Clinical significance and biology of circulating tumor DNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy

• Published in: Cancer cell Vol. 41; no. 6; pp. 1091 - 1102.e4
• Main Authors: Magbanua, Mark Jesus M., Brown Swigart, Lamorna, Ahmed, Ziad, Sayaman, Rosalyn W., Renner, Derrick, Kalashnikova, Ekaterina, Hirst, Gillian L., Yau, Christina, Wolf, Denise M., Li, Wen, Delson, Amy L., Asare, Smita, Liu, Minetta C., Albain, Kathy, Chien, A. Jo, Forero-Torres, Andres, Isaacs, Claudine, Nanda, Rita, Tripathy, Debu, Rodriguez, Angel, Sethi, Himanshu, Aleshin, Alexey, Rabinowitz, Matthew, Perlmutter, Jane, Symmans, W. Fraser, Yee, Douglas, Hylton, Nola M., Esserman, Laura J., DeMichele, Angela M., Rugo, Hope S., van ’t Veer, Laura J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.06.2023
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biology; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; circulating tumor DNA; Circulating Tumor DNA - genetics; Clinical Relevance; Female; gene expression; Humans; neoadjuvant chemotherapy; Neoadjuvant Therapy; pathologic complete response; receptor subtype; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; residual cancer burden; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; neoadjuvant chemotherapy; pathologic complete response; residual cancer burden; receptor subtype; gene expression; circulating tumor DNA
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2023.04.008

Circulating tumor DNA (ctDNA) analysis may improve early-stage breast cancer treatment via non-invasive tumor burden assessment. To investigate subtype-specific differences in the clinical significance and biology of ctDNA shedding, we perform serial personalized ctDNA analysis in hormone receptor (HR)-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. ctDNA positivity rates before, during, and after NAC are higher in TNBC than in HR-positive/HER2-negative breast cancer patients. Early clearance of ctDNA 3 weeks after treatment initiation predicts a favorable response to NAC in TNBC only. Whereas ctDNA positivity associates with reduced distant recurrence-free survival in both subtypes. Conversely, ctDNA negativity after NAC correlates with improved outcomes, even in patients with extensive residual cancer. Pretreatment tumor mRNA profiling reveals associations between ctDNA shedding and cell cycle and immune-associated signaling. On the basis of these findings, the I-SPY2 trial will prospectively test ctDNA for utility in redirecting therapy to improve response and prognosis. [Display omitted] •Early clearance of ctDNA in triple-negative patients associates with good response•ctDNA dynamics during neoadjuvant chemotherapy predict clinical outcomes•ctDNA negativity associates with improved survival despite having residual cancer•Expression analysis reveals pathways associated with ctDNA shedding Magbanua et al. examine the dynamics of ctDNA in plasma of high-risk early-stage breast cancer patients receiving neoadjuvant chemotherapy. Understanding the predictive and prognostic value of ctDNA and biology of ctDNA shedding in different breast cancer subtypes can inform the use of ctDNA for treatment selection to improve patient outcomes.