Knowing the favorable gut/BC microbiota status (i.e., its composition and functions) for anti-HER2 drugs’ efficacy will influence the decision over de-escalation strategies in terms of chemotherapy-free, single agents versus dual blockade, and add-on strategies, such as dual blockade plus chemotherapy and immune checkpoint inhibitors, minimizing overtreatment in patients who would benefit from single agents, such as trastuzumab. The gene discussed is ERBB2; the disease is breast cancer.