Evolution of the Use of Circulating DNA as a Biomarker in Neoadjuvant Therapy of Breast Cancer

Background: Breast cancer treatment is often based on multimodal approaches in locally advanced stages typically including neoadjuvant chemotherapy (NACT). There are limited options for the assessment of prognosis and early identification of future non-responders, which has led to the study of circulating cell-free DNA (cfDNA) and its tumor-derived subset, circulating tumor DNA (ctDNA), for potential use as non-invasive markers for prediction of response and prognosis associated with NACT. Methods: We have evaluated the literature on approaches to the use of cfDNA and/or ctDNA as potential biomarkers for NACT. Results: Out of 142 references going back to 2010, we found there were 87 original research reports, 39 reviews, 10 clinical trial reports and six case reports. A detailed analysis revealed several distinctive ways that markers were evaluated in a clinical setting. The original studies have focused on cfDNA, especially cfDNA integrity, whereby increasing integrity levels correlate with tumor shrinkage, reductions in proliferation markers, and hence indicate a better prognosis. Similarly, epigenetic alterations have shown promising results, with methylated ctDNA levels decreasing in responders. Further studies demonstrated the utility of ctDNA persistence through the NACT as strongly associated with shorter disease-free and overall survival. The most recent approaches of longitudinal ctDNA monitoring were found to be valuable for early identification of patients at high risk for post-operative recurrence. Conclusions: It should be noted that while most reports indicate the important role of circulating DNA in the assessment of prognosis and early detection of recurrence, there is currently only a limited utility in the prediction of eventual neoadjuvant therapy outcomes.