Genomic Assays Predict T-DXd Response in Metastatic Breast Cancer

New data derived from the phase 2 DAISY trial (NCT04132960) suggest that 2 novel genomic assays, HER2DX and DNADX, may serve as predictive biomarkers for clinical outcomes in patients with metastatic breast cancer (mBC) treated with the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd; Enhertu). The findings indicate that quantitative assessment of ERBB2/HER2 expression and genomic instability can refine patient selection beyond traditional immunohistochemistry (IHC) and in situ hybridization (ISH).^1,2

Predictors of Response to Trastuzumab Deruxtecan

T-DXd has revolutionized the treatment landscape for HER2-positive and HER2-low metastatic breast cancer. However, clinical response remains heterogeneous, particularly in patients with lower levels of HER2 expression. The DAISY trial was designed to evaluate the efficacy of T-DXd across varying levels of HER2 expression, including HER2-zero cohorts.

The recent analysis utilized HER2DX, a 27-gene expression signature, to evaluate its predictive utility.¹ Investigators found that the HER2DX ERBB2 score—a component of the assay measuring quantitative mRNA levels—significantly correlated with objective response rates (ORR) and progression-free survival (PFS). In the DAISY cohort, higher ERBB2 mRNA levels were associated with a higher probability of response to T-DXd regardless of the IHC status. This suggests that mRNA-based quantification may capture a more nuanced spectrum of HER2 biology than protein-based assays alone.

The Role of Genomic Instability

In addition to HER2 expression, the study explored the predictive value of DNADX, a DNA-based assay designed to measure genomic instability. The rationale stems from the mechanism of action of T-DXd; as an ADC carrying a topoisomerase I inhibitor payload, its efficacy may be influenced by the underlying DNA repair capacity of the tumor cells.

The analysis revealed that patients with high DNADX scores experienced significantly improved PFS compared with those with lower scores. This correlation suggests that tumors characterized by high genomic instability are more susceptible to the cytotoxic effects of the deruxtecan payload. When combined with HER2DX, the assays provided a comprehensive genomic profile that could potentially identify patients most likely to derive long-term benefit from this specific ADC.

Clinical Implications for Precision Oncology

The current standard for determining HER2 status relies on IHC and ISH, which are subject to inter-observer variability, especially in the HER2-low (IHC 1+ or IHC 2+/ISH–) and HER2-zero categories. As the therapeutic indications for trastuzumab deruxtecan expand, the need for precise, reproducible biomarkers becomes critical.

“Antibody-drug conjugates like [T-DXd] have transformed the treatment landscape for metastatic breast cancer, but reliable biomarkers to guide their use remain limited,” Paolo Tarantino, MD, PhD, medical oncologist, advanced fellow at Dana-Farber Cancer Institute and first author of the study, said in a news release.² “Our findings suggest that tests, including tissue-based HER2DX and plasma-based DNADX, may help better identify patients most likely to benefit from this therapy.”

In the DAISY trial, T-DXd demonstrated activity even in patients classified as HER2-zero by IHC, yet the degree of benefit varied. The ability of HER2DX to identify ERBB2 expression in these cases provides a molecular explanation for the observed clinical activity in HER2-negative populations.

Future Directions

While these results are promising, the application of HER2DX and DNADX in routine clinical practice requires further validation in larger, randomized controlled trials. The current data emphasize the evolving role of specialized genomic testing in optimizing treatment sequences for mBC. As oncologists manage an increasing number of ADCs in their armamentarium, the ability to predict which patients will achieve a durable response versus those who may require alternative strategies will be paramount.

T-DXd continues to be evaluated in multiple clinical settings, including the early-stage adjuvant environment. The potential to use these genomic tools to guide therapy in earlier lines of treatment remains an area of active investigation.

REFERENCES

1. Tarantino P, Kim SE, Hughes ME, et al. Quantitative HER2 tissue and plasma profiling predicts the activity of trastuzumab deruxtecan for breast cancer. NPJ Precis Oncol. 2026 Mar 13;10(1):141. doi: 10.1038/s41698-026-01365-6. PMID: 41826432; PMCID: PMC13046964.

2. Study links reveal genomics assays HER2DX and DNADX to response to trastuzumab deruxtecan in metastatic breast cancer. News release. Reveal Genomics. April 8, 2026. Accessed April 10, 2026. https://tinyurl.com/yc3e42dz