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.

Progress Report 1 (2013)

While chemotherapy has well documented benefits in the treatment of breast cancer, it is often limited by debilitating toxicities. Interpatient variability in the incidence and severity of toxicities is a function of both environmental and genetic influences. The overall goal of the studies supported by this grant is to identify genetic predictors of the most common toxicities associated with paclitaxel and adriamycin/cyclophosphamide treatment of breast cancer. Genetic markers of chemotherapy toxicity could ultimately be used prior to treatment to guide drug selection and dose, thus optimizing treatment outcome for an individual patient.

Significant progress was made on both specific aims. Patients were selected who had the most severe paclitaxel-induced sensory peripheral neuropathy and matched controls that experienced no toxicity. Following a significant delay in getting these samples plated and shipped as a result of regulatory requirements, these samples are now undergoing quality control analysis prior to targeted resequencing of the FGD4 genomic region to identify the best predictor of this toxicity. It is anticipated that the sequencing will be completed in about three months, after which the bioinformatic analysis will commence. The studies in the second aim seek to understand how genetic variation influences adriamycin/cyclophosphamide-induced neutropenia and ovarian suppression. A significant amount of effort has gone into curating the neutropenia data, including the need for queries to individual treatment centers for additional data and clarifications, and cases and controls have recently been identified. A logistic regression performed using genome-wide genotyping data failed to identify any strong predictors of neutropenia. Additional gene and pathway based analyses are ongoing to further explore the role genetic variation in the development of this toxicity.

In the coming year, efforts will be focused on completing the FGD4 resequencing and accompanying bioinformatic and statistical analysis, completing the neutropenia analysis and writing a manuscript for publication, and completion of curation of the ovarian suppression data and corresponding genome-wide association analysis.