomas (L-sarcomas) represented 43% of the cases and 18% had hyponatremia before the start of trabectedin. The median number of previous lines of chemotherapy was two (range 0–6) and the median number of chemotherapy cycles given before trabectedin was nine (range 0–85). The median number of trabectedin cycles was three (range 1–17). The median OS for the whole cohort was seven months. Poor performance status, non-L-sarcomas, and hyponatremia were statistically significant adverse prognostic factors with median survival of: 4, 5, and 2 months compared to 9, 12 and 13 months, respectively. Moreover, having achieved clinical benefit [complete response (CR), partial response (PR) or stable disease (SD)] from previous chemotherapy was a favorable prognostic factor for response to trabectedin. In multivariate analysis hyponatremia was the only independent significant poor prognostic factor affecting OS.Conclusions. This retrospective study confirmed the previously published safety and efficacy of trabectedin in patients with metastatic sarcoma and showed hyponatremia to be a strong independent statistically significant poor prognostic factor.

Predictive value of BRCA1 haplotype for trabectedin efficacy in patients with advanced soft-tissue sarcoma.

10598 Background: Trabectedin (T) has shown objective response and disease stabilisation in 5%–10% and 30-40% of unselected patients with advanced soft tissue sarcoma (STS) failing prior anthracycl...

Abstract 18: Predictive value of BRCA1 haplotype for trabectedin efficacy in patients with advanced soft-tissue sarcoma.

Abstract Background: Trabectedin (T) has shown objective response and disease stabilisation in 5%-10% and 30-40% of unselected patients with advanced soft tissue sarcoma (STS) failing prior anthracyclines and/or ifosfamide chemotherapy. Although the precise mechanism of action of T is not fully elucidated, this drug has been found to be more active in tumor cells with a deficient homologous recombination (HR) repair system. BRCA1 is a key player of the HER system. Our aim was to determine whether the status of 4 single nucleotide polymorphims (SNPs) was associated with clinical activity of T in advanced STS patients. Methods: We analyzed SNPs (rs16941, rs16942, rs 1799966, and rs 799917) of BRCA1 in two independent cohort of patients (training cohort: 113 patients, validation cohort: 84 patients) with advanced STS from nine major referral European centres for STS. All patients were treated between 1999 and 2011 in phase I-II clinical trials or in the context of a compassionate-use programme that was open to advanced STS patients who had failed conventional chemotherapy. T was given at different doses (0.5-3 mg/m2) with the use of two different schedules: a 3-h infusion or a 24-h continuous infusion. Results: Median age of the patients in the training set was 49 years (range 17-77). The two most frequent histological subtypes were: leiomyosarcoma (non-uterine: 21, uterine: 10) and liposarcoma (myxoid round cell: 21, other: 17). 632 cycles of T were administered, with a median of 4 cycles per patient (range 1-25). The median follow-up was 10 months (range, 0.6-96 months). One complete response, 18 partial responses, and 26 disease stabilizations that lasted for &amp;gt;6 months were observed. The median PFS was 3.5 months (95% confidence interval [CI], 2.7-4.4 months). The median OS was 13.6 months (95% CI, 8.7-18.5 months). PFS was significantly higher for patients who had at least 1 allele of the most frequent BRCA1 AAAG haplotype (median PFS: 5.6 months [95% CI, 1.4-9.8 months] vs 2.5 months [95% CI, 1.3-3.6 months]; P = .03). The same trend was observed for OS (median OS: 14.1 months [95% CI, 4.4-23.8 months] vs 5.4 months [95% CI, 1.7-9.0 months]; P = .0095). We observed a similar association between BRCA1 haptlotype and PFS in the independent validation cohort (median PFS: 5.2 vs 2.7 months, P = .02). Conclusion: BRCA1 haplotype may represent a predictive DNA-based biomarker for trabectedin efficacy in advanced STS patients. Such a biomarker assessable form paraffin-embedded tumor material could be easily used into routine practice provided it is validated in a prospective setting. Citation Format: Audrey Laroche-Clary, Vanessa Chaire, Valérie Le Morvan, Agnès Neuville, Sébastien Salas, François Bertucci, Philippe Pourquier, Antoine Italiano. Predictive value of BRCA1 haplotype for trabectedin efficacy in patients with advanced soft-tissue sarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 18. doi:10.1158/1538-7445.AM2013-18

Analysis of DNA Repair–Related Genes in Breast Cancer Reveals CUL4A Ubiquitin Ligase as a Novel Biomarker of Trabectedin Response

Trabectedin is more active in nucleotide excision repair (NER)-efficient and homologous recombination repair (HRR)-deficient cells. As up to 25% of sporadic breast tumors present somatic inactivation of the HRR pathway (BRCAness phenotype), we sought to characterize trabectedin effect in BRCA1-proficient and BRCA1-null breast cancer cell lines. We evaluated whether HRR and NER gene expression correlates with trabectedin sensitivity and explored the response predictive value of the CUL4A ubiquitin ligase, which ubiquitinates NER pathway members. We characterized trabectedin cytotoxicity, cell-cycle effects, and BRCA1, BRCA2, XRCC3, XPG, ERCC1, and CUL4A expression in 10 breast cancer cell lines. Gene expression and trabectedin sensitivity association were determined in cell lines. Survival assays after trabectedin treatment were conducted in CUL4A-silenced BRCA1-proficient and -deficient cells. Because of limited phase II clinical trials evaluating trabectedin efficacy in patients with breast cancer, we assessed CUL4A immunohistochemical staining in a retrospective series of 118 sarcomas from trabectedin-treated patients to validate in vivo our in vitro observations. In cell lines, greater trabectedin sensitivity was associated with higher CUL4A expression and lower BRCA1/ERCC5, BRCA1/CUL4A, and XRCC3/CUL4A expression ratios. In agreement, BRCA1-deficient CUL4A-knockdown cells presented higher cell survival after trabectedin exposure than did scramble control cells. Lack of effect in BRCA1-proficient cells suggests that HRR impairment is key in CUL4A-mediated trabectedin sensitivity. High CUL4A expression in nontranslocation-related patients with sarcoma predicted improved progression-free survival [PFS; HR, 0.37; 95% confidence interval (CI), 0.20-0.68, P = 0.001] and overall survival (OS; HR, 0.44; 95% CI, 0.21-0.93, P = 0.026). Our observations support the notion of greater trabectedin activity in tumors exhibiting BRCAness and reveal CUL4A as a potential biomarker for definition of trabectedin target patients.

Clinical benefit of trabectedin in uterine adenosarcoma

Uterine adenosarcoma is an extremely rare uterine malignancy, and the utility of chemotherapy in this disease is not well defined. This study assessed the safety and efficacy of trabectedin in patients with recurrent/metastatic uterine adenosarcoma with sarcomatous overgrowth. A retrospective search of a prospectively maintained database was performed to identify patients with adenosarcoma treated with trabectedin between 2010 and 2012, within a compassionate use trial. Three patients with recurrent/metastatic uterine adenosarcoma treated with trabectedin were identified. All three patients tolerated the drug well. Two patients obtained prolonged clinical benefit from treatment, one having received 17 cycles and another 11 cycles of therapy. Trabectedin is well tolerated and has clinical activity in recurrent/metastatic uterine adenosarcoma.

Trabectedin (Et-743): Evaluation of Its Use In Advanced Soft-Tissue Sarcoma

Trabectedin (ET-743; Yondelis) is a novel DNA-binding agent, originally derived from the marine tunicate, Ecteinascidia turbinata, and now produced synthetically. The efficacy of trabectedin in patients with advanced soft-tissue sarcoma has been demonstrated in three Phase II studies involving 189 previously treated patients. A pooled analysis of data from these studies showed that trabectedin induced tumor control (objective responses plus disease stabilization) in approximately 50% of patients; median overall survival was 10.3 months and progression-free survival at 6 months was 19.8%, with 29.3% of patients alive at 2 years. Responses were achieved in patients who were resistant to both doxorubicin and ifosfamide. Trabectedin is generally well tolerated, with adverse events being non cumulative, reversible and manageable. Unlike other commonly used cytotoxic agents, trabectedin is not associated with cardiotoxicity or neurotoxicity and alopecia is rare. Trabectedin is an interesting new anticancer agent that offers much promise for the treatment of advanced soft-tissue sarcoma.