In the HER2-negative and hormone receptor-positive (HER2–/HR+) metastatic breast cancer, the detection of PIK3CA mutations with the liquid biopsy can guide therapeutic choice with cyclin-dependent kinases 4/6 (CDK4/6) inhibitor alpelisib in combination with fulvestrant after endocrine therapy progression. The gene discussed is ERBB2; the disease is breast carcinoma.