An important future direction will be to determine how neoadjuvant/adjuvant therapy can be further developed to improve outcomes in high-risk ER-positive/HER2-negative breast cancer now that we have learned that neoadjuvant immune checkpoint therapy improves pCR rates in high-risk and ultra-high risk ER-positive/HER2-negative MammaPrint subgroups44. The gene discussed is ESR1; the disease is breast cancer.