Germline and Somatic Variation in Genes Involved in Metabolism of Chemotherapy Drugs and Breast Cancer Outcomes

Abstract

Triple-negative breast cancer (TNBC), which is characterized by minimal or lack of expression of estrogen receptors and progesterone receptors, and the absence of overexpression of human epidermal growth factor 2 (ER-/PR-/HER2-), makes up 15%-20% of breast cancers in the United States. Although there have been recent advances in breast cancer detection/treatment leading to improved survival overall, the prognosis for TNBC patients is much worse compared to other breast cancer types. Chemotherapy is the standard treatment for TNBC patients but patient response to treatment varies tremendously. Understanding the underlying molecular biological mechanisms is critical to improve outcomes for this group of aggressive breast cancers. Using resources available from the Shanghai Breast Cancer Survival Study, we evaluated the association between germline and somatic variation in chemotherapy metabolizing genes and breast cancer outcomes. Our study focused on genes involved in the metabolism of cyclophosphamide and 5-fluorouracil, the two most commonly used chemotherapy agents in our study population. Using a gene score approach, we evaluated the separate and joint association of germline polymorphisms and tumor-level gene expression with disease-free survival (DFS) and overall survival (OS) using Cox models. No association between the cyclophosphamide polymorphism score and DFS or OS was observed. The 5-fluorouracil polymorphism score was associated with marginally improved OS, particularly among those who took 5-fluorouracil. The cyclophosphamide gene expression score was associated with OS among all participants for events occurring in the first three years following breast cancer diagnosis. The 5-fluorouracil gene expression score was associated with worse DFS among all participants for events occurring in the first three years following cancer diagnosis. No association was observed for the joint effect of the polymorphism score and the gene expression score for either chemotherapy drug. However, our study had a low statistical power to investigate the joint effect. Future studies with larger sample size are needed to further elucidate the roles of genes involved in the pathways by which chemotherapy drugs are metabolized to understand the biology of chemotherapy responses.