Abstract PO4-13-07: Association of clonal hematopoiesis (CH) with clinical outcomes among survivors of breast cancer (BC)
Authors: Soldato Davide , Noce Antonin Della , Meglio Antonio Di , Marzac Christophe , Pistilli Barbara , Martin Anne-Laure , Everhard Sibille , Breckler Marie , Boyault Sandrine , Rousseau Marina , Trédan Olivier , Coutant Charles , Cottu Paul , Rigal Olivier , Levy Christelle , Jouannaud Christelle , Sauterey Baptiste , Droin Nathalie , Job Bastien , Bertaut Aurélie , André Fabrice , Luis Ines Vaz , Micol Jean-Baptiste 
Published: May 2024

Background: Clonal hematopoiesis (CH) refers to the identification of clonal expansion of hematopoietic cells due to somatic mutations in leukemia-associated genes without evidence of hematologic anomalies. CH, particularly with variant allele frequency (VAF) ≥ 10%, has been associated with adverse outcomes, including reduced survival in advanced malignancies and higher risk of cardiovascular events. The aim of this study was to evaluate the biological and prognostic relevance of CH in survivors of breast cancer (BC).

Methods: CANTO (NCT01993498) is a prospective, multicenter cohort enrolling patients diagnosed with stage I-III BC. CANTO collects clinical, tumor and treatment-related characteristics at diagnosis (dx). Follow-up visits are scheduled at 1, 2, 4 and 6 years after dx and data on disease status, type of recurrence, and survival status are collected. We assessed CH among pts ≥ 40 years, without previous solid or hematological cancer, with blood samples available at dx and year 4 or experiencing death or disease recurrence before year 4. CH was determined using Next-Generation Sequencing with unique molecular identifiers (HaloPlexHS, Agilent Technologies) for 17 genes (including DNMT3A, TET2, ASXL1, PPM1D, ATM, JAK2 and TP53) on blood samples obtained at dx. Outcomes of interest included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS) defined according to STEEP criteria. Kaplan-Meier estimator, log-rank test and multivariate Cox models assessed prognostic role of CH.

Results: In the cohort with available CH data (N=1219) mean age (SD) was 57.5 (10.1) years, 62% of pts were postmenopausal, 40.9% were current or former smokers, 46.2% had stage I BC, 77.7% had HR+/HER2- BC, 53.5% received chemotherapy and 80.8% hormonal therapy. CH was detected with a VAF ≥ 1% in 306 pts (25.1%) including 207 pts (67.6%) with DNMT3A mutation, ≥ 2% in 186 (15.3%) and ≥ 10% in 45 (3.7%) pts. Pts with CH ≥ 10% were more frequently older (65.3 vs 57.2 years, p&lt; .0001) and with a previous history of cardiovascular disease (53.3% vs 37.3%, p&lt; 0.02). At a median (IQR) follow-up of 7.0 (6.2-7.8) years 246 iDFS, 161 DDFS and 118 OS events were observed. Only 8 cases of new hematological malignancies were observed. Pts harboring CH with a VAF ≥ 10% had worse OS (log-rank p=0.04) and CH with a VAF ≥ 10% was associated with higher risk of death (HR= 2.4, 95%CI 1.04-5.6); presence of CH with lower VAF was not associated with worse OS. Table displays complete results for all tested associations.

Conclusions: CH at dx was identified in 25% of pts with stage I-III BC aged ≥ 40 years in the CANTO cohort, including 4% with a VAF ≥ 10%. In a large, prospective cohort of survivors of BC, we confirmed known associations of CH with older age and cardiovascular history. We observed few secondary hematological malignancies. CH with a VAF ≥ 10% was significantly associated with higher risk of death while adjusting for other relevant prognostic factors. Furthermore, a trend towards higher risk of DDFS events was observed among pts harboring CH with a VAF ≥ 10%.

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Citation Format: Davide Soldato, Antonin Della Noce, Antonio Di Meglio, Christophe Marzac, Barbara Pistilli, Anne-Laure Martin, Sibille Everhard, Marie Breckler, Sandrine Boyault, Marina Rousseau, Olivier Trédan, Charles Coutant, Paul Cottu, Olivier Rigal, Christelle Levy, Christelle Jouannaud, Baptiste Sauterey, Nathalie Droin, Bastien Job, Aurélie Bertaut, Fabrice André, Ines Vaz Luis, Jean-Baptiste Micol. Association of clonal hematopoiesis (CH) with clinical outcomes among survivors of breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-07.