Breast cancer is the most commonly diagnosed cancer in women in the United States. It is the second leading cause of cancer-related deaths in these women. Taxol (generic name paclitaxel) is one of the most commonly used chemotherapy drugs for treating breast cancer patients. Although paclitaxel is considered highly effective, only about half of patients benefit from receiving it. Currently, there is no way to predict which patients will benefit, so many women receive paclitaxel unnecessarily. These women have the potential to develop side effects from paclitaxel treatment that can be life-threatening. Other side effects result in tingling, pain, or numbness in the hands and feet that can interfere with daily life and may be permanent. Unnecessary treatment with paclitaxel also delays receipt of effective treatment. A test to identify which patients will benefit from paclitaxel would substantially improve the lives of hundreds of thousands of breast cancer patients. We believe we have found a way to predict which patients should and should not be treated with paclitaxel. Our proposal will test this idea.

We have discovered the mechanism by which paclitaxel kills breast cancer cells in women and developed a method to model this in breast cancer cells grown in the laboratory. Our results strongly suggest that tumors with a specific characteristic, known as chromosomal instability or CIN, are the ones that respond to paclitaxel therapy. This proposal will test the hypothesis that patients with CIN tumors should be treated with paclitaxel, while patients with tumors that do not have CIN should not receive paclitaxel. We will also seek ways to improve the sensitivity of tumors that do not have CIN.

This application addresses three of the overarching challenges in breast cancer, (1) conquering overtreatment, (2) revolutionizing treatment regimens, and (3) determining how to stop cancer growth. There are two major goals of this proposal. The first is to change clinical practice so that paclitaxel is only used in patients in whom it will be effective. The second is to identify drugs that increase the effectiveness of paclitaxel and reduce its side effects. Achieving these goals would significantly improve the lives of hundreds of thousands of patients diagnosed with primary or metastatic breast cancer.

This proposal has three aims. In the first aim, we will identify drugs that sensitize tumors to paclitaxel. In the second aim, we will determine whether CIN can be used to identify breast cancers that will respond to paclitaxel. In the third aim, we will determine how metastatic breast cancers that initially respond to paclitaxel eventually develop resistance. CIN can be identified on leftover tissue from diagnostic biopsies. Methods to do this are already in widespread clinical use, so CIN testing to identify which patients should be treated with paclitaxel could be used in clinical trials within a few years after successful completion of the experiments in this proposal. A biomarker test to predict sensitivity to this commonly used chemotherapy drug would substantially improve outcomes for breast cancer patients of all subtypes.