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Molecular Biomarkers of Response to Eribulin in Patients with Leiomyosarcoma
Agnieszka Wozniak1, Bram Boeckx2, Elodie Modave2
1Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. agnieszka.wozniak@kuleuven.be.
Purpose:
A randomized phase III study evaluated the efficacy of eribulin versus dacarbazine in patients with advanced liposarcoma and leiomyosarcoma. Improved overall survival (OS) led to approval of eribulin for liposarcoma, but not for leiomyosarcoma.
Experimental Design:
We explored the molecular profile of 77 archival leiomyosarcoma samples from this trial to identify potential predictive biomarkers, utilizing low-coverage whole-genome and whole-exome sequencing. Tumor molecular profiles were correlated with clinical data, and disease control was defined as complete/partial response or stable disease (RECIST v1.1).
Results:
Overall, 111 focal copy-number alterations were observed in leiomyosarcoma. Gain of chromosome 17q12 was the most common event, present in 43 of 77 cases (56%). In the eribulin-treated group, gains of 4q26, 20p12.2, 13q13.3, 8q22.2, and 8q13.2 and loss of 1q44 had a negative impact on progression-free survival (PFS), while loss of 2p12 correlated with better prognosis. Gains of 4q22.1 and losses of 3q14.2, 2q14.1, and 11q25 had a negative impact on OS in patients with leiomyosarcoma receiving eribulin. The most commonly mutated genes were TP53 (38%), MUC16 (32%), and ATRX (17%). The presence of ATRX mutations had a negative impact on PFS in both treatment arms; however, the correlation with worse OS was observed only in the eribulin-treated patients. TP53 mutations were associated with longer PFS on eribulin.
Conclusions:
Leiomyosarcoma has a complex genetic background, with multiple copy-number alterations and mutations affecting genes implicated in tumorigenesis. We identified several molecular changes with potential impact on survival of patients with leiomyosarcoma when treated with eribulin.
Insights
Molecular profiling of leiomyosarcoma revealed genetic alterations impacting survival. Specific copy-number changes and mutations in TP53 and ATRX influenced progression-free survival and overall survival in patients treated with eribulin.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Eribulin demonstrated improved overall survival (OS) in liposarcoma but not leiomyosarcoma in a phase III trial.
- Leiomyosarcoma exhibits a complex genetic landscape, necessitating the identification of predictive biomarkers for targeted therapies.
Purpose of the Study:
- To investigate the molecular profile of leiomyosarcoma samples from a phase III trial.
- To identify potential predictive biomarkers for eribulin efficacy in leiomyosarcoma patients.
Main Methods:
- Analysis of 77 archival leiomyosarcoma samples using low-coverage whole-genome and whole-exome sequencing.
- Correlation of tumor molecular profiles (copy-number alterations and gene mutations) with clinical outcomes, including progression-free survival (PFS) and OS.
Main Results:
- Identified 111 focal copy-number alterations, with 17q12 gain being the most frequent (56%).
- Specific copy-number gains (e.g., 4q26) and losses (e.g., 1q44) impacted PFS and OS in eribulin-treated patients.
- Common mutations included TP53 (38%), MUC16 (32%), and ATRX (17%). ATRX mutations correlated with worse PFS, while TP53 mutations were associated with longer PFS on eribulin.
Conclusions:
- Leiomyosarcoma harbors a complex genetic background with significant copy-number alterations and mutations.
- Identified molecular alterations, including specific gene mutations and copy-number changes, that may predict treatment response and survival in leiomyosarcoma patients receiving eribulin.
