DESTINY Breast06 study: HER2-Low and HER2-Ultralow status determination

Dr Elisa Agostinetto, a medical oncologist at Institut Jules Bordet in Brussels, discusses with Prof Dr Giuseppe Viale, a pathologist working at the European Institute of Oncology in Milan, Italy on the results of his study that he presented during the Mini Oral Session on metastatic Breast Cancer. 

The Destiny Breast 06 trial investigated the determination of HER2 status—whether HER2-Low or HER2-Ultralow—in patients with HR+, HER2- metastatic breast cancer. HER2-Ultralow refers to tumours with 10% or fewer cells showing membrane staining. Combined, HER2-Low and HER2-Ultralow tumours account for about 85% of this patient population.

More than 1,600 patient samples underwent local and central HER2 assessment in the trial. Around 20% of these patients were found to have HER2-Ultralow disease, while 80% had HER2-Low disease. A crucial finding was that 94-95% of cases identified as HER2-Low locally were confirmed as either HER2-Low or HER2-Ultralow through central testing. Additionally, local diagnoses of HER2-Low were confirmed centrally in 78% of cases, underscoring a need for improved training and education to enhance diagnostic accuracy. One of the most striking outcomes was the reclassification of patients initially diagnosed as HER2-0. The local assessments did not differentiate between HER2-0 with slight membrane staining and HER2-0 without staining. However, central testing revealed that 40% of these HER2-0 cases were actually HER2-Ultralow, and another 24% were HER2-Low. This means that 64% of patients initially considered HER2-0 were eligible for the trial, which is a significant finding.

Discussing future testing methods, Professor Viale pointed out that current immunohistochemical assays were not designed to detect low HER2 levels. While more precise assays may be developed, the focus should remain on predictive power, not just sensitivity. He suggested that any new test must be proven to be as predictive as current methods like immunohistochemistry, which are the basis for clinical data today.

The discussion also touched on whether T-DXd, the drug under investigation, could be effective in HER2-0 tumours. Professor Viale explained that even in HER2-0, some HER2 molecules are present. The Destiny Breast 15 trial will explore whether T-DXd can benefit patients without detectable HER2 expression. However, he emphasised the importance of distinguishing HER2-positive patients with more treatment options.

Finally, Professor Viale considered whether the benefit of T-DXd in HER2-Low and Ultralow tumours could be due to tumour heterogeneity or minimal HER2 expression. He suggested that in ultra-low HER2 cases, the drug might activate in the tumour’s microenvironment rather than relying directly on HER2 expression. This offers an alternative mechanism for the drug’s effectiveness beyond the bystander effect.