Abstract
IntroductionCyclophosphamide-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.MethodsWe 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.ResultsIn 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.ConclusionsThese data support the hypothesis that genetic variability in cyclophosphamide metabolism independently impacts outcome from adjuvant chemotherapy for breast cancer.
Highlights
Cyclophosphamide-based adjuvant chemotherapy is a mainstay of treatment for women with nodepositive breast cancer, but is not universally effective in preventing recurrence
Several small prior studies, including our own, support the hypothesis that functional single nucleotide polymorphisms (SNP) in these phase I and phase II enzymes impact clinical outcome in breast cancer [6,7,8]. To further evaluate this hypothesis, we examined whether cyclophosphamide-drug metabolizing enzymes (DME) SNPs were independently associated with disease-free or overall survival (DFS, OS) in a cohort of women enrolled in a multicenter, randomized, adjuvant breast cancer chemotherapy trial
Genotyped subjects were more likely to be enrolled in the CAF + high-dose chemotherapy (HDC) arm compared to the non-genotyped group (57% v. 38%, P < 0.001), likely due to the fact that some patients randomized to the observation arm did not have bone marrow or stem cells collected post-adjuvant therapy, resulting in more bone marrow/stem cell samples collected for those patients randomized to the transplant arm than to the observation arm
Summary
Cyclophosphamide-based adjuvant chemotherapy is a mainstay of treatment for women with nodepositive 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. Women with node-positive breast cancer typically receive cyclophosphamide-based adjuvant chemotherapy, but a significant proportion of these women relapse and die of their disease. BioMed Central tribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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