Dr Pistilli on Understanding Dynamic HER2 Expression in Metastatic Breast Cancer

Barbara Pistilli, MD, medical oncologist, chair, Breast Disease Committee, Gustave Roussy Institute, France, discusses the importance of understanding how HER2 expression can change over time when assessing target expression in metastatic breast cancer.

Third generation antibody-drug conjugates (ADC) demonstrate variable activity across a wide range of target expression. Although surface protein expression is often used to predict responses to these agents, the ADC’s activity is also influenced by the evolution of target expression, spacial distribution, and internalization Accordingly, understanding when and how to assess target expression can help maximize the efficacy of third-generation ADCs in this space, Pistilli says.

In a retrospective study presented at the 2023 ASCO Annual Meeting, investigators assessed the ability of successive biopsies to identify dynamic HER2-low status in patients with triple-negative breast cancer, Pistilli introduces. A total of 789 patients were selected from an institutional database of individuals treated at a single academic centerbetween 2000 and 2022. A total of 512 patients were enrolled in the overall study. Results showed that high probability of a HER2-low result correlated with a greater number of biopsies conducted, she reports. Moreover, new HER2-low results were also consistently detected with a second or third biopsy in 32% and 33% of patients who were originally HER2 negative according to immunohistochemistry (IHC), respectively, Pistilli adds. Overall, these results indicate discordance in HER2 expression, Pistilli states.

Prior research has also demonstrated this HER2 discordance in metastatic breast cancer, Pistilli continues. A previous retrospective study showed a HER2 discordance rate of 38% with unstable HER2-low expression in patients with hormone receptor (HR)–positive and HR-negative breast cancer from the discovery of primary disease to the time of disease recurrence. HER2 IHC score also increased in 45% of patients within this time.

Moreover, analysis of secondary resistance in the phase 2 DAISY trial (NCT04132960) showed a decrease in HER2 expression from baseline to the time of progression in 65% of patients treated with fam-trastuzumab deruxtecan-nxki (Enhertu).

Such results could potentially be attributed to recent changes in the definition of HER2 low as well as improved analytic methods. Although biopsies should be performed throughout disease evolution, the question remains as to the optimal frequency of biopsies performed in this population, Pistilli concludes.