Jessica E Maxwell1, Maria K Gule-Monroe2, Vivek Subbiah3, Mimi Hu4, Nancy D Perrier1, Maria E Cabanillas4, Jeffery E Lee1, Paul H Graham1, Gilbert J Cote4, Naifa L Busaidy4, Elizabeth G Grubbs5. 1. Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX. 2. Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX. 3. Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX. 4. Department of Endocrine Neoplasia and Hormonal Disorders University of Texas MD Anderson Cancer Center, Houston, TX. 5. Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: eggrubbs@mdanderson.org.
Abstract
BACKGROUND: The cyclin-dependent-kinase inhibitor/retinoblastoma pathway has been implicated in sporadic medullary thyroid carcinoma tumorigenesis. Somatic CDKN2C loss has been associated with decreased overall survival in medullary thyroid carcinoma patients. We evaluated CDKN2C loss in a prospective clinical environment using a novel Clinical Laboratory Improvement Amendments-certified assay to confirm its association with aggressive disease and to interrogate response to targeted therapy. METHODS: Patients with advanced sporadic medullary thyroid carcinoma underwent tumor genotyping for the purpose of management of targeted therapy and prognostication. RESULTS: Of patients with informative CDKN2C assay results, 30 (51.8%) were haploinsufficient/1N and 28 (48.3%) were 2N. Forty patients (69.0%) had a somatic RET mutation, and 36.9% had alterations of both genes. Thirty patients (51.7%) were treated with systemic therapy. Presence of genetic alterations in CDKN2C or RET did not predict treatment response. Patients with 1N CDKN2C loss had significantly shorter time-to-distant-metastasis than patients with normal copy number (P = .03). CONCLUSION: This is the first evaluation in the clinical setting of CDKN2C haploinsufficiency in sporadic medullary thyroid carcinoma. Although a larger cohort and longer follow-up will be required, loss seems to be associated with more aggressive disease and may indicate patients that might receive benefit from treatment with a CDK inhibitor.
BACKGROUND: The cyclin-dependent-kinase inhibitor/retinoblastoma pathway has been implicated in sporadic medullary thyroid carcinoma tumorigenesis. Somatic CDKN2C loss has been associated with decreased overall survival in medullary thyroid carcinomapatients. We evaluated CDKN2C loss in a prospective clinical environment using a novel Clinical Laboratory Improvement Amendments-certified assay to confirm its association with aggressive disease and to interrogate response to targeted therapy. METHODS:Patients with advanced sporadic medullary thyroid carcinoma underwent tumor genotyping for the purpose of management of targeted therapy and prognostication. RESULTS: Of patients with informative CDKN2C assay results, 30 (51.8%) were haploinsufficient/1N and 28 (48.3%) were 2N. Forty patients (69.0%) had a somatic RET mutation, and 36.9% had alterations of both genes. Thirty patients (51.7%) were treated with systemic therapy. Presence of genetic alterations in CDKN2C or RET did not predict treatment response. Patients with 1N CDKN2C loss had significantly shorter time-to-distant-metastasis than patients with normal copy number (P = .03). CONCLUSION: This is the first evaluation in the clinical setting of CDKN2Chaploinsufficiency in sporadic medullary thyroid carcinoma. Although a larger cohort and longer follow-up will be required, loss seems to be associated with more aggressive disease and may indicate patients that might receive benefit from treatment with a CDK inhibitor.
Authors: María San Román Gil; Javier Pozas; Javier Molina-Cerrillo; Joaquín Gómez; Héctor Pian; Miguel Pozas; Alfredo Carrato; Enrique Grande; Teresa Alonso-Gordoa Journal: Int J Mol Sci Date: 2020-07-13 Impact factor: 5.923