Is PPM1D a potential driver of myeloid malignancy transformation in neuroendocrine tumor (NET) patients: An underrecognized malignant CHIPeRpetRaTor?

Abstract

Abstract Background: Building on our prior work showing high baseline CHIP prevalence and cytopenias in NET patients (pts) receiving PRRT, we used NANETS support to analyze a new cohort with matched pre- (pre-tx) and post-treatment (post-tx) peripheral blood (PB) samples. This expanded dataset enabled a deeper investigation of specific CHIP-associated molecular signature emergence post –therapy exposure and resultant hematologic toxicity. Methods: Following IRB approval at CCF and Roswell, PB from NET pts was analyzed for CHIP using a 63-gene myeloid NGS panel (≥2% VAF cutoff). Sequencing was performed via anchored multiplex PCR and Illumina technology (>500× coverage). Clinical associations were assessed using chi-square and Mann-Whitney U tests, with significance set at p < 0.05. Results: At baseline/pre-tx, 8 of 41 pts (19.5%) were CHIP+ and had significantly older age (72.8 vs. 58.7 yrs, p = 0.002), lower ALC (1.1 vs. 1.5, p=0.044) and lower Hb (12.4 vs. 13.7 g/dL, p = 0.063, trend), suggesting reduced immune and marrow reserves. No associations were seen with sex, race, ECOG, WBC, ANC, platelets, or prior radiation/ctx. The majority of CHIP+ pts (5/8; 62.5%) at baseline had no prior RT/ctx exposure. Post-tx (post ctx and post- PRRT), pts who were CHIP+ at baseline demonstrated significantly higher mutation burden on follow up sequencing (2.0 ± 1.3 vs. 0.6 ± 1.1, p = 0.005), and greater rates of clonal progression (88.9% vs. 10.0%, p < 0.001), compared to those who were CHIP-negative at baseline. Recurrent post-tx mutations included PPM1D, DNMT3A, TET2, and ASXL1, with PPM1D emerging in 31.7% (13 of 41) despite being present in only one patient at baseline. PPM1D mutations (PPM1Dm) were characterized by multiple clinically significant truncating variants that were strongly selected for following tx. Among evaluable cases that acquired PPM1Dm post-tx (n=11), 9 pts (82%) had received PRRT prior to mutation development; 6 with PRRT alone and 3 with ctx followed by PRRT. 7 (54%) pts with new PPM1Dm acquisition had VAF>5%. The median PPM1D VAF increase in PRRT-exposed patients was 6.5168% (n=9), compared to 2.14045 (n=2) in non-PRRT patients. CHIP+ status was associated with greater clonal expansion post-tx and worse survival. Detailed mutation dynamics post-specific treatments will be presented. Conclusion: PPM1D emerged as the most common mutation post-tx following PRRT exposure. This therapy-related emergence and clonal dominance happened regardless of baseline CHIP status. PPM1Dms are closely linked to poor outcomes in overt myeloid malignancy, especially therapy related cases (Fandrei et al., Clin Cancer Res. 2025). Use of radioligand therapies, such as PRRT, is rapidly expanding and being incorporated into earlier lines of tx across multiple cancer types. Taken together, our findings underscore the need for serial sequencing and long-term follow-up in larger longitudinal studies to detect/confirm early mutations with PPM1D with emerging clonal evolution. The ability to identify such progression drivers early might enable prevention strategies to inform intervention.