Abstract A061: Detection and dynamic monitoring of clonal hematopoiesis mutations in women receiving systemic therapies for high grade serous ovarian carcinoma
Authors: Porter Rebecca L. , Qi Courtney H. , Feeney Carina , Narayan Swati , Tayob Nabihah , Curtis Jennifer , Campos Susana , Horowitz Neil , Krasner Carolyn , Lee Elizabeth , Stover Elizabeth , Wright Alexi , Weeks Lachelle , Gibson Christopher , Liu Joyce , Konstantinopoulos Panagiotis , Lindsley Robert C. , Matulonis Ursula 
Published: March 2024

Abstract
Background: Clonal hematopoiesis (CH), or the expansion of hematopoietic stem cells carrying recurrent somatic mutations, is associated with increased risk of cardiovascular disease, hematologic neoplasms, and all-cause mortality. After age, chemotherapy is the strongest risk factor for developing CH with a 5-10x increased prevalence compared to age-matched controls. The prevalence of CH in patients with high grade serous ovarian cancer (HGSOC) is high, but the dynamics of CH in response to systemic therapies and relationship with outcomes remains poorly understood. Methods: We performed targeted next generation DNA sequencing on peripheral blood mononuclear cells from baseline and prospectively collected serial blood samples at 3- and 6-month intervals from 40 women with either newly diagnosed, treatment naïve (Cohort 1, n=30) or with first recurrence of (Cohort 2, n=10) HGSOC to determine the presence and dynamics of CH. Results: A total of 128 peripheral blood samples were sequenced for detection of CH with a median of 3 samples per patient. Baseline CH mutations (CH-B) at any variant allele frequency (VAF) were observed in 33% and 60% of patients in Cohorts 1 and 2, respectively (p=0.082). Throughout treatment, CH mutations exhibited a variety of dynamics, including emergence, stability and expansion. Of 28 patients with at least 3 serial blood draws, emergent CH (CH-E) was detected in 39.3% with VAF ³2% and another 33% at any VAF. Age was positively correlated with CH-E (p=0.015); BRCA status was not correlated. The most common CH-B mutations were PPM1D, DNMT3A, TET2 and SF3B1 and CH-E mutations were PPM1D, DNMT3A, TET2 and TP53. TP53 mutations were not detected at baseline; TP53 CH-E emerged in later samples in 3 patients with pre-existing DNMT3A or PPM1D CH. Conversely, PPM1D and DNMT3A mutations were observed early in treatment courses, particularly in patients with recurrent disease and prior platinum exposure. Most CH-E VAF remained stable over time, but 4 patients exhibited robust expansion of PPM1D (n=3) or RAD21 (n=1) clones with at least 3-fold increase in VAF over 2-4 time points. In Cohorts 1 and 2, 14 and 3 patients were initiated on PARPi maintenance, respectively. Of 10 patients with CH-E on PARPi maintenance, 6 displayed stable PPM1D, DNMT3A or TET2 mutations over serial PB draws. Interestingly, CH-E with expanding VAF and emergence of new mutations was observed in 4 patients on PARPi. Deeper sequencing is underway in the cases of expanding CH-E during chemotherapy or PARPi therapy for the discovery of novel mutations linked with expansion of hematopoietic clones associated with neoplastic potential. Conclusions: Our study shows that CH is common and dynamic in women with HGSOC undergoing systemic therapies. These results highlight the need for efforts to further understand the biological and clinical importance of CH in ovarian cancer and the risks associated with dynamic changes over subsequent lines of therapy.
Citation Format: Rebecca L. Porter, Courtney H. Qi, Carina Feeney, Swati Narayan, Nabihah Tayob, Jennifer Curtis, Susana Campos, Neil Horowitz, Carolyn Krasner, Elizabeth Lee, Elizabeth Stover, Alexi Wright, Lachelle Weeks, Christopher Gibson, Joyce Liu, Panagiotis Konstantinopoulos, Robert C. Lindsley, Ursula Matulonis. Detection and dynamic monitoring of clonal hematopoiesis mutations in women receiving systemic therapies for high grade serous ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A061.