Abstract PS4-02-18: Detection of germline and somatic pathogenic variants in patients with de novo metastatic breast cancer (dnMBC) and assessment of their prognostic relevance: A Hellenic Cooperative Oncology Group (HeCOG) translational cohort study

Abstract Background: Robust clinico-genomic predictors of survival in dnMBC remain ill defined. We employed next generation sequencing (NGS) to explore the mutational spectrum of a Greek dnMBC cohort alongside key clinicopathological factors and evaluated their prognostic impact for overall survival (OS). Patients and Methods: Formalin-fixed, paraffin-embedded tumor tissue blocks were collected from the HeCOG Biobank for 106 patients with dnMBC alongside peripheral blood samples for 91 cases. NGS was performed on Ion Torrent platforms with AmpliSeq DNA panels targeting genes recurrently altered in BC. Variants classified as pathogenic or likely pathogenic (PVs) according to Clinvar and ACMG/AMP criteria were then processed for analysis. Cox proportional-hazards regression models were applied to assess prognostic relevance of both genomic and clinicopathological variables. Results: The total study population consisted of 106 women with a median age of 63 years (31-86); 67 patients (64%) were postmenopausal Overall, 62.5% presented with a PS of 0 and 74% with NST histology. Regarding tumor profiling, 82% were hormone receptor (HR) positive, 28.8% HER2+, 50% grade 3. Family history of cancer was positive in 17.3% of patients. Notably, 42% of patients underwent some type of breast surgery. First-line treatment included a combination of aromatase inhibitor (AI) and CDK4/6 inhibitor in 36 (34%) patients, chemotherapy (CT) alone in 27 (23.6%), combination of CT and other targeted agents in 30 (28.3%), hormonal therapy only in 7 (6.6%), while for 6 patients (5.6%) treatment data were missing. Moreover, 11 patients (10.3%) were diagnosed with locoregional (LR) disease only, 45 (42.5%) with distant and 42 (39%) with LR and distant metastases. Regarding IHC subtypes tested locally, 70 patients (66%) were classified as Luminal A/B, 31 (29.2%) HER2+ and 5 (4.7%) as TNBC. At least one PV was present in 69 of 106 tumors (65.1 %), with most carrying PVs in PIK3CA (40 cases; 37.7 %) and TP53 (29 cases; 27.4 %). Recurrent, albeit less frequent, PVs were also observed in ERBB2, GATA3, PTEN, CDH1 and AKT1 (each present in ≥ 2 tumors). Meanwhile, germline sequencing revealed single PVs in two patients, one in TP53 and the other in PTEN. In univariate analyses, none of the standard clinicopathological parameters (age, menopausal status, performance status, histology, T-stage, grade, ER/HER2 status) or individual PVs reached statistical significance for OS. No significant difference was found between Luminal and HER2+ subgroups. Conclusion: The mutational landscape of our Greek dnMBC series reveals a high prevalence of actionable PIK3CA, TP53 and ERBB2 alterations. These findings emphasize further the biological heterogeneity of dnMBC disease and the need for the identification of novel integrative biomarkers beyond standard clinico-genomic parameters to improve prognosis and guide therapeutic decisions. The study was registered on ClinicalTrials.gov under the identifier NCT05758948 Citation Format: E. Fountzilas, K. Papadopoulou, N. Korfiatis, A. Goussia, A. Christopoulou, E. Moirogiorgou, N. Tsoukalas, G. Petrakis, C. Gouedard, F. Zagouri, D. Stefanou, F. Kyriakou, E. Vorrias, S. Karageorgopoulou, F. Dimitrakopoulos, A. Vernadou, S. Murray, G. Fountzilas. Detection of germline and somatic pathogenic variants in patients with de novo metastatic breast cancer (dnMBC) and assessment of their prognostic relevance: A Hellenic Cooperative Oncology Group (HeCOG) translational cohort study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-02-18.