Clival chordoma molecular subtypes and clinical behavior

Abstract

10538 Background: Chordoma is a primary bone cancer of the axial skeleton with predilection for local invasion. Primary treatment modalities consist of surgery and radiation therapy with limited role for chemotherapy. Because patients with chordoma exhibit heterogeneous clinical history and response to therapy, we investigated potential markers predictive of clinical behavior. Methods: This study analyzed 35 clival chordoma specimens with documented immunohistochemistry (IHC) staining for Ki-67 proliferation index from 29 patients. Detailed additional pathologic studies were performed prospectively on 12 consecutive patients. This consisted of the following: IHC for brachyury, cytokeratin, p53, and epidermal growth factor receptor (EGFR); fluorescent in situ hybridization (FISH) analysis for EGFR amplification and presence of 1p36, 9p21, and 19q13 loci; polymerase chain reaction based loss of heterozygosity analysis (LOH) of 1p, 9p, 10q, 17p, and 19p loci. Results: All confirmed chordoma specimens were positive for brachyury and negative for amplification of EGFR. Increase in Ki-67 index was associated with recurrence in 5 of 6 cases. Out of the 12 patients with detailed molecular pathologic studies, 5 had loss of 1p, 2 had deletion of 9p21 (p16), and 2 had loss of 10q (PTEN). The loss of 1p and 9p were detected via both FISH and LOH analyses. 3 of the 12 patients’ tumor specimens showed a Ki-67 index of greater than 10%; the remaining specimens were less than 5%. All 3 patients with high Ki-67 index had loss of either 9p (p16) or 10q (PTEN). The tumor specimen from these 3 patients also exhibited enhanced in vitro propagation. Conclusions: Subtyping of clival chordomas based on molecular phenotype may provide prognostic information. The prospective nature of this study in concert with assessment of residual disease after surgery may allow for identification of distinct subpopulations of patients at greater risk of disease recurrence for consideration of adjuvant therapy. The correlative in vitro study will provide an opportunity to evaluate targeted therapies customized to individual molecular subgroups. No significant financial relationships to disclose.