In the context of hormone receptor positive, HER2 negative Metastatic breast cancer (MBC), CDK 4/6 inhibitors (CDK4/6i) combined with endocrine therapy represent the standard first-line treatment, improving Progression-Free Survival (PFS) and Overall Survival (OS). Despite these benefits, resistance to treatment develops, necessitating early risk classification to guide clinical management. This study explores the potential of cell-free DNA (cfDNA) fragmentomics, specifically ACTB fragments, in predicting tumor dynamics and treatment outcomes in luminal MBC, based on the principle that shorter DNA fragments are generally indicative of circulating tumor DNA (ctDNA) from tumor cells, while longer fragments are associated with leukocyte lysis. In the MAGNETIC.1 study, 141 women with luminal-like MBC were enrolled between January 2018 and January 2023. Blood samples were collected at baseline (BL), and after 3 (T3) and 6 (T6) months of treatment. cfDNA was extracted and analyzed using droplet digital PCR (ddPCR) to quantify ACTB fragments (136 bp, 420 bp, and 2,000 bp). Continuous variables were compared using the Mann-Whitney test and Kruskall Wallis test depending on data distribution and number of groups. Categorical variables were compared using the Chi-square test or Fischer's exact test whenever appropriate. Differences in survival were tested by log-rank test and uni- and multivariable Cox regression. By categorizing the values of actinic fragments into interquartiles (Q1, Q2, and Q3), ACTB_short Q3 at baseline was significantly associated with negative PR expression (RRR 0.27, P = 0.012) and a higher frequency of liver metastasis (RRR = 3.75, P = 0.009). In terms of clinical outcomes, regarding PFS a significant role was observed for baseline ACTB_short Q3 (HR 1.92, P = 0.041) and ACTB_medium Q3 (HR 0.47, P = 0.043), the latter maintaining significance in multivariable analysis (HR 0.33, 95 %, P = 0.012). For OS, ACTB_short Q3 demonstrated a significant impact in both univariable (HR 3.94, P = 0.003) and multivariable analyses (HR 3.25, P = 0.023). This study demonstrates the feasibility of employing a fragmentomics mutation agnostic approach in luminal MBC. Baseline and longitudinal changes in ACTB fragments were significantly associated with clinical outcomes, suggesting their potential as non-invasive biomarkers for early risk classification and monitoring tumor dynamics.

Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in HER2-positive and HER2-low breast cancer. Its main safety concern is interstitial lung disease, while clinically relevant hepatotoxicity is rarely reported. In our case report we describe a 49-year-old woman with HER2-positive advanced breast cancer that developed persistent grade 3 transaminase elevations after 2 cycles of T-DXd, refractory to corticosteroid treatment and requiring treatment discontinuation. This case underlines the unpredictable and idiosyncratic nature of T-DXd associated hepatotoxicity and the importance of liver function monitoring. Clinicians should consider DILI in patients with unexplained liver enzyme elevations during therapy. Further studies are needed to clarify mechanisms and risk factors.

Optimal imaging intervals for patients with hormone receptor-positive/HER2-negative metastatic breast cancer (MBC) remains undefined. Aim of this study was to analyze the temporal patterns of disease progression to identify high risk subgroups that may benefit from intensified monitoring. we analyzed 149 hormone receptor-positive/HER2-negative MBC patients prospectively enrolled in the MAGNETIC.1 trial (NCT05814224) and treated with first line endocrine therapy. Hazard rates (HR) for disease progression were determined according to clinico-pathological and liquid biopsy features. in the overall population, two distinct progression-risk peaks emerged at 2-3 months (32.9/1000 person-months) and at 24 months (28.0/1000). Higher risk of progression was observed in lobular carcinoma (61.1) [HR 61.12 per 1000 person month (pm)], progesterone receptor-negative status (HR 39.07), fulvestrant-based treatment (HR 46.88), liver metastases (HR 59.00), and presence of ≥ 3 metastatic sites (HR 40.10). Hazard distribution in hormone receptor-positive/HER2-negative MBC is biphasic and modulated by readily available clinical variables. High-risk subgroups may benefit from intensified radiologic and liquid-biopsy surveillance during the first three months and around two years after treatment start.