Abstract B019: Clinical and molecular correlates of circulating tumor DNA (ctDNA) dynamics in breast tumors resistant to neoadjuvant therapy (NAT)

• Published in: Clinical cancer research 2024-11, Vol.30 (21_Supplement), p.B019-B019
• Main Authors: Magbanua, Mark Jesus M., Wolf, Denise M., Rivera-Hinojosa, Samuel, Ahmed, Ziad, Manon, Nayelis A., Sayaman, Rosalyn, Tin, Antony, Kalashnikova, Ekaterina, Swigart, Lamorna Brown, Hirst, Gillian L., Yau, Christina, Li, Wen, Isaacs, Claudine, Shatsky, Rebecca A., Delson, Amy L., Palsuledesai, Charuta C., Rodriguez, Angel, Liu, Minetta C., Pohlmann, Paula R., Esserman, Laura J., Rugo, Hope S., DeMichele, Angela, Veer, Laura van 't
• Format: Article
• Language: English
• ISSN: 1557-3265; 1557-3265
• DOI: 10.1158/1557-3265.LIQBIOP24-B019

Purpose: We examined the utility of serial ctDNA testing for refining risk stratification of NAT- resistant tumors (RTs, defined as residual cancer burden, RCB-II/III) and predicting early treatment response. We also characterized the molecular correlates of ctDNA dynamics in RTs to elucidate the mechanisms associated with increased metastatic potential. Methods: We performed serial ctDNA testing using a tumor-informed personalized assay (SignateraTM, Natera Inc.) in 723 patients (pts) with high-risk early-stage breast cancer receiving NAT (I-SPY2). Tumors were stratified according to RCB class and ctDNA dynamics (clearance patterns), and the distant recurrence-free survival (DRFS) between groups was compared. We examined the predictive value of ctDNA dynamics using the RCB index (the continuous measure of RCB) as the response endpoint. Serial whole exome sequencing (WES), gene expression profiling (GEP), and reverse-phase protein analysis (RPPA) data were analyzed to elucidate the molecular biology of RTs. Results: Of the 723 pts, 300 (41%) had hormone receptor (HR)+HER2-, 237 (33%) triple-negative (TN), and 186 (26%) HER2+ breast cancers with pretreatment ctDNA-positivity rates of 76%, 92%, and 77%, respectively. 321 (45%) pts had responding tumors (RCB-0/I), and 55% had RTs: RCB-II (n=255) and RCB-III (n=132). CtDNA dynamics revealed heterogeneity in the metastatic potential of RTs, including tumors with a reduced propensity to metastasize (persistent ctDNAneg and early clearance). Failure to clear ctDNA after NAT was associated with an increased risk of metastatic recurrence and death (3-yr DRFS rates: no clearance=35% vs. persistent ctDNAneg=98%, p