A translational study was designed to analyze the expression of nucleotide excision repair (NER) and homologous recombination (HR) genes as potential predictive biomarkers for trabectedin in soft-tissue sarcoma (STS). This study is part of a randomized phase II trial comparing trabectedin plus doxorubicin versus doxorubicin in advanced STS. Gene expression levels were evaluated by qRT-PCR, while CUL4A protein levels were quantified by immunohistochemistry. Expression levels were correlated with patients’ progression-free survival (PFS) and overall survival (OS). Gene expression was also evaluated in cell lines and correlated with trabectedin sensitivity. In doxorubicin arm and in the whole series, which includes samples from both arms, no significant differences in terms of PFS were observed amongst the analyzed genes. In the group treated with trabectedin plus doxorubicin, the median of PFS was significantly longer in cases with CUL4A, ERCC1, or ERCC5 overexpression, while BRCA1 expression did not correlated with PFS. Gene expression had no prognostic influence in OS. CUL4A protein levels correlated with worse PFS in doxorubicin arm and in the whole series. In cell lines, only overexpression of ERCC1 was significantly correlated with trabectedin sensitivity. In conclusion, CUL4A, ERCC5, and mainly ERCC1 acted as predictive factors for trabectedin efficacy in advanced STS.
e12608 Background: Achieving a pCR (absence of residual invasive disease in breast and measurable disease in any of the axillary nodes sampled, ypT0/is and ypN0) after NAT correlates with improved survival. TNBC phenotype have a poor prognosis. However, it is associated with higher NAT response rates. With traditional schemes based on anthracyclines and taxanes, pCR rates of around 25-40% are obtained. Different schemes have been studied providing an increase in pCR such as using nab-paclitaxel, platinum salts, bevacizumab or dose dense (dd) anthracyclines. The purpose of the present study is to explore feasibility, toxicity and pCR of new aproach with carboplatine, nab-paclitaxel and antracycline in TNBC. Methods: Retrospective study with early and locally advanced TNBC pts, ECOG 0-1, without contraindications to antracyclines, were included. Treatment consisted of carboplatine AUC2 with nab-paclitaxel 80 mg/m2 i.v. weekly for 12 doses followed by epirubicin 90 mg/m2 (elderly pts recieved at 75 mg/m2) with cyclophosphamide 600 mg/m2 i.v., every 2 weeks (dd) or 3 weeks (if pts had G3-4 toxicity) for 4 doses. G-CSF support was allowed in pts with neutropenia G3-4. Pts with residual disease after NAT were offered capecitabine as adjuvant treatment. The primary endpoint was pCR. Results: From 02/2018 to 06/2022, 96 pts was included. Median age was 53 years (27-78). Clinical stage was I in 16 pts, II in 50 pts and III in 30 pts (N+ in 40'6%). 98% pts had tumours with a Ki67 20% or higher. 36’5% pts was premenopausal. 10 pts were germline BRCA mutated (8/10 gBRCA1, 2/10 gBRCA2) 50/96 pts (55’2%) had dd epirubicin-cyclophospamide (EC) and 44’8% pts recieved EC every 3 weeks (for G3 adverse events (AE)). pCR in pts who had dd treatment was 65’4% and 40’9% in pts with EC non-dd (p 0’016). 89’9% pts with residual disease completed adjuvant treatment with 8 cycles of capecitabine. 53/96 pts had an AE related with NAT. Neutropenia G3-4 (45’5% pts, all of them recieved dd treatment) and any grade of alopecia and mucositis (60% and 25% respectively) were the most frecuent AE reported. Pts with neutropenia G3-4 on blood test recieved G-CSF in subsequent cycles with resolution of haematological AE. All pts with dd treatment recieved G-CSF. One patient had a disease progression by radiological evaluation during the treatment. During follow-up 9 pts relapsed (1 had a pCR with NAT) and 5 pts died for progression disease. Conclusions: NAT on TNBC pts with carboplatine, nab-paclitaxel and antracycline dd is a feasible, safe and highly effective option. Even though survival analysis is not yet mature in our study, pCR has been shown to be a surrogate for overall survival. The excellent results obtained with this scheme, make it a good treatment option and could be an alternative to pembrolizumab (Keynote-522) in pts with autoinmmune diseases or immune-AE due to similar pCR.
11546 Background: Despite several second-line options are accessible for the treatment of advanced STS, there is a lack of predictive biomarkers available to support the rational selection of these drugs. Trabectedin specifically targets mononuclear cell lineage (macrophages and monocytes) that ultimately could inhibit tumor angiogenesis. Moreover, trabectedin seems to induce the expression of immune-checkpoint proteins (e.g. PD-L1); however, the predictive value of these factors remains unknown. We present the analyses of immune-checkpoint genes ( CD274, CD86, CTLA4, HAVCR2, LAG3 and PDCD1) and CD163, CD4, CD68 and CD8A expression as potential predictive factors of response to trabectedin in a subset of STS patients of the GEIS registry. Methods: Selection criteria included patients with STS, pretreated with at least 2 lines in the advanced setting (one line being trabectedin), with paraffin block available and ethic committee’s approval. Direct transcriptomics was performed using HTG Molecular Oncology Biomarker Pathway panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA), following manufacturers’ instructions. Data analyses were performed taking into account the median Log2 of expression of each gene and by correlating it with progression-free survival (PFS) for trabectedin, and overall survival measured from the starting date of trabectedin treatment (OS). Results: Among 387 registered patients, fitting with the inclusions criteria, 139 cases were used for gene expression analyses, as the discovery set. Patients had median age of 52 years, 54% were females and had a median follow-up from diagnosis of 44 months. High expression of CD274 (PD-L1) was significantly associated with better PFS of trabectedin (5.4 vs. 3.0 months; p= 0.006). Similar results were obtained with high expression of CTLA4 and LAG3: 6.0 vs 3.1 months; p = 0.005 and 5.4 vs 2.7 months; p = 0.042, respectively. Expression of CTLA4 and LAG3 showed no significant impact in OS; whereas CD274 high expression showed a trend towards better OS (17.9 vs 10.2 months; p = 0.077). Also, no significant correlation was achieved for CD163, CD4, CD68, CD8A, CD86 and HAVCR2; PDCD1 (PD-1) showed a trend towards better PFS of trabectedin, p = 0.114. Conclusions: The expression of selected immune-checkpoint genes exhibited a potential predictive value for trabectedin in advanced STS. Validation studies (at the transcriptional and protein level) are currently ongoing to confirm their potential predictive role.
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