Novel targeted therapies have provided advantage in extending survival in cancer patients. However, these therapies do not benefit all patients. They also have severe toxicities and high costs. Inappropriate selection of first- or second-line therapies can drastically limit the long-term survival especially in patients with metastatic disease. One such novel targeted therapy is the class of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i’s). Three agents (palbociclib, ribociclib, abemaciclib) are approved by the FDA in hormone receptor-positive, human epidermal growth factor receptor-2-negative (HR+/HER2-) metastatic breast cancer. They improve survival when combined with standard endocrine ...

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Novel targeted therapies have provided advantage in extending survival in cancer patients. However, these therapies do not benefit all patients. They also have severe toxicities and high costs. Inappropriate selection of first- or second-line therapies can drastically limit the long-term survival especially in patients with metastatic disease. One such novel targeted therapy is the class of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i’s). Three agents (palbociclib, ribociclib, abemaciclib) are approved by the FDA in hormone receptor-positive, human epidermal growth factor receptor-2-negative (HR+/HER2-) metastatic breast cancer. They improve survival when combined with standard endocrine therapy. However, the tumor response is seen in less than 50% of patients. CDK4/6i’s also have severe toxicities requiring dose reductions and delays in up to 77% of patients. They are also expensive with an average monthly cost of ~$13,000. Therefore, a biomarker assay that can predict response to CDK4/6i’s is needed to select patients who are likely to derive clinical benefit from therapy and spare others from toxicities and cost. The overall goal of our research is to optimize a biomarker assay to predict response to CDK4/6i’s and determine the feasibility of performing the assay in patients. The proposed assay will test if CDK4/6i’s inhibit the signaling pathway using the tumor cells found in the blood of patients. This type of assays is less invasive compared to others requiring repeated tumor biopsies but is not commonly available. The immediate benefit will be to over 100,000 women in the United States living with HR+/HER2- metastatic breast cancer, who are expected to live only 2-3 years on average. In future, a similar approach can be applied to CDK4/6i’s being tested in clinical trials for other cancers. Successful completion of the proposed research will advance the cancer biomarker field and promote the designing of similar tests for other targeted therapies.

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