Uterine leiomyosarcoma progression: A study of serial recurrences

Uterine leiomyosarcomas (uLMS) have high recurrence rates and are frequently characterized by genetic alterations affecting TP53 and RB1. We sought to compare the molecular profiles of primary uLMS and matched serial recurrences to assess tumor evolution.

Patients diagnosed with uLMS between 1/1/2000-11/31/2020 who had primary tumor, ≥2 serial recurrences, and normal tissue available were identified. Samples were microdissected to enhance tumor purity and subjected to tumor-normal targeted DNA next-generation sequencing (NGS).

NGS was performed on 42 tumor samples from 10 patients. The median age at diagnosis was 54 years (range 30-69). The median number of recurrences was 3 (range 2-7). At least one homozygous deletion affecting RB1 (50 %), PTEN (30 %), TP53 (30 %), and/or BRCA2 (20 %), as well as clonal mutations affecting TP53 (30 %) and ATRX (10 %), were early events and present across subsequent samples of a given patient. In addition, non-pathogenic missense mutations were frequently shared across samples from a given case. In general, no additional cancer gene mutations were acquired during progression, including ESR1 hotspot mutations. Chromosomal instability was found to be significantly higher, albeit marginally so, in the recurrences compared to the patient-matched primary tumors (median fraction of genome altered 31 % v 29 %, p = 0.043).

Primary uLMS and subsequent recurrences display genomic intra-individual concordance, with sustained driver cancer gene alterations over time. Chromosomal instability was higher in recurrent tumors.