Abstract 5070: Landscape of clonal hematopoiesis prior to PARP inhibitor treatment in patients with ovarian cancer
Authors: Amma Asare, Sara Corvigno, Jun Yao, Li Zhao, Nicole D. Fleming, Joseph Celestino, Richard A. Hajek, Mark S. Kim, Alejandra Flores Legarreta, Karen H. Lu, Koichi Takahashi, P Andrew Futreal, Amir A. Jazaeri, Shannon N. Westin, Anil K. Sood, Sanghoon Lee
Journal: Cancer Research (2024)

Abstract Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are an important tool for treatment of ovarian and other cancers, particularly for those with mutations in BRCA1 or 2 genes or homologous recombination deficiency. The risk of developing secondary hematologic malignancy, particularly myelodysplastic syndrome or acute myeloid leukemia (MDS/AML), is substantially higher (4-12%) after PARPi maintenance or treatment in the second line and beyond in patients with ovarian cancer. This elevated risk necessitates additional investigation into the pathogenesis of PARPi-related secondary malignancy. Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with the development of therapy-related myeloid neoplasms. We aim to understand the patterns of CHIP in patients with high grade serous ovarian carcinoma who receive PARPi therapy. Methods: We performed ultra-high-depth whole exome sequencing of plasma derived cfDNA or white blood cells (WBCs) barcoded with unique molecular identifiers from patients with high grade serous ovarian carcinoma who were treated with multiple lines of chemotherapy (n=6) or with PARPi in addition to chemotherapy (n = 10). Using spike-in mutated DNAs as positive controls, we detected variant alleles as low as 1% variant allele frequency. Gene set enrichment analysis was performed on identified groups. Results: We identified 7162 recurrent variants among our patients. We began by comparing quantities of CHIP between the samples from patients who eventually receive PARPi and those who do not. Samples contained a median of 2030 recurrent CHIP variants and 4300 total variants. No differences in total CHIP quantity or mutation type was discernable among samples from patients who will receive PARPi (BRCA1/2 enriched) vs those who will not. Among our 16 patients, 14 ultimately developed secondary hematologic malignancy (t-MN+ Comparison of t-MN+ (n=14) and t-MN- (n=2) defined a group of 14 variants enriched in the t-MN+ population and a group of 85 variants depleted in the t-MN+ population. The t-MN+ enriched variants we identified were not previously associated with CHIP and had significant overlaps with alkyl transferase activity (FDR q val &amp;lt; 0.01) and nucleotide binding gene sets (FDR q val &amp;lt; 0.01). Conclusions: We used a novel methodology to identify unbiased low variant mutational changes in the hematopoietic system. These results suggest that baseline clonal hematopoiesis variants are similar among patients newly diagnosed with ovarian carcinoma. We have also identified a signature potentially related to future risk of leukemia requiring further validation. Citation Format: Amma Asare, Sara Corvigno, Jun Yao, Li Zhao, Nicole D. Fleming, Joseph Celestino, Richard A. Hajek, Mark S. Kim, Alejandra Flores Legarreta, Karen H. Lu, Koichi Takahashi, P Andrew Futreal, Amir A. Jazaeri, Shannon N. Westin, Anil K. Sood, Sanghoon Lee. Landscape of clonal hematopoiesis prior to PARP inhibitor treatment in patients with ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5070.