New early-phase trial data is starting to show that HER2-targeting agents elicit clinical benefits for patients with low HER2 expression, leading to the question, ‘how low can we go?’. Guy Jerusalem, MD, PhD, Domaine Universitaire du Sart Tilman, Liège, Belgium, discusses how the indications for HER2-targeting agents are evolving beyond just patients with HER2-overexpressing tumors, to individuals with estrogen receptor (ER)-positive and triple negative breast cancer who show small amounts of HER2 expression. Dr Jerusalem highlights the need for standardization of tests to detect HER2-positivity and in-depth investigations into how different agents work in these populations. Evidence from Phase III trials comparing HER2-agents to standard of care in a randomized fashion will be important in addressing this question. This interview took place at the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting.