Molecular Biomarkers of Response to Eribulin in Patients with Leiomyosarcoma
Autor: | Bruce A. Littlefield, Elodie Modave, Amy Weaver, Bram Boeckx, Diether Lambrechts, Agnieszka Wozniak, Patrick Schöffski |
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Rok vydání: | 2021 |
Předmět: |
Adult
Leiomyosarcoma Male 0301 basic medicine Oncology X-linked Nuclear Protein Cancer Research medicine.medical_specialty DNA Copy Number Variations Carcinogenesis Dacarbazine Liposarcoma medicine.disease_cause Disease-Free Survival 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Text mining Stable Disease Internal medicine Biomarkers Tumor medicine Humans Furans ATRX Aged Whole Genome Sequencing business.industry Membrane Proteins Ketones Middle Aged Prognosis medicine.disease 030104 developmental biology chemistry CA-125 Antigen 030220 oncology & carcinogenesis Female Tumor Suppressor Protein p53 business Chromosomes Human Pair 17 medicine.drug Eribulin |
Zdroj: | Clinical Cancer Research. 27:3106-3115 |
ISSN: | 1557-3265 1078-0432 |
Popis: | 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. |
Databáze: | OpenAIRE |
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