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. In the current era of precision medicine, liquid biopsy holds potential to provide clinicians with additional insights into disease biology, including mechanisms underlying endocrine resistance and disease progression. Several liquid-based biomarkers are entering clinical practice and hold prognostic and predictive values in Luminal-like mBC, while many others are currently being investigated. The present work aims to summarize the current evidence regarding the clinical meanings of hormone receptors and their downstream molecular pathways, alongside their implications for therapeutic decision-making in Luminal-like mBC

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 IVaggressive. Conversely, fewer than five CTCs per 7.5 mL of blood indicates a less aggressive, stage IVindolent disease. Additionally, molecular CTCs characterization provides a real-time snapshot of tumor biology, capturing its temporal and spatial variability and providing insights into tumor behavior. Beyond their role in predicting outcomes, CTCs can help guide treatment intensity as shown in clinical trials like the STIC trial, offering a new way to tailor therapy alongside other liquid biopsy biomarkers such as circulating tumor DNA. The aim of our review is to focus on both enumeration and phenotyping of CTCs and examine how CTC-guided strategies can improve treatment tailoring and patient outcomes. We also explore the potential for integrating CTCs with other biomarkers, such as circulating tumor DNA, and discuss how innovative biomarker-driven clinical trial designs could further advance personalized treatment strategies

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i): Mechanisms of resistance and where to find them

CDK4/6 inhibitors (CDK4/6i) have significantly impacted on the treatment of HR + HER2 negative (HER2-) metastatic breast cancer (BC) when combined with endocrine therapy. Nonetheless, despite significant research efforts, the mechanisms of de novo and acquired resistance to CDK4/6i have not yet been fully elucidated, highlighting the need for a deeper understanding of these process. Additionally, the importance of dissecting CDK4/6i resistance from endocrine resistance for personalized treatment is increasingly recognized. Liquid biopsy has emerged as a minimally invasive tool for identifying circulating biomarkers of resistance through the integration of multiparametric and dynamic assessments that encompass ctDNA, CTCs, exosomes, and epigenetic ctDNA alterations, representing a promising perspective for the clinical characterization of treatment resistance and guiding post-progression strategies to improve patient outcomes. Aim of this review is summarize potential mechanisms of CDK4/6i resistance, along with the advantages of using liquid biopsy to identify resistance biomarkers in HR+/HER2- MBC patients treated with CDK 4/6 inhibitors

Interplay between ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype in patients with metastatic breast cancer (MBC): Comprehensive circulating tumor DNA (ctDNA) analysis

BACKGROUND: although being central for the biology and druggability of hormone-receptor positive, HER2 negative metastatic breast cancer (MBC), ESR1 and PIK3CA mutations are simplistically dichotomized as mutated or wild type in current clinical practice. METHODS: The study analyzed a multi-institutional cohort comprising 703 patients with luminal-like MBC characterized for circulating tumor DNA through next generation sequencing (NGS). Pathway classification was defined based on previous work (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB. Only pathogenic variants were included in the models. Associations among clinical characteristics, pathway classification, and ESR1/PIK3CA codon variants were explored. RESULTS: The results showed a differential pattern of associations for ESR1 and PIK3CA codon variants in terms of co-occurring pathway alterations patterns of metastatic dissemination, and prognosis. ESR1 537 was associated with SNVs in the ER and RAF pathways, CNVs in the MYC pathway and bone metastases, while ESR1 538 with SNVs in the cell cycle pathway and liver metastases. PIK3CA 1047 and 542 were associated with CNVs in the PI3K pathway and with bone metastases. CONCLUSIONS: The study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDS) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making

Circulating Tumor Cells Prediction in Hormone Receptor Positive HER2-Negative Advanced Breast Cancer: A Retrospective Analysis of the MONARCH 2 Trial

Background: The MONARCH 2 trial (NCT02107703) showed the efficacy of abemaciclib, a cyclin-dependent kinase 4 & 6 inhibitor (CDK4/6i), in combination with fulvestrant for hormone receptor-positive, HER2-negative metastatic breast cancer (MBC). The aim of this analysis was to explore the prediction of circulating tumor cells (CTCs) stratification using machine learning for hypothesis generation of biomarker-driven clinical trials. Patients and Methods: Predicted CTCs were computed in the MONARCH 2 trial through a K nearest neighbor (KNN) classifier trained on a dataset comprising 2436 patients with MBC. Patients were categorized into predicted Stage IVaggressive (pStage IVaggressive, ≥5 predicted CTCs) or predicted Stage IVindolent (pStage IVindolent, <5 predicted CTCs). Prognosis was tested in terms of progression-free-survival (PFS) and overall survival (OS) through Cox regression. Results: Patients classified as predicted pStage IVaggressive and predicted pStage Stage IVindolent were, respectively, 183 (28%) and 461 (72%). After multivariable Cox regression, predicted CTCs were confirmed as independently associated with prognosis in terms of OS, together with ECOG performance status, liver involvement, bone-only disease, and treatment arm. Patients in the pStage Stage IVindolent subgroup treated with abemaciclib experienced the best prognosis both in terms of PFS and OS. The treatment effect of abemaciclib on OS was then explored through subgroup analysis, showing a consistent benefit across all subgroups. Conclusion: This study is the first analysis of CTCs modeling for stage IV disease stratification. These results show the need to expand biomarker profiling in combination with CTCs stratification for improved biomarker-driven drug development

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. selective estrogen receptor degraders (SERDs); third-generation aromatase inhibitors (AI) and targeted therapies (e.g., CDK4/6, PI3K, and mTOR inhibitors)) as well as antibody drugs conjugates (ADC, eg. T-DXd and SG) showed promising results with meaningful improvements in survival for patients with metastatic HR + HER2 − BC. Therapy selection is mainly based on clinical, tumor pathological and molecular characteristics as well as on efficacy based on trial data, nevertheless, side effect profiles are key differentiators of treatments in the metastatic setting. Therefore, understanding how patients evaluate various treatment attributes and how these change in different clinical situations is fundamental toward the choice of optimal therapeutic strategies for treating metastatic HR + HER2 − Stage IV patients. Here, we investigated treatment preferences of a total of 102 stage IV HR + HER2 − breast cancer patients in Italy by developing and applying a survey instrument based on discrete choice experiment (DCE). Treatment efficacy was the top valued attribute across all patient segments and the second most important attribute was the risk of grade ≥ 3 adverse events (AE). Overall, therapies with better outcomes of PFS or AE grade 3 or higher would have a higher impact on the preference to choose a treatment from a patient perspective

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). Risk assessment may be daunting and clarity regarding definitions and data is needed. An interdisciplinary workshop, termed the Multiple In-treatment Risk Assessment & Management, was conceived to provide dermatologists with a platform for multidisciplinary exchange on risk assessment in patients with MACE, cancer and VTE to correctly recognise patients with increased risk. In this review, we characterised common and less common patient profiles in order to assess the risk. With the cooperation of a cardiologist, oncologist, respiratory medicine specialist and haematologists, we identified the risk factors for MACE, cancer and VTE. The results show that taking a careful medical history is the basis of risk assessment and that a careful medical history should be performed regardless of the intended therapy in AD. We propose that risk levels be used in the general population as a benchmark to evaluate risk levels in patients with AD, and provide a checklist to support such risk assessments in routine clinical practice. Our work provides a clear framework for risk assessment to the community of dermatologists and, therefore, contributes to improving the standard of care in AD