Abstract 4280: Potential molecular biomarkers of response to eribulin in patients with leiomyosarcoma
Authors: Wozniak Agnieszka , Boecks Bram , Modave Elodie , Weaver Amy , Lambrechts Diether , Littlefield Bruce A. , Schöffski Patrick 
Published: September 2020

Background. The recent randomized phase 3 trial Eisai Study 309 evaluated efficacy of eribulin (ERI) compared to dacarbazine (DTIC) in advanced liposarcoma (LPS) and leiomyosarcoma (LMS). Improved overall survival (OS) in ERI-treated patients led to US and EU regulatory approval of ERI for LPS, but not in LMS where DTIC has clinically relevant activity.

As part of the translational effort in this trial we have now explored the molecular profile of LMS tumors from North American study sites, in order to identify potential predictive molecular factors for treatment with ERI.

Material and Methods. From 82 archival primary tumor or metastatic LMS samples collected prior to study entry, 78 specimens were available for low-coverage whole genome sequencing. We analyzed copy number alterations (CNAs) and performed whole exome sequencing (WES) for mutational profiling. Forty patients received experimental treatment with ERI, while 38 were treated with DTIC. Treatment response was evaluated using RECIST v1.1; disease control was defined as complete/partial response and stable disease.

Results. Overall 111 focal CNAs were observed in the entire group of LMS, including 55 gains and 56 loses. Gain of 17q12 was the most common CNA (43/78 cases; 55.1%) observed in the entire group analyzed, with 26 samples showing high level amplification. MYOCD is a suggested target of 17q12 gains in LMS, encodes myocardin which induces smooth muscle differentiation and promotes cell migration. In the ERI-treated group, gains of 4q26, 20p12.2, 13q13.3, 8q22.2, 8q13.2 and loss of 1q44 had a negative impact on progression-free survival (PFS) (p&lt;0.05; log rank test), while loss of 2p12 was a positive prognosticator. Gains of 4q22.1 and losses of 3q14.2, 2q14.1 and 11q25 had a negative impact on OS in ERI-treated patients.

Using WES we detected an average of 266.1 (143-626) nonsynonymous substitutions and 4.7 indels (0-16) per sample, with an average of 11.5 (0-28) variants affecting Cancer Consensus Genes. The most commonly mutated genes in analyzed samples were TP53 (38%), MUC16 (31%) and ATRX (17%). In ERI-treated patients, the presence of ATRX mutations was more frequently observed in patients progressing on ERI (7/20 in patients with PD vs. 1/20 in group with disease control; p=0.0435). The presence of ATRX mutation had a negative impact on both PFS and OS. TP53 mutations were associated with longer PFS, and these mutations were more frequently observed in patients achieving disease control, although this was not statistically significant (11/20 vs. 5/20). ATRX andTP53 mutations were not linked with clinical benefit/response to DTIC.

Conclusions. LMS has a complex genetic background, with multiple CNAs and mutations affecting genes implicated in tumorigenesis. We identified several molecular changes with potential impact on disease control and survival of LMS patients treated with ERI. These observations require further prospective validation.

Citation Format: Agnieszka Wozniak, Bram Boecks, Elodie Modave, Amy Weaver, Diether Lambrechts, Bruce A. Littlefield, Patrick Schöffski. Potential molecular biomarkers of response to eribulin in patients with leiomyosarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4280.