Clinically, the work argues for treating HER2 as a continuous variable, supports rebiopsy or longitudinal monitoring, and suggests ctDNA-based signatures could guide ADC therapy, moving toward integrated molecular profiling over binary HER2 categories.

Temporal dynamics matter: patients whose tumors stayed HER2-low from primary to metastatic sites had longer time-to-next-treatment on T-DXd than those whose tumors shifted to HER2-0, emphasizing longitudinal profiling.

The HER2DX transcriptomic signature shows that higher ERBB2-related gene expression and ERBB2 mRNA levels predict longer TTNT and survival, while other immune or proliferation signatures are less predictive.

The work spans four years with mentorship from Sara Tolaney and collaboration across Dana-Farber, Yale, Reveal Genomics, Ignite Proteomics, Duke Cancer, and patient advocates.

Real-world data from 191 metastatic breast cancer patients show meaningful T-DXd activity across HER2 subgroups, with median overall survival of 23.1 months (HER2-positive), 14.2 months (HER2-low), and 9.5 months (HER2-0), highlighting differences from controlled trials.

If validated in larger prospective studies, these approaches could refine patient selection, sequencing, and personalization of ADC therapies in metastatic breast cancer.

A new study in npj Precision Oncology investigates whether quantitative profiling of HER2 in tissue and plasma improves prediction of responses to trastuzumab deruxtecan (T-DXd) in metastatic breast cancer beyond standard HER2 IHC categorization.

The Nature-affiliated journal npj Breast Cancer publishes the paper, titled “Quantitative HER2 tissue and plasma profiling predicts the activity of trastuzumab deruxtecan for breast cancer,” reflecting broad collaboration.

Paolo Tarantino and colleagues find that precise HER2 profiling in tissue and plasma better predicts T-DXd activity than traditional IHC scoring, suggesting ADCs may need more sensitive assays.

Genomic analyses identify resistance mechanisms, including ERBB2 loss in about 15% of HER2-negative cases linked to shorter TTNT and survival, with baseline TP53 mutations predicting poorer outcomes and ARID1B enrichment after treatment indicating clonal evolution.

Proteomic analysis shows higher HER2 levels and activation (phosphorylation at Y1248) align with better outcomes, while payload markers (TOPO1, SLFN11) reveal additional factors shaping efficacy beyond HER2 alone.

Funding and support acknowledged from the Terri Brodeur Foundation, METAvivor, and the Saverin family to advance precision in ADC therapy.