GWAS for Breast Cancer Chemotherapy Toxicities in S0221

When undergoing treatment for breast cancer, many women experience severe side effects, some of which result in treatment-related death and some that can persist for years. Little is understood regarding factors that may predict drug toxicities. Pharmacogenetics, the investigation of variants in candidate genes in drug metabolism pathways, has been used to determine susceptibility to treatment-related toxicities, as well as to cancer recurrence. Although there have been some strong and important findings using this approach, such as identification of single nucleotide polymorphisms (SNPs) that predispose to side effects associated with thiopurines and irinotecan, there has been less progress in assessment of genetic variants that predispose to toxicities resulting from the multi-drug regimen commonly used to treat breast cancer, anthracyclines (A), cyclophosphamide (C), and taxanes (T). These difficulties in identification of key gene variants may be due to the complex metabolic pathways of these drugs, the lack of rate limiting enzymes in the processes, or the limitations of single SNP analysis, rather than capturing all of the variability across the genes. In addition to drug metabolism pathways, however, there may be a number of constitutional factors or other processes that affect damage to normal tissues in the course of chemotherapy, some known or hypothesized, such as DNA repair and oxidative stress pathways, and others not yet discovered. However, there have been no clear candidate genes that account for a large part of the variation in drug or treatment response, and there are likely important genes that influence sensitivity of cells to chemotherapy through unknown pathways which have not yet been identified or hypothesized. The present technological capabilities to screen the entire genome for variants that discriminate populations allows the opportunity to identify these as yet unknown pathways, and open the doors to exciting new avenues of research into mechanisms that had not been previously considered. We conducted a genome-wide scan (GWAS) in a clinical trial (S0221), in which women with high risk breast cancer were treated with different dosing schedules of C, A and T. Blood specimens were collected and banked, and DNA extracted for genotyping on the Illumina OMNI 1M platform. The GWAS data were used to examine genetic variants significantly associated with grades 3 and 4 toxicities, including peripheral neuropathy recorded during the T segment. In S0221, toxicities were graded according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE). The neurotoxicity is predominantly a distal sensory neuropathy, which is characterized by pain, numbness, tingling, and reduced functional capacity in the extremities. Other symptoms include parasthesias, ataxia, impaired vibration and joint position sense, and loss of tendon reflexes. By using a GWAS approach, it is likely that important pathways not previously considered can be revealed as important in susceptibility to treatment-related toxicities, identifying those at greatest risk for alternate drugs or dose reduction, and opening new areas of research for prevention of taxanes-related neuropathy among patients receiving chemotherapy for breast cancer. ]]>
The S0221 trial was open to women or men age 18 or over with a histologically confirmed diagnosis of operable Stage II or III invasive breast cancer with known estrogen or progesterone receptor status, and no previous malignancies. They must have high risk breast cancer by meeting at least one of the following criteria: tumor >/=2 cm in greatest diameter; one or more axillary or intra-mammary nodes involved by metastatic breast cancer. They must have had either a modified radical mastectomy or local excision of all tumors plus axillary node dissection or sentinel node resection, and not received prior chemotherapy or radiation therapy for the current malignancy. There must be no history of congestive heart failure or angina pectoris, and creatinine, bilirubin and alkaline phosphatase must be normal. Patients must have a performance status of 0-2 by Zubrod criteria and be HIV negative (if known). To be eligible for this axillary pharmacogenomic study, patients must consent for having their peripheral blood samples banked for research use. The final dataset contains a total of 1,847 patients with both phenotype data and genotype data, including 215 who developed grade 3 or 4 peripheral neuropathy during taxanes treatment and 1,638 patients who did not experience neuropathy. ]]>