ESMO Open | Application of DNADX ctDNA Testing in Metastatic Breast Cancer

This article reviews DNADX ctDNA testing in metastatic breast cancer patients and demonstrates its subtypes are significantly associated with SG therapy prognosis. It highlights DNADX's value as a potential biomarker for predicting survival outcomes.

 

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, systematically summarizes clinical characteristics and survival outcomes of metastatic breast cancer patients receiving SG therapy while exploring associations between DNADX ctDNA subtypes and treatment efficacy. The study reveals significant correlations between DNADX subtypes and TTNT/OS, where TF-low subtypes correlate with prolonged survival, while proliferative and basal-like-related subtypes indicate poor prognosis. Despite SG's clinical trial efficacy, real-world data and validated biomarkers remain limited, necessitating further research.

Background Knowledge
Metastatic breast cancer (MBC) treatment has advanced through antibody-drug conjugates (ADCs). Sacituzumab govitecan (SG), a Trop2-targeting ADC approved for HER2-negative MBC patients, shows superior PFS and OS versus chemotherapy in registration trials. However, real-world effectiveness and predictive biomarkers remain understudied. DNADX, a ctDNA-based multi-gene expression profiling test, identifies five tumor subtypes: TF-low (X0), CNA-flat (X1), luminal-high (X2), basal-related (X3), and proliferative (X4). These subtypes correlate with distinct tumor biology features including proliferation status, differentiation, and ER status. While DNADX has previously demonstrated associations with CDK4/6 inhibitor efficacy, this study represents the first reported application in ADC therapy.

 

 

Research Methods and Experiments
This single-center retrospective observational study included MBC patients receiving monotherapy with SG between June 2014 and January 2023. Patients with less than 3 months of post-treatment follow-up were excluded. Clinical data including age, race, tumor subtypes, metastatic sites, and treatment lines were collected from DFCI's EMBRACE database. DNADX subtyping used plasma ctDNA low-pass whole-genome sequencing to classify patients into five subtypes, followed by association analysis with TTNT and OS.

Key Conclusions and Perspectives

• 184 patients were analyzed, including 121 TNBC, 59 HR+/HER2-, and 4 HER2+. 75% had visceral metastases, 23.4% had brain metastases.
• Median pre-SG follow-up was 94 days. DNADX subtyping was performed for 74 patients: 46% TF-low (X0), 16% X2, 20% X3, and 18% X4.
• Median TTNT was 4.2 months and OS 10.3 months for overall population without inter-subtype differences. However, DNADX subtypes showed significant associations: X0 subtypes had TTNT 4.3 months and OS 11.3 months; X4 subtypes had TTNT 2.17 months and OS 4.5 months.
• Multivariable analysis revealed X4 subtypes had 2.68-fold increased TTNT risk (P=0.006) versus X0, while X3 subtypes showed 2.29-fold higher mortality risk (P=0.019) versus X0.
• TF-low subtypes comprised 54% of TNBC patients but only 31% of HR+/HER2- cases, potentially reflecting fewer treatment lines and reduced ctDNA release in TNBC populations.

Research Significance and Prospects
This study represents the first systematic analysis of DNADX subtype associations with SG treatment outcomes, suggesting TF-low may predict better efficacy while X3/X4 subtypes necessitate more aggressive treatment strategies. Findings support DNADX as a potential biomarker for treatment selection and prognosis evaluation. Future prospective studies should validate its application in treatment sequencing and explore cross-ADC generalizability.

 

 

Conclusion
This article systematically analyzes SG's real-world efficacy and first reveals significant associations between DNADX ctDNA subtypes with TTNT and OS. TF-low subtypes correlate with prolonged survival, while proliferative and basal-like-related subtypes demonstrate poor prognosis. Although SG's efficacy aligns with clinical trials, overall survival remains below 12 months, highlighting urgent needs for post-ADC treatment strategies. Additionally, the study emphasizes ctDNA's potential for dynamic tumor biology monitoring, suggesting future treatment optimization through combined DNADX subtype analysis.

 

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.