Research article

Cyclophosphamide- metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study

Priya P Gor^1,10 , H Irene Su^2,3 , Robert J Gray⁵ , Phyllis A Gimotty^3,4 , Michelle Horn³ , Richard Aplenc⁶ , William P Vaughan¹⁰ , Martin S Tallman^5,7,8 , Timothy R Rebbeck^3,4 and Angela DeMichele^3,4,9,10

¹  Current address: Center for Cancer and Hematologic Disease, Executive Mews Office Complex, 1930 E. Route 70, Suite V-107, Cherry Hill, NJ 08003, USA

²  Department of Obstetrics and Gynecology, University of California, San Diego, Moores UCSD Cancer Center, 3855 Health Sciences Drive, Dept. 0901, La Jolla, CA 92093-0901, USA

³  Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA 19104, USA

⁴  Abramson Cancer Center of the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA

⁵  Eastern Cooperative Oncology Group, Frontier Science, 900 Commonwealth Avenue, Boston, MA 02215, USA

⁶  Division of Oncology, Children's Hospital of Philadelphia, Room 916G, ARC 3615 Civic Center Blvd, Philadelphia, PA 19104, USA

⁷  Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Ste 850, Chicago, IL 60611, USA

⁸  Robert H. Lurie Comprehensive Cancer Center, Clinical Cancer Center, Galter Pavilion 675 North St Clair, 21st Floor, Chicago, Illinois 60611, USA

⁹  Department of Hematology & Oncology, University of Alabama at Birmingham, 1900 University Blvd, Ste THT 541, Birmingham, AL 35294, USA

¹⁰  Rena Rowan Breast Cancer Center, Division of Hematology-Oncology, Department of Medicine,, University of Pennsylvania Health System, Perelman Center, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA

author email corresponding author email

Breast Cancer Research 2010, 12:R26doi:10.1186/bcr2570

Published:	10 May 2010

Abstract

Introduction

Cyclophosphamide-based adjuvant chemotherapy is a mainstay of treatment for women with node-positive breast cancer, but is not universally effective in preventing recurrence. Pharmacogenetic variability in drug metabolism is one possible mechanism of treatment failure. We hypothesize that functional single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs) that activate (CYPs) or metabolize (GSTs) cyclophosphamide account for some of the observed variability in disease outcomes.

Methods

We performed a retrospective cohort study of 350 women enrolled in a multicenter, randomized, adjuvant breast cancer chemotherapy trial (ECOG-2190/INT-0121). Subjects in this trial received standard-dose cyclophosphamide, doxorubicin and fluorouracil (CAF), followed by either observation or high-dose cyclophosphamide and thiotepa with stem cell rescue. We used bone marrow stem cell-derived genomic DNA from archival specimens to genotype CYP2B6, CYP2C9, CYP2D6, CYP3A4, CYP3A5, GSTM1, GSTT1, and GSTP1. Cox regression models were computed to determine associations between genotypes (individually or in combination) and disease-free survival (DFS) or overall survival (OS), adjusting for confounding clinical variables.

Results

In the full multivariable analysis, women with at least one CYP3A4 *1B variant allele had significantly worse DFS than those who were wild-type *1A/*1A (multivariate hazard ratio 2.79; 95% CI 1.52, 5.14). CYP2D6 genotype did not impact this association among patients with estrogen receptor (ER) -positive tumors scheduled to receive tamoxifen.

Conclusions

These data support the hypothesis that genetic variability in cyclophosphamide metabolism independently impacts outcome from adjuvant chemotherapy for breast cancer.