(P 224) CO-MUTATION-DEPENDENT PROGNOSIS IN PATIENTS WITH ADVANCED SOFT TISSUE SARCOMA

Objective: To examine the impact of the most common genomic alterations TP53, CDKN2A, RB1, PTEN, and ATRX mutations on prognosis of advanced soft tissue sarcoma (STS).

Methods: This cohort included patients from Kaiser Permanente Northern California and Stanford Cancer Center with grade 2 or higher locally advanced and metastatic STS with next-generation sequencing performed. We used Cox regression modeling to examine the association between the individual mutations and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of systemic therapy, histology subtypes, and co-mutations.

Results: Of 602 total eligible patients, 28.9% had leiomyosarcoma (LMS), 22.6% had undifferentiated pleomorphic sarcoma (UPS), 13.0% had liposarcoma (LS), and 35.5% had other histology subtypes (Others). Among all patients, 49.7% had TP53 mutation (mutTP53), 23.1% had CDKN2A mutation (mutCDKN2A), 21.8% had RB1 mutation (mutRB1), 15.0% had ATRX mutation (mutATRX), and 9.5% had PTEN mutation (mutPTEN). Compared to LMS, OS of UPS and Others was worse (HR = 1.53, [95% CI 1.11-2.14] and HR = 1.52, [95% CI 1.10-2.10]) while OS of LS was similar (HR = 1.22, [95% CI .78-1.91]). MutPTEN was associated with worse OS compared to wild-type PTEN (wtPTEN, HR = 1.58, [95% CI 1.11 – 2.23]) and this association was preserved across different molecular subgroups. Worse OS with mutPTEN versus wtPTEN was much stronger in patients with wtTP53 (HR = 3.97, [95% CI 1.85 – 8.52]) and less strong in patients with mutTP53 (HR = 1.27, [95% CI .85 – 1.91]). Similarly, worse OS associated with mutCDKN2A versus wtCDKN2A was primarily driven by patients with wtTP53 (HR = 1.50, [95% CI 1.01 – 2.23]) but not patients with mutTP53 (HR = 1.00, [95% CI .60 – 1.60]). We also found that mutPTEN and mutRB1 appeared to be cooperative in driving adverse OS effect.

Conclusion: Prognosis of advanced STS appears to be histologic subtype and co-mutation-dependent. TP53 mutations appear to attenuate the adverse OS effect by mutPTEN and mutCDKN2A. Our results provide new insight that could be helpful for prognostic stratification in clinical practice and clinical trials and for understanding further the molecular mechanisms of STS.