The Breast Cancer Susceptibility Gene (BRCA)-associated tumors represent a constantly evolving and intriguing scenario in oncology, in which the availability of novel systemic treatment, mainly including the poly (ADP-ribose) polymerase (PARP) inhibitors, has enabled an improved survival benefit in clinical subgroups. The expanding regulatory approvals of PARP inhibitors have inevitably reshaped the clinical indications for BRCA testing, moving the BRCA1/2 profiling from the traditional and preventive workflows to therapeutic paths. Despite advances in technology and treatment, substantial limitations remain in current genetic and genomic tools for the detection of deleterious BRCA1/2 variants. Germline and tumor tissue testing provide only a snapshot of a patient’s disease, failing to capture the dynamic and longitudinal aspects of tumor clonal evolution. In this scenario, liquid biopsy (LB) profiling of BRCA1/2 genes, primarily as circulating tumor DNA, represents a highly active area of research potentially affecting many aspects of cancer screening, diagnosis, and monitoring in individuals who are carriers of BRCA1/2 deleterious variants. Beyond the attractive potential to surrogate the tumor tissue testing, to overcome the cancer spatial and temporal heterogeneity, and to monitor the tumor mutational profile over time, accurately detecting all clinically relevant BRCA genetic variants and epigenetic modifications using LB remains technically challenging.
L. Incorvaia, V. Gristina, F. Pepe et al.· ESMO Open· 0 citations
Circulating tumor DNA (ctDNA) is a tumor‐derived, circulating bioanalyte that can be detected in blood using minimally invasive, blood‐based biomarker procedures and has prognostic value in early breast cancer. Quantitative features of ctDNA, including baseline detectability and levels, have shown prognostic potential in early breast cancer by reflecting tumor burden and biologic aggressiveness, thereby supporting risk stratification. Post‐treatment ctDNA detection may identify minimal residual disease and can precede radiologic or symptomatic recurrence by several months to years. Nevertheless, ctDNA has not yet been adopted in routine clinical practice in early breast cancer, partly because of biologic constraints, including low and heterogeneous tumor DNA shedding, as well as pre‐analytical and analytical variability that can affect testing sensitivity. Ongoing efforts are focused on methodological standardization and clarification of the clinically actionable context. This narrative review examines the challenges in applying ctDNA to early breast cancer, spanning patient selection, sampling logistics, specimen handling, assay performance, and sources of assay failure. The authors outline determinants of ctDNA measurement that restrict the proportion of evaluable patients and limit translation to clinical practice and then summarize evidence supporting ctDNA for early response monitoring during neoadjuvant therapy, postoperative minimal residual disease detection, and longitudinal molecular surveillance. Finally, ctDNA‐guided therapeutic interception strategies and emerging multimodal cell‐free DNA approaches are discussed.
Serena Di Cosimo, V. Appierto, C. Reduzzi et al.· Cancer· 0 citations
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