bims-myxlip 2021-09-05 papers

Issue of 2021–09–05
two papers selected by
Laura Mannarino, Humanitas Research

Clin Cancer Res. 2021 Sep 02. pii: clincanres.2001.2021. [Epub ahead of print]

Phase II study of pembrolizumab in combination with doxorubicin in metastatic and unresectable soft tissue sarcoma.

Michael B Livingston, Megan H Jagosky, Myra M Robinson, William A Ahrens, Jennifer H Benbow, Carol J Farhangfar, David M Foureau, Deirdre M Maxwell, Emily A Baldrige, Xhevahire Begic, James T Symanowski, Nury M Steuerwald, Colin J Anderson, Joshua C Patt, Jeffrey S Kneisl, Edward S Kim.

PURPOSE: Doxorubicin is standard therapy for advanced soft tissue sarcoma (STS) with minimal improvement in efficacy and increased toxicity with addition of other cytotoxic agents. Pembrolizumab monotherapy has demonstrated modest activity and tolerability in previous advanced STS studies. This study combined pembrolizumab with doxorubicin to assess safety and efficacy in frontline and relapsed settings of advanced STS.
EXPERIMENTAL DESIGN: This single-center, single-arm, Phase 2 trial enrolled unresectable or metastatic patients with STS with no prior anthracycline therapy. Patients received pembrolizumab 200 mg IV and doxorubicin (60 mg/m2 cycle 1 with subsequent escalation to 75 mg/m2 as tolerated). The primary endpoint was safety. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression free survival (PFS) based on RECIST v1.1 guidelines.
RESULTS: 30 patients were enrolled (53.3% female; median age 61.5 years; 87% previously untreated) with 4 (13.3%) patients continuing treatment. The study met its primary safety endpoint by pre-specified Bayesian stopping rules. The majority of grade 3+ TEAEs were hematologic (36.7 % 3+ neutropenia). ORR was 36.7% (95% CI 19.9-56.1%), with documented disease control in 80.0% (95% CI 61.4-92.3%) of patients. Ten (33.3%) patients achieved partial response, one (3.3%) patient achieved complete response and 13 (43.3%) patients had stable disease. Median PFS and OS were 5.7 months (PFS-6 mo: 44%) and 17 months (OS-12 mo: 62%), respectively. PD-L1 expression was associated with improved ORR, but not OS or PFS.
CONCLUSIONS: Combination pembrolizumab and doxorubicin has manageable toxicity and preliminary promising activity in treatment of patients of anthracycline-naive advanced STS.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-2001

Mol Cancer Res. 2021 Aug 31. pii: molcanres.MCR-21-0354-E.2021. [Epub ahead of print]

Identification of a novel FUS/ETV4 fusion and comparative analysis with other Ewing sarcoma fusion proteins.

Megann A Boone, Cenny Taslim, Jesse C Crow, Julia Selich-Anderson, Mike Watson, Peter Heppner, James Hamill, Andrew C Wood, Stephen L Lessnick, Mark Winstanley.

Ewing sarcoma is a pediatric bone cancer defined by a chromosomal translocation fusing one of the FET family members to an ETS transcription factor. There have been seven reported chromosomal translocations, with the most recent reported over a decade ago. We now report a novel FET/ETS translocation involving FUS and ETV4 detected in a Ewing sarcoma patient. Here, we characterized FUS/ETV4 by performing genomic localization and transcriptional regulatory studies on numerous FET/ETS fusions in a Ewing sarcoma cellular model. Through this comparative analysis, we demonstrate significant similarities across these fusions, and in doing so, validate FUS/ETV4 as a bona fide Ewing sarcoma translocation. This study presents the first genomic comparison of Ewing sarcoma-associated translocations and reveals that the FET/ETS fusions share highly similar, but not identical, genomic localization and transcriptional regulation patterns. These data strengthen the notion that FET/ETS fusions are key drivers of, and thus pathognomonic for, Ewing sarcoma. Implications: Identification and initial characterization of the novel Ewing sarcoma fusion, FUS/ETV4, expands the family of Ewing-fusions and extends the diagnostic possibilities for this aggressive tumor of adolescents and young adults.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0354