Abstract P4-02-18: Impact of clonal hematopoiesis on disease progression following CDK4/6 inhibitor therapy
Authors: Tao Jacqueline , Vela Pablo Sanchez , Safonov Anton , Ferraro Emanuela , Exposito Sebastia Franch , Menghrajani Kamal , Ptashkin Ryan , Comen Elizabeth , Braunstein Lior Z. , Robson Mark E. , Chandarlapaty Sarat , Reis-Filho Jorge , Berger Michael , Zehir Ahmet , Norton Larry , Levine Ross , Razavi Pedram 
Published: March 2023

Background Clonal Hematopoiesis (CH) is a well-established risk factor for adverse clinical outcomes including all-cause mortality, cardiovascular disease, and progression to hematologic malignancies. The presence of CH has been shown to adversely impact overall survival in non-hematologic cancers, however whether CH modulates response to specific therapies in breast cancer is not known. Here we investigate the impact of CH mutations on disease progression in patients with metastatic estrogen receptor (ER) positive breast cancer undergoing treatment with first line CDK4/6 inhibitors and endocrine therapy (CDK4/6i+ET). Methods We analyzed data from a well annotated cohort of patients with ER+ breast cancer who received endocrine therapy and CDK4/6 inhibitors. All patients underwent prospective tumor and matched WBC sequencing utilizing the MSK-IMPACT assay. CH variants were detected in blood samples utilizing the well-validated variant detection and filtration pipeline of MSK-IMPACT. CH mutations were defined as putative drivers (CH-PD) or non-putative drivers (CH) as previously described. To ensure the presence of CH at the time of therapy initiation, only patients who had CH sampling performed from 6 months before through 4 months after initiation of CDK4/6i+ET were included. We compared progression free survival (PFS) in patients with and without CH, as well as by CH-PD status and DNMT3A CH mutations. We investigated clinical covariates including type of endocrine therapy, receipt of prior neoadjuvant or adjuvant chemotherapy, and age at start of CDK4/6i+ET. Results The final cohort was comprised of 378 patients, of whom 135 (35.7%) had CH. The median time between sample collection and CDK4/6i+ET initiation was 0 (IQR -0.79 to 0.47 months). Patients with CH were older at time of therapy initiation (median 63.0 versus 54.7 years, p &lt; 0.001). There were no significant differences between groups in terms of endocrine therapy (aromatase inhibitor or fulvestrant), prior chemotherapy, and time from CH sample collection to CDK4/6i+ET start. Univariate Cox-proportional hazard analysis did not reveal a difference between progression free survival and overall CH (HR 0.96, 95% CI 0.75 – 1.23, p = 0.76), CH-PD (HR 1.05, 0.77 – 1.43, p = 0.77), or DNMT3A mutations (HR 1.12, 0.80 – 1.60, p = 0.52) compared to patients without CH. Interestingly, age less than 60 years was found to be associated with PFS outcome (univariate HR 1.57, 1.22 – 2.01, p = 0.0004). Multivariate analysis adjusted for endocrine therapy partner and age at CDK4/6i+ET therapy did not reveal an association between outcome and overall CH (HR 1.07, 0.83 – 1.39, p = 0.59). In patients younger than age 60, presence of overall CH did not confer a significant PFS difference (HR 0.90, 0.63 – 1.29, p = 0.57). In the subset of patients older than 60 (n = 168) presence of CH conferred numerically, but not statistically, significant shorter PFS (HR 1.41 [0.96 – 2.09], p = 0.08). In this population, CH-PD conferred a shorter PFS (HR 1.75, 1.12 – 2.72, p = 0.02). Conclusion We found that CH, CH-PD and DNMT3A CH mutations did not affect PFS among metastatic ER+ breast cancer patients treated with first line CDK4/6 inhibitors. Younger age was associated with increased risk of progression, warranting further investigation. In the subset of patients with age older than 60, CH-PD conferred a shorter PFS. Further data, incorporating records of dose reductions, will be presented at the meeting.

Citation Format: Jacqueline Tao, Pablo Sanchez Vela, Anton Safonov, Emanuela Ferraro, Sebastia Franch Exposito, Kamal Menghrajani, Ryan Ptashkin, Elizabeth Comen, Lior Z. Braunstein, Mark E. Robson, Sarat Chandarlapaty, Jorge Reis-Filho, Michael Berger, Ahmet Zehir, Larry Norton, Ross Levine, Pedram Razavi. Impact of clonal hematopoiesis on disease progression following CDK4/6 inhibitor therapy [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 P4-02-18.