Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations inCTNNB1orAPC: A Multi-institutional Retrospective Study

Abstract

Purpose: Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments.Experimental Design: We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or nextgeneration sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), and overall survival (OS). Kaplan-Meier analysis and Cox proportional hazards regression were performed to identify differences in cPFS, rPFS, TTNT, and OS by mutation subtype, desmoid tumor location, and treatment regimen.Results: A total of 259 evaluable patients were analyzed for at least one of the survival outcomes, with 177 patients having mutation data. First-and second-line cPFS, rPFS, and TTNT were not significantly affected by mutation subtype; however, APCmutant desmoid tumors demonstrated nonstatistically significant inferior outcomes. Extremity/trunk desmoid tumor location and treatment with doxorubicin-based, methotrexate/vinca alkaloids and sorafenib regimens were associated with better clinical outcomes compared with surgery or "other" therapies, including estrogen-receptor blockade and imatinib. OS was significantly worse with APC or CTNNB1 negative/other mutations.Conclusions: Mutation subtype did not affect responses to specific systemic therapies. APC mutations and nonextremity desmoid tumor locations remain prognostic for worse outcomes, and earlier initiation of systemic therapy for these higher-risk desmoid tumors should be prospectively evaluated.

Bilateral breast desmoid-type fibromatosis, case report and literature review

“…Hence, it is possible to diagnose sporadic BDF with no evidence of CTNNB1 mutation ( 8 ). Finally, identifying mutations might be helpful in case of diagnostic doubt but mutation status does not predict systemic therapy responses ( 29 ).…”

Clinical results of active surveillance for extra‐abdominal desmoid‐type fibromatosis

“… 17 Contrarily, drug treatment with considerable side effects, including anticancer drugs and molecular targeted drugs, has been reported to control DF with any type of CTNNB1 mutation. 35 , 36 Altogether, DF that cannot be controlled by AS can be suppressed by anticancer drugs or molecular target drugs even if it is S45F. Tumor diameter, gender, recurrent cases, limb location, and juvenile development have been reported as risk factors for recurrence regarding surgery.…”

“…The CTNNB1 S45F mutation has been previously reported as a risk factor for recurrence after surgical treatment 5,32–34 and associated with tumor progression in patients with oral COX‐2 inhibitor treatment 17 . Contrarily, drug treatment with considerable side effects, including anticancer drugs and molecular targeted drugs, has been reported to control DF with any type of CTNNB1 mutation 35,36 . Altogether, DF that cannot be controlled by AS can be suppressed by anticancer drugs or molecular target drugs even if it is S45F.…”

Biclonal Desmoid-Type Fibromatosis With Two Beta-Catenin Mutations: Evidence for the Recruitment of Normal Myofibroblasts

“…Thus, most studies have suggested that DTF with a p.S45F mutation is more clinically aggressive. A recent large retrospective multi-institutional study found no significant impact of mutation subtype on the efficacy of chemotherapy or tyrosine kinase inhibitors, although there was a trend toward worse outcomes with an APC mutation [ 26 ].…”