Higher Pretreatment HER2 Amplicon mRNA Signature Predicts Improved Outcomes With Trastuzumab Deruxtecan in Metastatic Breast Cancer

T-DXd in Metastatic Breast Cancer |

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Patients with metastatic breast cancer who had higher pre-treatment HER2 amplicon mRNA (HER2DX) signatures and HER2 proteins (RPPA) who were treated with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) experienced a longer median time to next treatment (TTNT) compared with those with lower signatures and RPPA levels, according to data from a retrospective study presented in a poster during the 2025 ASCO Annual Meeting.

In HER2 amplicon tertiles, the reference group for low had a median TTNT of 4.52 months (95% CI, 3.13-7.23), the medium group was 5.33 months (95% CI, 4.7-not applicable [NA]; HR, 0.71; 95% CI, 0.33-1.55; log-rank P = .019), and the high group was 12.02 months (95% CI, 7.37-NA; HR, 0.23; 95% CI, 0.08-0.69; P = .019).

The median TTNT was 4.03 months (95% CI, 2.87-NA) for those with HER2 protein expression of 25% or less, 5.83 months (95% CI, 2.13-NA) for 25% to 50% (HR, 0.64; 95% CI, 0.25-1.61), 8.0 months (95% CI, 5.33-NA) for 50% to 75% (HR, 0.28; 95% CI, 0.10-0.74), and 9.07 months (95% CI, 5.83-NA) for more than 75% (HR, 0.30; 95% CI, 0.12-0.75; log-rank P = .019). Additionally, RPPA-based HER2 protein expression showed a significant association for TTNT with T-DXd when it was divided into quartiles (P = .02).

The median TTNT for shorter RPPA expression of TOPO1 was 5.87 months (95% CI, 4.90-NA), and it was 2.7 months (95% CI, 2.47-NA) for higher expression (HR, 3.49; 95% CI, 1.02-11.96; log-rank P = .036). This expression showed a significant association for TTNT with T-DXd use for patients with HER2-negative metastatic breast cancer who have a higher association of TOPO1 and are associated with shorter TTNT and T-DXd use (P = .036).

Of note, the HER2DX signature was found to be significantly associated with T-DXd (P = .001).

“Higher pre-treatment HER2 amplicon mRNA signature [HER2DX] and HER2 protein [RPPA] expression predicted improved outcomes with T-DXd for [metastatic breast cancer],” Paolo Tarantino, MD, PhD, an advanced research fellow in the Breast Oncology Program at Dana-Farber Cancer Institute in Boston, Massachusetts, and co-authors wrote in the presentation. “Higher Topo1 protein expression was associated with worse outcomes with T-DXd among patients with HER2-negative metastatic breast cancer.”

The aim of the trial was to evaluate the association for each marker, continuously and by tertiles/quartiles with TTNT while on T-DXd. Pre-treatment tumor samples of FFPE were retrieved from patients with metastatic breast cancer at Dana-Farber Cancer Institute between July 2017 and January 2023. At the beginning of T-DXd treatment, patients were categorized by HER2 immunohistochemistry status.

The RPPA-based protein assessment for HER and Topo1 was performed in the CLIA laboratory and was conducted after laser capture microdissection enrichment of tumor epithelium. The HER2DX standardized assay was performed after the RNA extraction.

Overall, 41 patients were tested for HER2DX, with 25 having HER2-positive metastatic breast cancer and 16 having HER2-negative disease; while 38 patients were tested for RPPA, with 24 having HER2-positive disease and 14 having HER2-negative.

For HER2 amplicon mRNA expression, there was a 1-unit increase (HR, 0.70; 95% CI, 0.56-0.87; Wald test, P = .001). HER2 RPPA protein expression had a 10-unit increase (HR, 0.95; 95% CI, 0.90-1.01; Wald test; P = .083).

Tarantino and co-authors explained that the evaluation of the novel assays was to help quantify T-DXd antibody expression and payload target, with the association of real-world outcomes. However, a limitation of this study was that it was retrospective with small sample sizes and no correction for multiple hypothesis testing.

“Work is ongoing to expand the sample size and validate the findings from these pilot studies,” Tarantino concluded.

Reference

Tarantino P, Kim A, Hughes M, et al. Quantitative pre-treatment assessment of trastuzumab deruxtecan (T-DXd) antibody target (HER2) and payload target (topoisomerase 1, topo1) to predict outcomes in metastatic breast cancer (MBC). J Clin Oncol. 2025;43(suppl 16):1032. doi:10.1200/JCO.2025.43.16_suppl.1032