Elucidating the Impact of TROP2 on T-DXd Efficacy in Breast Cancer

For Adriana Kahn, MD, an assistant professor of Medical Oncology and Hematology in the Center for Breast Cancer and the Drug Development Department at Yale Cancer Center, future research will explore the relationship between TROP2 expression and the efficacy of a HER2 antibody drug conjugate (ADC), such as fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), among patients with advanced, previously treated breast cancer.

In an interview with CancerNetwork®, Kahn discussed a presentation of the phase 2 HER2 PARADIGM trial (NCT06750484) she gave at the 2025 San Antonio Breast Cancer Symposium (SABCS), which examined T-DXd in previously treated HER2-immunohistochemistry (IHC) 0 advanced breast cancer.¹ Specifically, she touched upon hypotheses synthesized based on the impact of TROP2 levels on responses to T-DXd in this patient population.

She began by highlighting the Troplex^TM assay that David Rimm, MD, PhD, the Anthony N. Brady Professor of Pathology and Professor of Medical Oncology at the Yale Cancer Center, published results for at the conference, which revealed an inverse relationship between HER2 and TROP2 expression: typically, when one is higher, the other one is lower.²

Applying that to her own presentation, she explained that the phase 2 trial is still accruing, but data would help to understand whether patients would still derive benefit from T-DXd with HER2-low or HER2-negative disease, regardless of TROP2 expression. She concluded by highlighting her hypothesis for T-DXd among TROP2-expression patients: “Does TROP2 have anything to do with the activity of a HER2 ADC?”

Transcript:

[David Rimm, MD, PhD], has released the results of his assay. As I mentioned, his Troplex assay does quantification of both HER2 and TROP2. He has seen, so far, that the more HER2 you express with his assay in that tumor, the less TROP2 you would have. And the other way around, the more TROP2 you have, the less HER2 you would have. It might seem that patients with HER2 immunohistochemistry (IHC) 0 may have lower expression of HER2, but may [have] higher expression of TROP2.

We are yet to see that in our patient population since we are still accruing, but that can [help] us understand if, indeed, these are low HER2-expressers, they might not derive that much benefit. Also, to understand does TROP2 play a role in that too? Does having TROP2, independent of your HER2 levels, also dictate your response to a totally different drug targeting another antibody? Since we have access to the data, we will understand [whether] they interplay. Are there any mechanistic processes that make HER2 and TROP2 communicate, or allow these drugs to respond differently depending on [their levels]? This is one of our hypotheses: Does TROP2 have anything to do with the activity of a HER2 ADC?

References

1. Kahn A, Du J, Casasanta N, et al. Open-label single-arm phase 2 trial of trastuzumab deruxtecan in previously treated HER2-immunohistochemistry (IHC) 0 advanced breast cancer – HER2 PARADIGM trial. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract PS5-08-07
2. Chan N, Bates KM, Benanto J, et al. Abstract P2-01-19: Measurement of ADC targets HER2 and TROP2 in breast cancer for accuracy and selection. Clin Cancer Res. 2025;31(suppl 12):P2-01-19. doi:10.1158/1557-3265.SABCS24-P2-01-19