Abstract P5-14-03: Clonal hematopoiesis of indeterminate potential after (neo)adjuvant chemotherapy versus endocrine therapy for early breast cancer: the CIRCE-eBC prospective cohort study
Authors: Morganti Stefania , Jin Qingchun , Santos Katheryn , Gibson Christopher , Patel Ashka , Wilson Alex , Merrill Margaret , Vincuilla Julie , Stokes Samantha , Lipsyc-Sharf Marla , Parker Tonia , King Tari , Mittendorf Elizabeth A. , Curigliano Giuseppe , Hughes Melissa E. , Tayob Nabihah , Lin Nancy U. , Miller Peter , Tolaney Sara , Garber Judy , Parsons Heather A. 
Published: March 2023

Abstract
Clonal hematopoiesis of indeterminate potential after (neo)adjuvant chemotherapy versus endocrine therapy for early breast cancer: the CIRCE-eBC prospective cohort study Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with higher risk of hematologic malignancies, cardiovascular disease, and all-cause mortality. Patients (pts) with early breast cancer (eBC) receiving chemotherapy (CT) have increased risk of treatment-related myeloid neoplasms (tMN); the benefit of CT in eBC pts is often limited. Little is known about the prevalence and dynamics of CHIP in eBC pts. Methods: We prospectively identified two cohorts of pts with eBC: cohort A – pts receiving (neo)adjuvant CT with or without adjuvant endocrine therapy (ET); cohort B – pts receiving ET only. Blood was collected prior to initiation of treatment (T1) and after either (neo)adjuvant CT or 6-18 months of adjuvant ET (T2). We performed targeted sequencing of cryopreserved peripheral blood mononuclear cell (PBMC)-derived genomic DNA and defined CHIP as the presence of ≥1 pathogenic somatic mutation at variant allele fraction (VAF) ≥0.02. In additional analyses we used VAF≥0.005. Results: We enrolled 118 and 116 pts in cohorts A and B, respectively. Pts in cohort A were younger (median age 51 vs 57, p&lt; 0.001), less frequently Caucasian (83.9 vs 96.6%; p=0.005) and former/current smokers (28.0 vs 43.1%, p=0.038). All pts in cohort B had hormone receptor-positive (HR+) eBC; in cohort A 50% of pts had HR+/HER2-, 16% had HR+/HER2+, 8.5% had HR-/HER2+ and 25.4% had HR-/HER2- eBC (p&lt; 0.001). Pts in cohort A had higher stage (stage II-III 68.7 vs 27.6%; p&lt; 0.001) and grade (grade 3 65.3 vs 15.5%; p&lt; 0.001) tumors. Genetic testing was more frequently performed in pts receiving CT (88.1 vs 68.1%, p&lt; 0.001), though the rate of germline pathogenic variants was similar (13.5 vs 17.7%, p=0.079). In cohort A, 38% received anthracyclines, 7% platinum and 57% anthracycline/platinum-sparing CT. Median time between T1 and T2 was 189.5 (150,406) and 280 (147, 425) days in cohort A and B (p&lt; 0.001). The prevalence of CHIP, defined by mutations at VAF ≥ 0.02, was similar at T1 in cohort A (14.4%) vs B (18.1%) (p=0.556). Number of pts with new CHIP variants at T2 was also similar (A 3.4% vs B 6.0%) (p=0.373). After adjusting for age and stage, odds ratio (OR) of developing new CHIP variants in cohort B vs A was 1.28 (95% CI 0.32 – 5.68, p=0.733). Age correlated with baseline prevalence of CHIP (p&lt; 0.001). Most frequent new CHIP variants at T2 in cohort A were DNMT3A (3), PPM1D (1), NF1 (1). To investigate whether pts receiving CT were more likely to have emergence of small hematopoietic clones, we assessed pathogenic variants present at VAF ≥0.005. These were detected at T1 in 55 (46.6%) and 61 (52.6%) pts in cohort A and B, respectively. Few pts without pathogenic variants at T1 developed them at T2 (3 pts in cohort A and 4 in cohort B). 21 pts (27 variants) in cohort A and 11 pts (12 variants) in cohort B had new variants at T2. Pts with new variants vs not (32 vs 202 pts) had similar characteristics, excepting age (median 60.5 vs 54.0, p=0.011). After correcting for age and stage, OR of developing new pathogenic variants given ET vs CT was 0.25 (95% CI 0.10-0.62, p=0.003). Most frequent newly detected variants were in DNMT3A (14), PPM1D (5), TET2 (4) and TP53 (2) in cohort A; DNMT3A (3), TET2 (3) and ZNF318 (2) in cohort B. Conclusions: In the CIRCE-eBC study, CT administration did not lead to emergence of CHIP over a 6-9 month period vs ET alone. This finding is reassuring in the setting of long life-expectancy for eBC pts and the association of CHIP with significant morbidity and mortality. However, consistent with known risk of development of MN, CT was associated with emergence of low frequency pathogenic variants in PPM1D and TP53, which have been associated with elevated risk of tMN. The evolution and prognostic role of these small clones is unclear and warrants additional investigation.
Citation Format: Stefania Morganti, Qingchun Jin, Katheryn Santos, Christopher Gibson, Ashka Patel, Alex Wilson, Margaret Merrill, Julie Vincuilla, Samantha Stokes, Marla Lipsyc-Sharf, Tonia Parker, Tari King, Elizabeth A. Mittendorf, Giuseppe Curigliano, Melissa E. Hughes, Nabihah Tayob, Nancy U. Lin, Peter Miller, Sara Tolaney, Judy Garber, Heather A. Parsons. Clonal hematopoiesis of indeterminate potential after (neo)adjuvant chemotherapy versus endocrine therapy for early breast cancer: the CIRCE-eBC prospective cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-14-03.