Tracking Early Immunotherapy Response in mTNBC Using cfDNA-Based Copy-Number Profiling

A study published in Cell Reports Medicine (December 2025) explores a non-invasive biomarker approach for tracking immune checkpoint blockade (ICB) response in metastatic triple-negative breast cancer (mTNBC). They leveraged plasma-derived cell-free DNA (cfDNA) to measure genomic instability through copy-number alteration (CNA) profiling.

Researchers from the Netherlands Cancer Institute and collaborators analyzed data from 87 patients with mTNBC enrolled in phase II of the TONIC clinical trial evaluating the anti-PD1 treatment nivolumab (NCT02499367). Their focus was on the copy-number profile abnormality (CPA) score, which is a quantitative measure of plasma cfDNA-based CNA burden. CPA scores were calculated by comparing each patient’s cfDNA-based CNA profile to the average CNA profile of healthy reference samples, with higher scores reflecting profiles with greater genomic instability. 

Key Findings

• Early CPA Score Dynamics Correlate with Response
  Patients classified as responders (n=26) to nivolumab therapy demonstrated a marked reduction in CPA scores after three treatment cycles (week 6), with a median drop of 2.77 points (p = 0.0006). Non-responders (n=61), in contrast, showed stable or increasing CPA scores over time.
• CPA Score Reduction Is Associated with Improved Survival
  A fold change in CPA scores (week 6 vs. baseline) below the cohort median (0.93) was significantly associated with improved overall survival (HR = 1.86, 95% CI = 1.16–2.97, p = 0.01) and progression-free survival (HR = 1.84, 95% CI = 1.19–2.85, p = 0.006), even after adjusting for PD-L1 expression and disease-free interval.
• Baseline Predictors of Favorable Dynamics
  Tumors with higher baseline stromal tumor-infiltrating lymphocytes and PD-L1 combined positive scores were more likely to exhibit significant decreases in CPA scores.
• cfDNA Levels Alone Were Less Informative
  Unlike dynamic CPA scores, absolute cfDNA concentrations at baseline or during treatment did not correlate significantly with treatment response or survival. 

Limitations

While CPA score dynamics show promise, the study was exploratory and non-randomized. Because patients received short, low-dose induction treatments prior to nivolumab, a potential influence of induction therapy on CPA dynamics cannot be fully excluded, despite no tumor responses by iRECIST. 
Validation in larger, real-world cohorts, particularly in chemo-immunotherapy settings, and establishment of standardized CPA thresholds are therefore needed.

Clinical Implications

This study highlights the potential use of cfDNA-based CNAs as non-invasive biomarkers for assessing early ICB response. The approach is particularly relevant for mTNBC, a genomically unstable cancer type with limited actionable mutations but frequent CNAs. The CPA score may serve as a complementary biomarker to existing tissue-based markers such as PD-L1, which have limited predictive accuracy in this setting.

Reference
Lin AY, Isaeva OI, Deger T, et al. CfDNA-based copy-number dynamics during anti-PD1 treatment in metastatic triple negative breast cancer. Cell Rep Med. 2025;6(12):102512. doi:10.1016/j.xcrm.2025.102512