Despite clinical practice traditionally categorizing HER2 status as positive (IHC 3+ or IHC 2+/ISH-positive) or negative (IHC 0, IHC 1+, IHC 2+/ISH-negative) (9), studies have found that breast cancers with IHC 0 and IHC 1+ differ not only in HER2 protein expression levels but also in estrogen receptor (ER) status, primary tumor size, lymph node involvement, pathologic complete response (pCR) rates after neoadjuvant therapy, and disease-free survival (DFS) (11–13). The gene discussed is ESR1; the disease is breast cancer.