Both Δ16HER2 and p95HER2, representing distinct variants of HER2, are essential contributors to the emergence of resistance against trastuzumab in the process of its development.[28,115] Breast cancers expressing p95HER2 have a worse prognosis and are more likely to develop resistance to trastuzumab.[84] The cyclin D1–cyclin-dependent kinase 4 (CDK4) pathway has been shown to participate in resistance to HER2-targeted treatments, and CDK 4/6 inhibitors can make resistant tumor cells more responsive to HER2 treatment.[115]. This evidence concerns the gene ERBB2 and breast cancer.