ECE2024 Oral Communications Oral Communications 9: Pituitary and Neuroendocrinology | Part II (6 abstracts)
Loss of heterozygosity predicts treatment-refractory behavior in pituitary neuroendocrine tumors
Andrew Lin 1 , Vasilisa Rudneva 1 , Allison Richards 1 , Yanming Zhang 2 , Marc Rosenblum 1 , Mark Donoghue 1 , Viviane Tabar 1 & Eliza Geer 1
1Memorial Sloan Kettering Cancer Center New York, New York, United States; 2Memorial Sloan Kettering Cancer Center New York, Department of Pathology and Laboratory Medicine, New York, United States
Background: Pituitary neuroendocrine tumors (PitNETs) exhibiting treatment-refractory behavior are the rare subset that progress after radiation and are characterized by unrelenting growth and metastatic dissemination.
Methods: To identify biomarkers of treatment-refractory behavior, two groups of patients with PitNETs were consented to matched tumor-normal whole exome and targeted next-generation DNA sequencing on a clinical protocol: a prospective group (n=66) that was enrolled prior to surgery and a retrospective group (n=26) comprised of aggressive PitNETs.
Results: Across the cohort, treatment-refractory behavior, defined by progression following standard treatments including radiation, was associated with a higher mutational burden, P=1.3×10-10 . Common genetic alterations in the treatment-refractory corticotroph PitNETs include mutations in TP53, ATRX, DAXX, and potentially targetable mutations in TSC2 and mismatch repair genes (MSH2, MSH6, and MLH1 with corresponding loss of protein expression on mismatch repair immunohistochemistry); only TP53 was recurrently mutated in treatment-refractory lactotroph tumors. Treatment-refractory behavior was associated with increased fraction of loss of heterozygosity (LOH), P=8.5×10-9, and a higher fraction of LOH was associated with TP53 mutations, P=3.3×10-8 . Within the corticotroph lineage, treatment-refractoriness correlated with a characteristic pattern of recurrent chromosomal LOH, P=1.7×10-4 . A machine learning approach confirmed that LOH is the most predictive variable tested for treatment-refractory behavior, outperforming the most common gene-level alteration. A fraction of LOH-based classifier identified treatment-refractory behavior with an accuracy of 0.88 (95% CI:0.70-0.96), sensitivity of 0.83, and specficity of 0.90.
Conclusion: Treatment-refractory PitNETs are genomically distinct from their benign counterparts; LOH predicts treatment-refractory behavior with high sensitivity and specificity.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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