Genetic Predictors of Chemotherapy Toxicity in Breast Cancer

Institution: University of California, San Francisco
Investigator(s): Deanna  Kroetz , Ph.D. -
Award Cycle: 2012 (Cycle 18) Grant #: 18IB-0027 Award: $100,000
Award Type: IDEA
Research Priorities
Innovative Treatments>Hormone and chemotherapy targets: improving today's arsenal

Initial Award Abstract (2012)

In the attempt to provide breast cancer patients with “individualized therapy”, there has been little attention to understanding the genetic basis for the common debilitating side effects from chemotherapy. Paclitaxel and adriamycin/cyclophosphamide are both effective therapies in the treatment of breast cancer, but are also associated with significant and in some cases long-lasting toxicity. This can lead to suboptimal dosage and an increased risk of recurrence, especially in the adjuvant setting. Women having high response rates and persistent toxicities, such as sensory peripheral neuropathy and ovarian suppression, experience significant effects on the quality of life. The large degree of interpatient variability in these side-effects from treatment suggests that genetic variation may influence a patient’s risk for toxicity.

We will test whether differences in a patient’s DNA sequence are associated with the risk of developing either paclitaxel-induced sensory peripheral neuropathy or with the development of neutropenia and menopause during treatment with adriamycin/cyclophosphamide. These studies will be carried out using DNA samples collected from women with primary breast cancer enrolled on a Phase III clinical trial (CALGB 40101), which tests whether single agent paclitaxel is as efficacious as adriamycin/cyclophosphamide for disease-free survival. Toxicity data was collected during the treatment trial and this data will be used for the current studies. Genotyping data is also available for >500,000 markers scattered across the human genome. Statistical methods will be used to identify if any of these genetic markers predict the risk of developing paclitaxel or adriamycin/cyclophosphamide toxicity. Replication of our findings will be carried out using similar datasets from the use of these drugs in the primary and metastatic setting.

To date, pharmacogenetic studies of drug toxicity in breast cancer treatment have looked at single genes that are thought to be important since they control the level of drug within the body. In most of these studies, only small numbers of patients were evaluated and few, if any, of these findings have been replicated in a different patient population. Our study is innovative because it is taking an unbiased, genome-wide approach coupled with state-of-the-art “next generation sequencing” technology to identify novel genetic markers. The identification of novel genetic biomarkers will inform our understanding of the molecular basis of the toxicities, so these can be targeted in future studies.