Drug-metabolizing enzyme polymorphisms predict clinical outcome in a node-positive breast cancer cohort.
OBJECTIVE
Adjuvant chemotherapy cures only a subset of women with nonmetastatic breast cancer. Genotypes in drug-metabolizing enzymes, including functional polymorphisms in cytochrome P450 (CYP) and glutathione S-transferases (GST), may predict treatment-related outcomes.


METHODS
We examined CYP3A4*1B, CYP3A5*3, and deletions in GST mu (GSTM1) and theta (GSTT1), as well as a priori-defined combinations of polymorphisms in these genes. Using a cohort of 90 node-positive breast cancer patients who received anthracycline-based adjuvant chemotherapy followed by high-dose multiagent chemotherapy with stem-cell rescue, we estimated the effect of genotype and other known prognostic factors on disease-free survival (DFS) and overall survival (OS).


RESULTS
Patients who carried homozygous CYP3A4*1B and CYP3A5*3 variants and did not carry homozygous deletions in both GSTM1 and GSTT1 (denoted low-drug genotype group) had a 4.9-fold poorer DFS (P = .021) and a four-fold poorer OS (P = .031) compared with individuals who did not carry any CYP3A4*1B or CYP3A5*3 variants but had deletions in both GSTT1 and GSTM1 (denoted high-drug genotype group). After adjustment for other significant prognostic factors, the low-drug genotype group retained a significantly poorer DFS (hazard ratio [HR] = 4.9; 95% CI, 1.7 to 14.6; P = .004) and OS (HR = 4.8; 95% CI, 1.8 to 12.9; P = .002) compared with the high- and intermediate-drug combined genotype group. In the multivariate model, having low-drug genotype group status had a greater impact on clinical outcome than estrogen receptor status.


CONCLUSIONS
Combined genotypes at CYP3A4, CYP3A5, GSTM1, and GSTT1 influence the probability of treatment failure after high-dose adjuvant chemotherapy for node-positive breast cancer.
DeMichele
Angela
A
Department of Biostatistics and Epidemiology, Abramson Cancer Center, PA, USA. dma@mail.med.upenn.edu
Aplenc
Richard
R
Botbyl
Jeffrey
J
Colligan
Theresa
T
Wray
Lisa
L
Klein-Cabral
Melissa
M
Foulkes
Andrea
A
Gimotty
Phyllis
P
Glick
John
J
Weber
Barbara
B
Stadtmauer
Edward
E
Rebbeck
Timothy R
TR
D000328:Adult; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis
D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C510163:CYP3A4 protein, human; C413545:glutathione S-transferase T1