Overview

Rare slow-growing malignant bone tumor from notochordal remnants. Occurs along axial skeleton: sacrum (50%), skull base/clivus (35%), mobile spine (15%). Peak age 50-60 years. Locally aggressive with high recurrence. En bloc resection with negative margins critical but technically challenging. Proton beam or carbon ion radiotherapy preferred. Chemotherapy limited efficacy. Brachyury (T) transcription factor is hallmark. Targeted therapies under investigation.

Clinical Management: Treatment individualized based on stage, histology, molecular profile, and patient factors. Multidisciplinary tumor board review recommended. Refer to NCCN guidelines and FDA package inserts for complete dosing and administration.

Epidemiology & Impact

Chordoma is an extremely rare primary bone tumor arising from embryonic notochord remnants, with an incidence of approximately 0.08 per 100,000 people annually — fewer than 400 new cases per year in the United States. The tumor occurs exclusively along the axial skeleton, with approximately 30% arising in the skull base (clivus), 20% in the mobile spine, and 50% in the sacrococcygeal region. Chordoma has a male predominance (approximately 2:1) and typically presents in the fifth to seventh decades of life, though a rare dedifferentiated variant occurs in younger patients. Despite being classified as low-grade, chordomas are locally aggressive and have a high propensity for local recurrence (50-60% at 5 years). Metastatic disease develops in approximately 20-40% of patients, typically late in the disease course. Median overall survival is approximately 7 years, though the clinical course is variable.

Molecular Biology & Biomarkers

The molecular biology of chordoma is characterized by near-universal expression of the transcription factor brachyury (encoded by the TBXT gene), which is both a diagnostic biomarker and a potential therapeutic target. Duplication of the TBXT locus at 6q27 represents a susceptibility allele, and somatic TBXT amplification is common. Chordomas generally have a quiet genomic landscape with low mutational burden, but recurrent alterations include CDKN2A/B homozygous deletion (approximately 20-40%), PBRM1 and SMARCB1 loss (particularly in poorly differentiated chordoma), and PI3K/AKT/mTOR pathway activation. Poorly differentiated chordoma, characterized by complete loss of SMARCB1 (INI1), is a distinct aggressive variant more common in children. The relative genomic stability and lack of high-frequency actionable mutations has made targeted therapy development challenging, though EGFR and PDGFR expression have been exploited therapeutically.

Evolving Treatment Landscape

Surgery with maximal safe en bloc resection remains the cornerstone of chordoma management, as completeness of resection is the strongest predictor of local control. Radiation therapy, particularly proton beam therapy or carbon ion therapy, plays a critical adjuvant role due to the ability to deliver high doses to the tumor bed while sparing adjacent critical structures. There are no FDA-approved systemic therapies specifically for chordoma, representing a major unmet need. Off-label use of EGFR inhibitors (lapatinib, erlotinib), mTOR inhibitors (rapamycin), and PDGFR inhibitors (imatinib) has shown modest activity in individual patients and small series. Immunotherapy has limited evidence in chordoma, likely due to the low mutational burden and immunosuppressive microenvironment. Brachyury-directed therapeutic vaccines and novel combination approaches are under investigation in clinical trials, and the Chordoma Foundation has played a pivotal role in coordinating research efforts for this rare disease.

Approved Chordoma Therapies

Note: There are no FDA-approved drugs specifically indicated for chordoma. Treatment is primarily surgical resection with radiation therapy (proton beam or carbon ion). Off-label use of imatinib (for PDGFR-positive tumors), erlotinib, and immunotherapy has been reported. Pembrolizumab may be available via the TMB-H tumor-agnostic indication for eligible patients.