Abstract A014: Cell-free DNA concentration as a biomarker of response and recurrence in HER-2 negative breast cancer receiving neoadjuvant chemotherapy
Authors: Magbanua Mark Jesus M. , Ahmed Ziad , Sayaman Rosalyn W. , Brown-Swigart Lamorna , Hirst Gillian L. , Yau Christina , Wolf Denise M. , Li Wen , Delson Amy L. , Perlmutter Jane , Symmans W. Fraser , Yee Douglas , Hylton Nola M. , Esserman Laura J. , DeMichele Angela M. , Rugo Hope S. , van ’t Veer Laura J. 
Published: February 2024

Abstract
Purpose: Cell-free DNA (cfDNA) shed into the blood by dying cells and its subset—circulating tumor DNA (ctDNA) exclusively released by tumors—are promising non-invasive biomarkers for predicting treatment response and survival. We sought to determine the clinical significance of cfDNA concentration in comparison to that of circulating tumor DNA (ctDNA) in patients with high-risk HER2-negative breast cancer receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. Methods: 283 patients with early-stage breast cancer (145 hormone receptor (HR)-positive/HER2-negative and 138 triple-negative) who had ctDNA data from a previous study (Magbanua et al. Cancer Cell 2023) were included in the analysis. CfDNA concentration in plasma was measured at pretreatment, during, and after NAC before surgery. Associations of cfDNA concentration (as a continuous and dichotomous variable using the median as cutoff) with clinicopathologic variables, response, and survival were examined. In addition, ctDNA data from the same cohort using a personalized tumor-informed test was available for comparative analysis (Magbanua et al., Cancer Cell 2023). The response endpoint was residual cancer burden (RCB) after NAC. The survival endpoint was distant recurrence-free survival (DRFS). Results: There were no significant differences in cfDNA concentration between the HR-positive/HER2-negative and TNBC groups at any time point. In the TNBC group, but not in HR-positive/HER2-negative group, high pretreatment cfDNA concentration was significantly associated with larger tumors (clinical stage T3/T4, Wilcoxon p=0.023) and higher grade (grade 3, Fisher p=0.0134). TNBC patients with no residual cancer (RCB-0 or pathologic complete response) after NAC had significantly higher cfDNA concentration 3 weeks after treatment initiation than those with extensive residual cancer after NAC (RCB-III, Kruskal-Wallis adjusted p=0.034). In the HR-positive/HER2-negative group, cfDNA concentration did not associate with response to NAC, but survival analysis showed that high cfDNA shedders at pretreatment had a significantly worse DRFS than low shedders (hazard ratio 2.12, 95% confidence interval 1.05-4.60, p=0.037). However, in the TNBC group, the difference in survival between high vs. low cfDNA shedders at all time points was not statistically significant. In contrast, as previously reported, ctDNA at all time points was significantly correlated with metastatic recurrence and death in both HR-positive/HER2-negative and TNBC groups (Magbanua et al., Cancer Cell 2023). Conclusions: In TNBC, cfDNA concentration reflected tumor burden, aggressiveness, and early response to NAC. In the HR-positive/HER2-negative group, pretreatment cfDNA concentration was prognostic for DRFS. Overall, the predictive and prognostic value of cfDNA concentration was more limited than that of ctDNA. Thus, ctDNA should be the measurement of choice when planning clinical interventions.
Citation Format: Mark Jesus M. Magbanua, Ziad Ahmed, Rosalyn W. Sayaman, Lamorna Brown-Swigart, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Wen Li, Amy L. Delson, Jane Perlmutter, W. Fraser Symmans, Douglas Yee, Nola M. Hylton, Laura J. Esserman, Angela M. DeMichele, Hope S. Rugo, Laura J. van ’t Veer. Cell-free DNA concentration as a biomarker of response and recurrence in HER-2 negative breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A014.