For first-line therapy with CDK4/6i plus ET (n = 549), APOBEC3- and HRD-dominant MBC were associated independently with lower median PFS compared with other cancers regardless of ET partner and line of therapy (Fig. 3b) suggesting increased genomic instability confers resistance to standard frontline therapy in HR+/HER2− MBC. The gene discussed is ERBB2; the disease is cancer.