Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations in CTNNB1 or APC: A Multi-institutional Retrospective Study.

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 next-generation 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, APC-mutant 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. See related commentary by Greene and Van Tine, p. 3911.

Guillain-Barre syndrome observed with adoptive transfer of lymphocytes genetically engineered with an NY-ESO-1 reactive T-cell receptor.

BACKGROUND: Adoptive transfer of autologous T-lymphocytes transduced with a high affinity NY-ESO-1-reactive T-cell receptor (NY-ESO-1c259 T-cells) has emerged as a promising therapeutic strategy for patients with refractory synovial sarcoma. Secondary autoimmune T-cell mediated toxicities can occur long after initial adoptive T-cell transfer. We report on the first two cases of the development and management of Guillain-Barre syndrome in synovial sarcoma patients who received NY-ESO-1c259 T-cells. CASE PRESENTATION: A 47 year-old woman and 39 year-old woman with refractory metastatic SS were treated with fludarabine-cyclophosphamide lymphodepletion followed by adoptive transfer of NY-ESO-1c259 T-cells. On day 42 after adoptive T-cell therapy, patient one presented to the emergency room with a one-week history of numbness, paresthesia, and heaviness to both legs progressing to difficulty walking on the day of presentation. Although MRI brain and lumbar puncture were negative, electromyography (EMG) and nerve conduction studies (NCS) of the lower extremities and right arm performed revealed an abnormal study suggestive of a very mild, distal, motor, axonal polyneuropathy. Patient two presented on day 113 with bilateral foot numbness, left foot drop, unsteady gait, and pain in the left thigh, which progressed over two week to bilateral leg weakness, inability to walk, and numbness bilaterally in the hands, legs, and feet. Both patients received intravenous immunoglobulin (IVIG) 0.4 g/kg/day for 5 days for possible acute inflammatory demyelinating polyneuropathy (AIDP) likely related to NY-ESO-1 targeting T-cell therapy. After 3 and 5 doses, respectively, of IVIG, the patients reported improvement in symptoms and strength, and were later transferred to an inpatient rehabilitation facility to continue gaining strength. At patient one's neurology follow-up on day 95, she reported only mild left lower extremity (LLE) weakness and was gradually successfully regaining independence in motor function. At patient two's 9-month follow-up, the patient had regained normal function and independence. CONCLUSIONS: Given the expanding applications of immunotherapy in cancer management, clinicians should stay vigilant against the potential development of unusual but life-threatening immune-mediated toxicities.