Abstract 18: Predictive value of BRCA1 haplotype for trabectedin efficacy in patients with advanced soft-tissue sarcoma.
Authors: Laroche-Clary Audrey , Chaire Vanessa , Le Morvan Valérie , Neuville Agnès , Salas Sébastien , Bertucci François , Pourquier Philippe , Italiano Antoine 
Published: August 2014

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 &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