Neoadjuvant therapy and translational biomarkers for metastatic risk in early breast cancer

Distant recurrence remains a significant cause of mortality in patients with breast cancer (BC). While metastasis was once considered a late event, current evidence suggests that metastatic seeding occurs early. There is thus significant interest in neoadjuvant therapy (NAT) as a window of opportunity to decrease metastatic risk. While NAT has classically consisted of chemotherapy, targeted therapies, such as human epidermal growth factor 2 (HER2)-targeted therapies and immune checkpoint inhibitors (ICIs), are now offered to patients with HER2-positive and triple-negative (TN) BC, respectively. As therapies evolve, there is a growing need to identify reliable biomarkers to predict NAT response and monitor microscopic disease post-NAT. This review explores the interplay between metastasis biomarkers and NAT for HER2-positive and TNBC. Circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), disseminated cancer cells (DCCs), and tumour-infiltrating lymphocytes (TILs) provide longitudinal insights into residual disease, immune dynamics, and genomic alterations. This review critically examines the established and emerging prognostic, predictive, and response-adaptive roles of these biomarkers in the neoadjuvant setting and beyond. Clinical adoption of novel biomarker approaches has been challenging due to reliance on tissue biopsy during an already challenging treatment journey. However, liquid biopsy approaches like CTC and ctDNA analyses provide minimally invasive means of monitoring metastatic risk. Technological advancements, such as methylome sequencing and variant-based ctDNA detection, offer promise for improved sensitivity and validity. While further trials are required to establish their clinical utility, integrating these biomarker-informed assays may inform precise metastasis risk assessment and improve patient outcomes.