MNGI-31. pFOXM1 PROTEIN EXPRESSION IN WHO GRADE III MENINGIOMAS CORRELATES WITH CDK4/6 GENOTYPE AND TRANSFORMATION HISTORY. (5th November 2018) - Mooney, Michael
Abstract: BACKGROUND: World Health Organization (WHO) Grade III meningiomas are associated with poor clinical outcomes due to high rates of recurrence and limited adjuvant treatment options. The Forkhead Box M1 (FOXM1) transcription factor is a phosphorylation target of CDK4/6 that protects cancer cells from senescence and is upregulated in Grade III meningiomas. We sought to investigate FOXM1 and phosphorylated FOXM1 (pFOXM1) expression in WHO Grade III meningiomas in relation to proliferative index, CDK4/6 cytogenetic profile, and clinical history. METHODS: We examined 38 tissue specimens from 27 patients with Grade III meningiomas. CDK4, CDK6, and CDKN2A cytogenetic profiles were studied using fluorescence in situ hybridization. FOXM1 and pFOXM1 were identified with immunohistochemistry and quantified using imaging analysis software. RESULTS: pFOXM1 nuclear staining (positive nuclei/mm2) correlated with tumor proliferative index in Grade III meningiomas (mitotic rate > 20, 115.5 vs. mitotic rate < 20, 34.7, P=0.02). Cytogenetic loss of CDK4/6 was associated with significantly decreased pFOXM1 staining (30.8 vs. 111.1, P=0.017). No significant differences in FOXM1 or pFOXM1 staining were observed with gain/amplification of CDK4/6 or with loss of CDKN2A. Grade I/II meningiomas that transformed to Grade III were accompanied by an increase in pFOXM1 staining compared to their de novo counterparts (138.3 vs. 45.9, P < 0.05). CONCLUSIONS: pFOXM1 expression correlated with tumor proliferative rate, CDK4/6 cytogenetic status, and prior Grade I/II meningiomas, suggesting a role of FOXM1 signaling in the transformation of lower-grade meningiomas to Grade III lesions. These findings support the potential role for selective CDK4/6 inhibitors as an adjuvant therapy for Grade III meningiomas.