Abstract PO4-05-03: Cell-free tumor DNA analysis in advanced or metastatic breast cancer patients enrolled in the German registry study PRAEGNANT

Abstract Background Accurate molecular profiling is crucial for optimal treatment decisions in advanced or metastatic breast cancer. Liquid biopsies, such as circulating cell-free tumor DNA (cfDNA, cftDNA or ctDNA), provide a non-invasive approach to monitor molecular alterations in the tumor. The German PRAEGNANT registry study aims to investigate such molecular biomarkers for precision medicine and their practical integration into clinical practice. In this context, cftDNA testing was performed as part of a PRAEGNANT research subproject, with the objectives of understanding the physician's rationale for initiating cftDNA testing, identifying detected alterations, and assessing the clinical impact of the associated findings Methods Patients with advanced or metastatic breast cancer were prospectively enrolled in the PRAEGNANT registry study (NCT02338167). The decision to undergo cftDNA testing was based on the physician's discretion. Blood samples were collected using Streck cfDNA BCT tubes and sent to the GUARDANT Health central laboratory for cftDNA extraction and subsequent next-generation sequencing analysis, employing the FDA-approved GUARDANT360 CDx test, a 74 gene panel including all guideline-recommended biomarkers, including single nucleotide variants (SNVs), indels, fusions and amplifications. Recruitment of patients occurred at four PRAEGNANT study centers between April 2022 and July 2023. The GUARDANT360 CDx report, along with a questionnaire regarding the testing intent and clinical impact of the results, was provided to the treating physician. Results 46 patients were eligible for analysis as per clinical characteristics. CftDNA analysis was successfully performed for all 46 cases. 38 (83%) harbored at least one somatic alteration in the analyzed genes. Fifteen patients (33%) harbored alterations in TP53, thirteen (28%) in PIK3CA. Five patients (11%) harbored mutations in ESR1. Somatic mutations in BRCA1 or BRCA2 were detected for five (11%) and six (13%) patients, respectively. One BRCA2 mutation was categorized as synonymous and one BRCA2 and three BRCA1 alterations as variants of uncertain significance. Eight patients (17%) harbored mutations in ATM. Most patients included were HR+HER2- (N=27, 58%). In this subgroup, eight (30%) patients had a PIK3CA alteration, five (19%) with an indication for treatment with alpelisib, eight (30%) a mutation in ATM, BRCA1 or BRCA2 and four (15%) in ESR1. Questionnaires regarding intention of testing and clinical impact were completed by 43 treating physicians (93%). Among them, 33% of patients had current indications for PARP inhibitor treatment, and 61% would consider it at the next change of therapy if a BRCA1 or BRCA2 mutation was detected. Additionally, 21% of patients had a current indication for alpelisib treatment if a relevant PIK3CA mutation was found, and 58% would consider it in the next line of treatment. Overall, cfDNA testing influenced the current or future treatment decisions in 35% of patients. Discussion The high prevalence of somatic alterations in TP53, PIK3CA, ESR1, and BRCA1/2 genes, identified through cftDNA testing with GUARDANT360 CDx, highlights their potential as biomarkers for targeted therapies in advanced/metastatic breast cancer. Detection of specific mutations influenced treatment decisions, such as eligibility for alpelisib or PARP inhibitors and might further facilitate treatment with elacestrant in future treatment lines after its approval in Germany. These findings demonstrate the clinical impact of cftDNA testing in guiding personalized treatment selection. Additionally, the identification of such somatic alterations within a registry study like PRAEGNANT presents a unique opportunity to consider enrolling these patients into biomarker-guided clinical trials. Citation Format: Hanna Hübner, Pauline Wimberger, Elena Laakmann, Eugen Ruckhäberle, Matthias Ruebner, Theresa Link, Erik Belleville, Iris Faull, Marcus Hausch, Diethelm Wallwiener, Andreas Schneeweiss, Hans Tesch, Sara Brucker, Peter A. Fasching, Volkmar Müller, Tanja Fehm. Cell-free tumor DNA analysis in advanced or metastatic breast cancer patients enrolled in the German registry study PRAEGNANT [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 PO4-05-03.