title: Durable Response of Spinal Chordoma to Combined Inhibition of IGF-1R and EGFR.
abstract: Chordomas are rare primary malignant bone tumors arising from embryonal notochord remnants of the axial skeleton. Chordomas commonly recur following surgery and radiotherapy, and there is no effective systemic therapy. Previous studies implicated receptor tyrosine kinases, including epidermal growth factor receptor (EGFR) and type 1 insulin-like growth factor receptor (IGF-1R), in chordoma biology. We report an adult female patient who presented in 2003 with spinal chordoma, treated with surgery and radiotherapy. She underwent further surgery for recurrent chordoma in 2008, with subsequent progression in pelvic deposits. In June 2009, she was recruited onto the Phase I OSI-906-103 trial of EGFR inhibitor erlotinib with linsitinib, a novel inhibitor of IGF-1R/insulin receptor (INSR). Treatment with 100 mg QD erlotinib and 50 mg QD linsitinib was well-tolerated, and after 18 months a partial response was achieved by RECIST criteria. From 43 months, a protocol modification allowed intra-patient linsitinib dose escalation to 50 mg BID. The patient remained stable on trial treatment for a total of 5 years, discontinuing treatment in August 2014. She subsequently experienced further disease progression for which she underwent pelvic surgery in April 2015. Analysis of DNA extracted from 2008 (pre-trial) tissue showed that the tumor harbored wild-type EGFR, and a PIK3CA mutation was detected in plasma, but not tumor DNA. The 2015 (post-trial) tumor harbored a mutation of uncertain significance in ATM, with no detectable mutations in other components of a 50 gene panel, including EGFR, PIK3CA, and TP53. By immunohistochemistry, the tumor was positive for brachyury, the molecular hallmark of chordoma, and showed weak-moderate membrane and cytoplasmic EGFR. IGF-1R was detected in the plasma membrane and cytoplasm and was expressed more strongly in recurrent tumor than the primary. We also noted heterogeneous nuclear IGF-1R, which has been linked with sensitivity to IGF-1R inhibition. Similar variation in IGF-1R expression and subcellular localization was noted in 15 further cases of chordoma. In summary, this exceptionally durable response suggests that there may be merit in evaluating combined IGF-1R/INSR and EGFR inhibition in patients with chordomas that recur following failure of local treatment.
authors.affiliation: Department of Oncology, Old Road Campus Research Building , Oxford , UK.
authors.forename: Tamara
authors.initials: T
authors.lastname: Aleksic
authors.affiliation: Department of Cellular Pathology, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford , UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Browning
authors.affiliation: Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford , UK.
authors.forename: Martha
authors.initials: M
authors.lastname: Woodward
authors.affiliation: Department of Radiology, Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford , UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Phillips
authors.affiliation: BRC Oxford Molecular Diagnostic Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford , UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Page
authors.affiliation: BRC Oxford Molecular Diagnostic Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford , UK.
authors.forename: Shirley
authors.initials: S
authors.lastname: Henderson
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, Nuffield Orthopaedic Centre , Oxford , UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Athanasou
authors.affiliation: Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital , Oxford , UK.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, Nuffield Orthopaedic Centre , Oxford , UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Whitwell
authors.affiliation: Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford , UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pratap
authors.affiliation: Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford , UK.
authors.forename: A Bassim
authors.initials: AB
authors.lastname: Hassan
authors.affiliation: Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford , UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: Department of Oncology, Old Road Campus Research Building, Oxford, UK; Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Valentine M
authors.initials: VM
authors.lastname: Macaulay
keywords: EGFR; IGF-1R; chordoma; nuclear IGF-1R; tyrosine kinase inhibitor