Prognostic Value of DNADX ctDNA Subtypes in Triple-Negative and Hormone Receptor-Positive Metastatic Breast Cancer

This study is the first to explore the significant association between DNADX ctDNA subtypes and prognosis of metastatic breast cancer patients receiving sacituzumab govitecan in real-world clinical practice, providing new directions for personalized treatment strategies.

 

Literature Overview
This article titled 'Survival outcomes and the role of DNADX ctDNA testing in patients treated with sacituzumab govitecan for metastatic breast cancer' published in ESMO Open conducted a retrospective review and summarized clinical characteristics and efficacy data from 184 metastatic breast cancer patients treated with SG monotherapy. It further investigated the prognostic implications of DNADX ctDNA subtypes while validating their correlation with time to next treatment (TTNT) and overall survival (OS).

Background Knowledge
Metastatic breast cancer (MBC) represents a highly heterogeneous disease where traditional therapeutic approaches have limited efficacy. Antibody-drug conjugates (ADCs) like sacituzumab govitecan (SG) have emerged as crucial treatment options, particularly for HER2-low or negative patients. SG achieves targeted cancer cell destruction by binding Trop2 (encoded by TACSTD2 gene) and delivering topoisomerase I inhibitor SN-38. While SG demonstrated significant progression-free survival (PFS) and OS improvements in phase III clinical trials (e.g., ASCENT and TROPICS-02), real-world efficacy data and predictive biomarkers remain insufficient. DNADX is a plasma-based multi-gene expression profiling assay for circulating tumor DNA (ctDNA) that identifies five tumor subtypes (TF-low, CNA-flat, luminal-high, basal-related, proliferative), each associated with distinct biological features including proliferation status, differentiation levels, and ER expression. Previous studies confirmed DNADX subtypes' correlation with CDK4/6 inhibitor responses, but this is the first report demonstrating their application in ADC therapy. This study aims to fill the evidence gap regarding real-world SG efficacy and evaluate DNADX subtypes as potential prognostic biomarkers to optimize treatment sequencing and outcome prediction.

 

 

Research Methods and Experiments
This retrospective single-center study included 184 MBC patients treated with SG monotherapy at Dana-Farber Cancer Institute between June 2014 and January 2023. Clinical, pathological, and treatment data were extracted from the EMBRACE database. TTNT and OS were analyzed with DNADX subtyping performed on baseline ctDNA samples through low-pass whole genome sequencing. Tumor fraction (TF) was calculated and subtypes classified into five DNADX categories. Survival curves were analyzed using Kaplan-Meier methods, with univariate and multivariate Cox regression models assessing associations between DNADX subtypes and clinical outcomes.

Key Conclusions and Perspectives

• Among 184 patients, 121 had triple-negative breast cancer (TNBC), 59 had HR+/HER2− MBC, and 4 had HER2+ MBC. Median TTNT was 4.3 months and median OS was 10.3 months, consistent with registration trial results.
• TF-low (X0) subtype correlated with longest TTNT and OS, while proliferative (X4) and basal-related (X3) subtypes demonstrated poorer prognoses. Multivariate analysis showed proliferative subtype had significantly higher TTNT risk than TF-low (HR=2.68).
• Findings support DNADX subtypes as potential biomarkers for predicting SG efficacy, providing evidence for optimizing treatment sequencing and outcome prediction.
• Despite stable real-world efficacy, 42.9% TNBC patients had prior immunotherapy and 7.1% received trastuzumab deruxtecan (T-DXd), highlighting the need to monitor cross-resistance potential.

Research Significance and Prospects
This study provides the first real-world clinical evidence validating significant associations between DNADX subtypes and SG efficacy. Future prospective studies with larger cohorts are needed to confirm these predictive values, while exploring optimal combination strategies following SG treatment.

 

 

Conclusion
Through retrospective analysis of 184 metastatic breast cancer patients receiving sacituzumab govitecan (SG), this study first demonstrated DNADX ctDNA subtypes' clinical relevance to TTNT and OS in real-world settings. TF-low subtype showed most favorable prognosis while proliferative and basal-related subtypes correlated with poorer survival outcomes. These findings identify potential biomarkers for SG efficacy prediction and emphasize the necessity for optimized treatment strategies following ADC therapies.

 

S Morganti, RJ Kusmick, ME Hughes, SM Tolaney, and A Giordano. Survival outcomes and the role of DNADX ctDNA testing in patients treated with sacituzumab govitecan for metastatic breast cancer. ESMO Open.