EP1676 - ECE_1686 - Predictive molecular biomarkers in aggressive Pituitary Tumors

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Abstract Aggressive behavior in pituitary tumors is characterized by rapid growth or progression despite standard treatments, including surgery, radiotherapy (RT), and medical therapies. Within this subset of tumors, there is heterogeneity in clinical behavior with limited predictive biomarkers. To identify prognostic biomarkers, we performed next-generation sequencing of tumor and a matched normal sample from 38 patients with aggressive pituitary tumors, comprised of 18 (47.4%) metastatic and 20 (52.6%) non-metastatic tumors, on a sequencing protocol. We then correlated genetic profile with clinical behavior, including progression-free survival (PFS), defined as the time from the first progression after RT until the time of next progression, which was available for 34 of 38 patients. A pathogenic or likely pathogenic mutation in TP53, ATRX, DAXX, or SF3B1 was identified in 52.9% of metastatic and 60.0% of locally aggressive tumors (P = .746) and was associated with shorter PFS (median 10.3 (n = 20) vs 25 (n = 13) months; P = .015). In contrast, the presence of a USP8 mutation in corticotroph tumors (14.3%) was associated with a longer PFS (150.0 (n = 3) vs 14.0 (n = 16) months; P = .026). Among the corticotroph tumors (n = 21), recurrent chromosomal loss of heterozygosity (defined as loss of ≥10 of the following chromosomes: 1, 2, 3, 4, 6, 10, 11, 15, 17, 18, 21, and 22) was identified in 80% of cases and was associated with shorter PFS (11.8 (n = 14) vs 150 (n = 5) months; P = .015). Cell-cycle pathway alterations (CCND1/2/3 amplification, CDK4/6 amplification, CDKN2A/B/C loss, RB1 loss) were identified in at least one tumor sample in 24.3% of the cohort in both corticotroph tumors and those within the PIT1 lineage. These alterations were frequently subclonal and associated with metastatic dissemination (47.1% metastatic cohort vs 5.0% locally aggressive cohort; OR = 15.6; P = .006). Given that cell cycle alterations drive tumor progression, we interrogated our cohort for patients treated with a CDK4/6 inhibitor. Of the 4 patients treated with an inhibitor, tumor stabilization was achieved in 2 patients for 12 and 24 months. This study demonstrates the utility of genetic profiling pituitary tumors for clinical decision making; sequential tumor sampling may be valuable for detecting acquired mutations of prognostic importance.

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