Unexplored targets in myeloid neoplasms: Investigating potential areas of clinical actionability using a comprehensive genomic database.

Abstract

e23269 Background: Mutations like EZH2, BRAF, KRAS, EGFR and others have been widely studied in lymphoid and solid malignancies where they are implicated in tumorigenesis and serve as therapeutic targets. However, the prevalence, characteristics, and clinical impact of these mutations in myeloid Neoplasms (MNs) remain underexplored. This study aims to assess the prevalence of these mutations in a cohort of MNs, providing a foundation for future research to explore their potential as therapeutic targets. Methods: We conducted a descriptive study using data from the AACR GENIE v17.0 (cBioPortal) on patients with MNs, including AML, MDS, and MPNs, excluding subtypes with fewer than 10 cases. The analysis was limited to a single distinct sample per patient to avoid duplication. Mutations were categorized as driver or Variant of Unknown Significance (VUS). Results: Among 7122 patients with MNs, 4644 unique patient samples were identified. Mutation frequencies were as follows (see Table): NRAS mutations in 384 cases (8.3%) with 426 total mutations (411 driver, 15 VUS); EZH2 mutations in 197 cases (4.3%) with 237 total mutations (104 driver, 133 VUS); KRAS mutations in 182 cases (3.9%) with 192 total mutations (186 driver, 6 VUS); NF1 mutations in 62 cases (2.8%) with 83 total mutations ( 56 driver, 27 VUS); BRCA2 mutations in 33 cases (1.5%) with 34 total mutations (3 driver, 31 VUS); BRAF mutations in 24 cases (0.5%) with 25 total mutations (21 driver, 4 VUS); ROS1 mutations in 23 cases (1%) with 25 total mutations, all VUS; EGFR mutations in 13 cases (0.5%) with 13 total mutations (2 driver, 11 VUS); NTRK1 mutations in 12 cases (0.5%) with 13 total mutations, all VUS; and RET mutations in 11 cases (0.4%) with 11 total mutations (1 driver, 10 VUS). Among significant mutations ( > 1.5% frequency), most were somatic, except for NF1 and BRCA2, with somatic mutation frequencies of 1.3% and 0.7%, respectively. Conclusions: Our findings identify actionable mutations in MNs (KRAS, EZH2, NF1, BRAF) with FDA-approved targeted therapies (e.g. sotorasib, tazemetostat, selumetinib, vemurafenib). These mutations are underexplored in MNs, though some studies have assessed MEK inhibitors for certain subtypes. The high prevalence of these mutations underscores the need for clinical trials evaluating these inhibitors starting in the relapsed/refractory setting, when outcomes are poor and alternatives are limited. This highlights the value of seeking care at dedicated Phase I programs like the Novel Therapeutics Centre at the Cleveland Clinic. Reference: The AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through An International Consortium, Cancer Discov. 2017 Aug;7(8):818-831 v 17.0- public. Target mutation Cases Altered Altered % NRAS 384 8.30% EZH2 197 4.30% KRAS 182 3.90% NF1 62 2.80% BRCA2 33 1.50% BRAF 24 0.50% EGFR 13 0.50% RET 11 0.40%