Clonal hematopoiesis of indeterminate potential mutations in neuroendocrine tumor patients: Cluster analysis and application of risk scores.

Abstract

e16354 Background: Clonal Hematopoiesis of Indeterminate Potential (CHIP) mutations are associated with an increased risk of myeloid malignancies and may expand with exposure to radiation or chemotherapy, which are standard therapies for neuroendocrine tumors (NET). We analyzed CHIP mutation prevalence and conducted cluster analysis in NET patients to identify subgroup features that may guide management and targeted interventions. Methods: Peripheral blood samples were collected from NET patients. The DNA was extracted and processed with a 63-gene myeloid NGS panel with a 2% VAF cutoff to identify CHIP mutations. Clonal Hematopoiesis Risk Score (CHRS) and Clonal Cytopenia Risk Score (CCRS) were calculated to assess risk of myeloid transformation, and their agreement was measured using Cohen’s kappa. Tumor grades, demographics and CBC data were collected for cluster analysis. Results: In our cohort of 102 NET patients, 24 (23.5%) had CHIP mutations. The prevalence of CHIP mutations (6.86%, 7.84%, 8.82%) and CHRS (8.29, 9.31, 9.72; p = 0.0298) showed an increasing trend across 10-year age intervals (50–59, 60–69, 70–80 years). We identified 2 distinct clusters: Cluster 1 (n = 10) had older patients (median age 72 vs. 60 years, p = 0.006), higher variant allele frequencies (0.15 vs. 0.03, p = 0.024), elevated CHRS scores (10.75 vs. 8.00, p < 0.001) compared to Cluster 2 (n = 14). Cluster 2 had significantly higher hemoglobin levels (14.45 vs. 12.8, p = 0.002). No significant differences were seen in CCRS, tumor grades, WBC and platelet counts. The clusters remained unchanged after excluding age as a parameter. Based on CHRS, 17 patients were identified as low risk with 5-year and 10-year risks of myeloid malignancy at 0.232 ± 0.048% and 0.669 ± 0.083%. Seven were intermediate risk with 5-year and 10-year risks of myeloid malignancy at 2.76 ± 0.482% and 7.83 ± 0.810%. According to CCRS, 19 patients were classified as low risk and 5 as intermediate risk, with 2-year risk of myeloid malignancy of 6.40% and 14.10%. Agreement between CHRS and CCRS was minimal (0.12, 95% CI -0.29, 0.53; p = 0.57). Conclusions: Our study identified distinct clinical and genetic profiles in NET patients prior to chemotherapy or radiation. Once the serial sample analysis is complete, we will assess if existing clusters change or additional clusters emerge after therapy exposure, highlighting potential subgroup-specific implications for patient management. Cluster analysis of CHIP positive patients. Characteristics Cluster 1, N = 10 1 Cluster 2, N = 14 1 p-value 2 Age 72 (65, 77) 60 (55, 67) 0.006 Variant allele frequency 0.15 (0.07, 0.27) 0.03 (0.03, 0.06) 0.024 CHRS 10.75 (9.75, 11.00) 8.00 (7.63, 8.88) <0.001 CCRS 0.00 (0.00, 3.00) 0.00 (0.00, 0.00) 0.12 WBC 5.89 (4.74, 6.26) 6.98 (5.54, 8.42) 0.2 Hb 12.80 (11.80, 13.13) 14.45 (14.13, 15.78) 0.002 Platelet 274 (249, 367) 245 (176, 295) 0.2 Tumor grade >0.9  Low grade 2 (50%) 6 (67%)  High grade 2 (50%) 3 (33%)  Unknown 6 5 1 Median (IQR); n (%). 2 Wilcoxon rank sum test; Fisher's exact test.