Evolutionary Overview and Future Perspectives: ESR1 Mutations, Liquid Biopsy, and Artificial Intelligence for a New Era of Personalized Medicine in ER+ Breast Cancer.

ESR1 gene mutations represent one of the main mechanisms of acquired resistance to endocrine therapy (ET) in estrogen receptor-positive (ER+) breast cancer. The introduction of liquid biopsy as a minimally invasive technique for analyzing circulating tumor DNA (ctDNA) has opened new avenues for real-time mutation monitoring and personalized treatment strategies. This review explores the clinical relevance of ESR1 mutations in endocrine resistance, the potential of liquid biopsy for early detection and monitoring, and the integration of advanced sequencing technologies and artificial intelligence to improve diagnostic accuracy.

Circulating tumor cells dynamics after CDK4/6 inhibitor for hormone-receptor positive metastatic breast cancer: a biomarker analysis from the PACE phase II study.

Purpose: Circulating tumor cells (CTCs) are biomarkers associated with poor prognosis and treatment resistance in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC). This analysis evaluates the prognostic role of baseline CTC enumeration and its interaction with treatment regimens in patients progressing on CDK4/6 inhibitors.

Experimental Design: The PACE trial is a phase II, multicenter, randomized study of HR+/HER2- MBC patients experiencing progression on aromatase inhibitors (AI) and CDK4/6 inhibitors.

Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2- metastatic breast cancer: a retrospective multi-institutional Consortium analysis.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) are the mainstay of treatment for hormone receptor positive, HER2 negative (HR + /HER2-) metastatic breast cancer (MBC). However, disease progression is inevitable and unveiling resistance mechanisms is crucial to guide post-CDK4/6i therapeutic strategies. In this study, we retrospectively analyzed a real-world, multi-institutional cohort of patients with HR + /HER2- MBC characterized by circulating tumor DNA (ctDNA) through next-generation sequencing (NGS) before starting second-line treatment.

Molecular characterization of patients with metastatic invasive lobular carcinoma (ILC): using real-world data to describe this unique clinical entity.

Purpose: Invasive lobular carcinoma (ILC) is the second most common type of breast cancer, but distinct treatment strategies are limited. Better characterization of the genomic and transcriptomic landscape is critical to elucidate ILC tumor biology, improve histologic classification, and define precision medicine treatment approaches.

Materials And Methods: We retrospectively analyzed de-identified next-generation sequencing data of 4,613 metastatic patients from the Tempus database including 637 with ILC, 91 with mixed lobular/ductal histology, and 3,885 with invasive breast carcinoma of no special type (IBC-NST).

Longitudinal profiling of hormone receptor positive, HER2 negative metastatic breast cancer through droplet digital PCR-based circulating tumor DNA fragmentomics.

Background: 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.

The evolving landscape of hormone receptor-positive/HER2-negative metastatic breast cancer (EVOLVE): An Italian Delphi consensus report.

Background: The expanding treatment landscape for patients with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) has led to the emergence of new "grey areas" not covered by international guidelines, where treatment decision making is particularly challenging.

Methods: Sixteen relevant statements regarding the management of HR+ /HER2- mBC were formulated by an Executive Board and validated by a Scientific Board, composed by internationally recognized experts in the field of BC. Subsequently, 50 Italian oncologists were surveyed between May 2024 and June 2024 through the modified Delphi method, in order to capture their rate of agreement and disagreement on the proposed statements.

Key decision factors in second-line therapy: Expert insights on HR+/HER2-metastatic breast cancer post-CDK4/6 inhibitor progression.

The progression of HR+/HER2- metastatic breast cancer after treatment with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) poses significant therapeutic challenges. Endocrine therapy (ET) remains a cornerstone of subsequent treatment, but its effectiveness depends on a nuanced understanding of clinical and genomic factors that drive therapy selection. For example, the duration of response to prior CDK4/6i therapy strongly predicts sensitivity to subsequent ET.

Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes.

Purpose: GATA3 mutations are among the most common alterations in hormone receptor-positive (HR+) breast cancer (BC), yet these have no targeted therapies. MDM2 is an E3 ubiquitin ligase that targets p53 for degradation, and pre-clinical data suggests MDM2 inhibition may effectively treat GATA3 HR+ BC. The GATA3 co-mutational landscape has been described only in primary BC tissue, and the mechanism of MDM2-driven efficacy is incompletely understood.

Patient preferences for treatments in hormone receptor-positive/HER2-negative metastatic breast cancer in Italy: a discrete choice experiment study.

Hormone receptor (HR) positive (HR +) and human epidermal growth factor receptor 2 (HER2) negative (aka HER2 -) breast cancer (BC) is the most frequently diagnosed subtype. Recent development of next-generation endocrine therapies (e.g.

Transcriptomic profiling of circulating tumor cells from metastatic breast cancer patients reveals new hints in their biological features and phenotypic heterogeneity.

The study of circulating tumor cells (CTCs) provides critical insights into the biological mechanisms underlying metastasis. This study aims to demonstrate the applicability of an integrated DEPArray-based phenotypic analysis combined with transcriptomic characterization to investigate the biology of CTCs isolated from 10 patients with metastatic breast cancer (MBC). The transcriptional profiles of CTCs were consistent with both the cancer type and epithelial characteristics.

Mapping breast cancer therapy with circulating tumor cells: The expert perspective.

Circulating tumor cells (CTCs) have emerged as a key prognostic biomarker for breast cancer, with their role becoming more pronounced in metastatic cases. In metastatic breast cancer, having five or more CTCs per 7.5 mL of blood is linked to poorer survival and more aggressive disease, marking it as stage IV.

Risk Assessment in Atopic Dermatitis: Guidance from a Multidisciplinary Expert Panel.

Guidelines recommend that patients with severe atopic dematitis (AD) be treated with Janus kinase inhibitors (JAKi). Recently, the safety of JAKi as a class was reviewed by the European Medicines Agency, leading to a modification of the Summaries of Product Characteristics. For upadacitinib, changes involve reduced posology and restriction of its use to patients with no other alternative amongst the elderly and those at an increased risk of major adverse cardiovascular events (MACE), cancer and venous thromboembolism (VTE).

Clinical Validity of Repeated Circulating Tumor Cell Enumeration as an Early Treatment Monitoring Tool for Metastatic Breast Cancer in the PREDICT Global Pooled Analysis.

Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in patients with metastatic breast cancer, focusing on its prognostic value in different breast cancer subtypes and clinical settings.

Experimental Design: In total, 4,436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types.

Results: Using the cutoff ≥1 CTC for CTC positivity, 913 (20.

Racial Differences in ctDNA Profiles, Targeted Therapy Use, and Outcomes in Metastatic Breast Cancer.

Importance: Black patients with metastatic breast cancer (mBC) have higher mortality rates than White patients despite advances in treatment.

Objectives: To examine whether Black patients with metastatic breast cancer have different genomic profiles compared with White patients and whether there are inequities in targeted treatment use between these groups.

Design, Setting, And Participants: This retrospective, population-based cohort study assessed adult patients with mBC who underwent genomic profiling at academic institutions in the US between January 1, 2015, and December 31, 2023.

Accessible model predicts response in hormone receptor positive HER2 negative breast cancer receiving neoadjuvant chemotherapy.

Hormone receptor-positive/HER2-negative breast cancer (BC) is the most common subtype of BC and typically occurs as an early, operable disease. In patients receiving neoadjuvant chemotherapy (NACT), pathological complete response (pCR) is rare and multiple efforts have been made to predict disease recurrence. We developed a framework to predict pCR using clinicopathological characteristics widely available at diagnosis.

Beyond Hormone Receptors: liquid biopsy tools to unveil new clinical meanings and empower therapeutic decision-making in Luminal-like metastatic breast cancer.

Immunohistochemical (IHC) tissue profiling is a standard practice in the management of metastatic breast cancer (mBC), that enables the identification of distinct biological phenotypes based on hormone receptors' expression. Luminal-like tumors primarily benefit from a first line treatment strategy combining endocrine therapy and cyclin-dependent kinase 4/6 inhibitors. However, IHC analyses necessitate invasive procedures and may encounter technical and interpretational challenges.

Clinico-pathological predictors of radiologic complete response to first-line anti-HER2 therapy in metastatic breast cancer.

This study aimed to identify the clinico-pathological variables predictive of radiologic complete response (rCR) to first-line anti-HER2 therapy in patients with HER2-positive metastatic breast cancer. Patients were selected from the database of the GIM14 study and classified according to the best radiologic response obtained to first-line anti-HER2 therapy and upon time-to-treatment-discontinuation (TTD). A total of 545 patients were included in the analysis.

Integrating machine learning-predicted circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in metastatic breast cancer: A proof of principle study on endocrine resistance profiling.

The study explored endocrine resistance by leveraging machine learning to establish the prognostic stratification of predicted Circulating tumor cells (CTCs), assessing its integration with circulating tumor DNA (ctDNA) features and contextually evaluate the potential of CTCs-based transcriptomics. 1118 patients with a diagnosis of luminal-like Metastatic Breast Cancer (MBC) were characterized for ctDNA through NGS before treatment start, predicted CTCs were computed through a K nearest neighbor algorithm. Differences across subgroups were analyzed through chi square or Fisher's exact test according to sample size and corrected for False Discovery Rate.

A comprehensive luminal breast cancer patient-derived xenografts (PDX) library to capture tumor heterogeneity and explore the mechanisms of resistance to CDK4/6 inhibitors.

Breast cancer (BC) is marked by significant genetic, morphological and clinical heterogeneity. To capture this heterogeneity and unravel the molecular mechanisms driving tumor progression and drug resistance, we established a comprehensive patient-derived xenograft (PDX) biobank, focusing particularly on luminal (estrogen receptor, ER+) and young premenopausal patients, for whom PDX models are currently scarce. Across all BC subtypes, our efforts resulted in an overall success rate of 17% (26 established PDX lines out of 151 total attempts), specifically 15% in luminal, 12% in human epidermal growth factor receptor 2 positive (HER2+) and 35% in triple negative BC.

Quantification of Letrozole, Palbociclib, Ribociclib, Abemaciclib, and Metabolites in Volumetric Dried Blood Spots: Development and Validation of an LC-MS/MS Method for Therapeutic Drug Monitoring.

Therapeutic drug monitoring (TDM) may be beneficial for cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), such as palbociclib, ribociclib, and abemaciclib, due to established exposure-toxicity relationships and the potential for monitoring treatment adherence. Developing a method for quantifying CDK4/6is, abemaciclib metabolites (M2, M20), and letrozole in dried blood spots (DBS) could be useful to enhance the feasibility of TDM. Thus, an optimized LC-MS/MS method was developed using the HemaXis DB10 device for volumetric (10 µL) DBS collection.

Exploring pharmacokinetic variability of palbociclib in HR+/HER2- metastatic breast cancer: a focus on age, renal function, and drug-gene interactions.

Palbociclib, an oral inhibitor of cyclin-dependent kinase 4 and 6, is approved for the treatment of metastatic breast cancer. This study investigated the influence of diverse clinical and biological factors-age, renal function, genetic variations, and concomitant medications ()-on palbociclib pharmacokinetics. Employing a validated LC-MS/MS method, we analyzed the minimum plasma concentrations (C) of palbociclib in 68 women and determined the percentage deviations from the median C for each dosage group.

Is ctDNA ready to outpace imaging in monitoring early and advanced breast cancer?

Introduction: Circulating tumor DNA (ctDNA) and radiological imaging are increasingly recognized as crucial elements in breast cancer management. While radiology remains the cornerstone for screening and monitoring, ctDNA holds distinctive advantages in anticipating diagnosis, recurrence, or progression, providing concurrent biological insights complementary to imaging results.

Areas Covered: This review delves into the current evidence on the synergistic relationship between ctDNA and imaging in breast cancer.

Early Evaluation of Risk Stratification and Clinical Outcomes for Patients with Advanced Breast Cancer through Combined Monitoring of Baseline Circulating Tumor Cells and DNA.

Purpose: Early evaluation of tumor heterogeneity related to metastasis and outcomes is a major challenge in the management of advanced breast cancer (BCa) in the clinic. In this study, we introduced the value of baseline circulating tumor cells (CTC) and ctDNA for early differentiation of clinical stages, tumor heterogeneity, and prognosis in clinic.

Experimental Design: A total of 292 patients with BCa were enrolled in this study, including 254 Stage IV and 38 Stage III patients, and examined the baseline levels of CTCs, CTC-clusters, and plasma ctDNA before initiating therapies.

Emerging Toxicities of Antibody-Drug Conjugates for Breast Cancer: Clinical Prioritization of Adverse Events from the FDA Adverse Event Reporting System.

Background: Antibody-drug conjugates (ADCs) are gaining widespread use in the treatment of breast cancer, although toxicity remains an underexplored issue in the real-world clinical setting. Individual case safety reports collected in large pharmacovigilance databases can advance our knowledge on their safety profile in routine clinical practice.

Objective: We prioritized adverse events (AEs) reported with ADCs approved for breast cancer using the Food and Drug Administration Adverse Event Reporting System (FAERS).