Antonescu, Cristina R.

Soft tissue tumors with GLI1 gene fusions or amplifications have been recently described as a unique pathologic entity with an established risk of malignancy. We herein expand these findings by investigating a cohort of 11 head and neck lesions with GLI1 alterations, including 8 from the tongue, for their clinicopathologic and molecular features. The tumors commonly affected males in their 30s (male:female ratio 2.7:1; range: 1 to 65). Tumors showed a multinodular growth pattern, nested architecture separated by a delicate, arborizing vascular network, monotonous round to ovoid nuclei, and clear cytoplasm. Tumor protrusion into vascular spaces was common. Genetic alterations were investigated by fluorescence in situ hybridization and/or targeted RNA sequencing. Seven tumors harbored GLI1 fusions with the following partners: ACTB (n=4), PTCH1 (n=2), or MALAT1 (n=1). The remaining 4 cases showed coamplifications of GLI1 with CDK4 and MDM2 genes. Tumors were commonly positive for S100 protein and CD56. CDK4, MDM2, and STAT6 were positive in GLI1 -amplified tumors. Two of 6 patients with available follow-up (1 each with GLI1 amplification and PTCH1-GLI1 fusion) developed distant metastases. Both tumors showed a high mitotic index and tumor necrosis. The head and neck region, particularly tongue, is a common location for GLI1 -related mesenchymal tumors. Although a morphologic overlap was noted with the previously reported “pericytoma with t(7,12) translocation,” often occurring in the tongue, our findings expand the original findings, to include a more variable immunophenotype, propensity for late distant metastases, and alternative mechanisms of GLI1 oncogenic activation, such as various GLI1 fusion partners or GLI1 coamplifications with MDM2 and CDK4 genes.

11007 Background: Patients (pts) with metastatic sarcoma (SAR) have limited options. Nivolumab(N), a fully human anti-PD-1 mAb and ipilimumab (I), a humanized anti-CTLA-4 mAb, have favorable safety & efficacy in other tumors. Pembrolizumab demonstrated a response rate (RR) of 12% in SAR pts. We evaluated N, independently from N+I, in SAR pts. Methods: This open-label multi-center phase II study enrolled pts failing prior regimens. Randomized (non-comparative) pts received either N3 [N (3 mg/kg q2W)] or N3+I1 [N(3 mg/kg Q3W x4, then Q2W) & [I(1 mg/kg q3W x4)]. Treatment continued beyond progressive disease (PD) in 1st12 weeks. 5 confirmed responses in 38 evaluable pts yielded 90% power (0.05 1-sided alpha) to detect a 20% (vs 5%) confirmed RR. Other endpoints: adverse events (AEs), progression-free, overall survival (PFS, OS), and correlative studies including PD-L1 expression by IHC, mutational burden/neoantigen analysis, TCR clonality and TIL characterization. Results: 85 pts (43 - N3; 42 - N3+I1) were enrolled [mean age 54 yrs (21–81), 52% female). No significant differences in histological subtypes across cohorts: 36% LMS, 4% LPS, 10% UPS/MFH, 6% synovial, 5% bone, 5% Ewing’s, and 34% other. Pts were refractory to 1(20%), 2(22%), and ≥3 (58%) regimens. Grade 3-4 treatment related adverse events (TRAE) occurred in 7% (N3) and 14% (N3+I1) and 0 Gr 5 TRAEs. 8% of pts stopped due to AEs (2% N3, 14% N3+I1). 2/3 confirmed responses on N3, with 2 ongoing (range 1.1-3.2 months). 6/7 confirmed responses (2 complete) on N3+N1, with 5 ongoing (range 6-13 months). Responses occurred in 7 histologies. See Table for pt outcomes. Conclusions: N + I showed acceptable safety and encouraging antitumor activity with most responses ongoing across multiple SAR histologies, passing efficacy criteria. There was minimal activity observed with N alone. Increased TRAEs were observed in N3+I1. Correlative analyses ongoing. NCT02500797. Support: U10CA180821, U10CA180882, Conquer Cancer Foundation, BMS. Clinical trial information: NCT02500797. [Table: see text]

Purpose The ACOSOG (American College of Surgeons Oncology Group) Z9001 (Alliance) study, a randomized, placebo-controlled trial, demonstrated that 1 year of adjuvant imatinib prolonged recurrence-free survival (RFS) after resection of primary GI stromal tumor (GIST). We sought to determine the pathologic and molecular factors associated with patient outcome. Patients and Methods There were 328 patients assigned to the placebo arm and 317 to the imatinib arm. Median patient follow-up was 74 months. There were 645 tumor specimens available for mitotic rate or mutation analysis. Results RFS remained superior in the imatinib arm (hazard ratio, 0.6; 95% CI, 0.43 to 0.75; Cox model–adjusted P < .001). On multivariable analysis of patients in the placebo arm, large tumor size, small bowel location, and high mitotic rate were associated with lower RFS, whereas tumor genotype was not significantly associated with RFS. Multivariable analysis of patients in the imatinib arm yielded similar findings. When comparing the two arms, imatinib therapy was associated with higher RFS in patients with a KIT exon 11 deletion of any type, but not a KIT exon 11 insertion or point mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor, although some of these patient groups were small. Adjuvant imatinib did not seem to alter overall survival. Conclusion Our findings show that tumor size, location, and mitotic rate, but not tumor genotype, are associated with the natural history of GIST. Patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer RFS.