Clinical implications of recurring mutations in myxoid liposarcoma (MLS).
Authors: Thirasastr Prapassorn , Lin Heather Y. , Nassif Elise F , Wang Wei-Lien , Araujo Dejka M. , Benjamin Robert S. , Conley Anthony Paul , Livingston J Andrew Andrew , Ludwig Joseph Aloysius , Patel Shreyaskumar , Ratan Ravin , Ravi Vinod , Zarzour Maria Alejandra , Zhou Xiao , Somaiah Neeta 
Published: June 2023

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Background: MLS is a subset of liposarcoma characterized by a translocation, (t(12;16), FUS-DDIT3 or less frequently t(12;22), EWSR1-DDIT3). Additional mutations have been reported in TERT promotor, PIK3CA, and PTEN and some were associated with the more aggressive round cell phenotype. Our study aimed at analyzing the clinical significance of these recurring mutations. Methods: MLS patients (pt) with available next-generation sequencing (NGS) data (any clinical grade) between Jan 2014 to Oct 2022 were included. Baseline characteristics, chemotherapy (CMT) response (partial response [PR] and stable disease [SD]), and survival were collected for doxorubicin-ifosfamide (AI), doxorubicin-dacarbazine (ADIC), trabectedin (T), and eribulin (E). Binary logistic regression was used to evaluate mutations associated with response. Cox proportional-hazard regression was used to investigate associations of variables with progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method was used to estimate survival and log-rank tests were used to compare survival between groups. Results: Of 18 MLS pt included, median age at diagnosis was 42 years (R 30-65). Majority were male (12/18, 67%), had localized disease at diagnosis (13/18, 72%), and had lower extremities as primary location (10/18, 56%). Eight (44%) had round-cell > 5% and 15 (83%) had primary tumor > 5 cm. Somatic mutations were reported in 15 pt (83%); the most common were TERT promotor (61%), PTEN (28%), PIK3CA (22%), and TP53 (17%). None showed significant association with clinical factors (age, sex, size, stage, round cell > 5%, primary location). Forty-eight records (18 AI, 6 ADIC, 19 T, and 5 E; 3 pt received AI and T twice for different recurrences), were evaluated for PFS and 47 records had response data available. For AI, ADIC, T, and E, PR rate was 39% (7/18), 17% (1/6), 32% (6/19), and 40% (2/5), while clinical benefit (CBR: PR + SD≥ 3 mo) was 67% (12/18), 50% (3/6), 63% (12/19), and 80% (4/5), respectively. PR or CBR were not associated with the common mutations for any regimen. Median follow up (FU) from start of CMT was 4 mo (R 0.5-31). PFS (95%CI) was 11 (6.7- Not Reached [NR]), 1.2 (1.1-NR), 23 (6.3-NR), and 8 (1.3-NR) mo for AI, ADIC, T, and E, respectively. PIK3CAm (n = 15) was associated with improved PFS with CMT (PFS [95%CI]: PIK3CAwt 7.8 [6.3-11.2] vs. PIK3CAm 23 mo [1.3-NR]; multivariate hazard ratio [HR] 0.23, p= 0.036, adjusted by gender and ADIC regimen). This appeared to be mainly driven by the PIK3CAm/ TERTwt (n = 8, HR 0.07, p= 0.006). For T, PIK3CAm/ TERTm (n = 3) showed a trend for lower PFS (1.3 mo) in contrast to other groups (23 mo). Conclusions: TERT promoter mutation was the most frequent mutation but was not associated with outcome in our small series. PIK3CAm suggested PFS benefit from CMT while, on the contrary, dual PIK3CAm/ TERTm showed a trend towards shorter PFS with T. The predictive and prognostic role of these mutations in MLS warrant further study.