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ABCB1 and ABCC2 and the risk of distant metastasis in Thai breast cancer patients treated with tamoxifen.

Sensorn I, Sukasem C, Sirachainan E, Chamnanphon M, Pasomsub E, Trachu N, Supavilai P, Pinthong D, Wongwaisayawan S - Onco Targets Ther (2016)

Bottom Line: However, the results are inconclusive.The combined genotype of ABCC2 -24CC - ABCB1 3435 CT+TT was associated with increased risk of distant and bone metastasis (P=0.020; adjusted HR=2.46; 95% CI, 1.15-5.26 and P=0.040; adjusted HR=3.70; 95% CI, 1.06-12.89, respectively).This study indicates that polymorphisms of ABCC2 and ABCB1 are independently associated with bone metastasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.

ABSTRACT

Background: Genetic polymorphisms of drug-metabolizing enzymes and transporters have been extensively studied with regard to tamoxifen treatment outcomes. However, the results are inconclusive. Analysis of organ-specific metastasis may reveal the association of these pharmacogenetic factors. The aim of this study is to investigate the impact of CYP3A5, CYP2D6, ABCB1, and ABCC2 polymorphisms on the risk of all distant and organ-specific metastases in Thai patients who received tamoxifen adjuvant therapy.

Methods: Genomic DNA was extracted from blood samples of 73 patients with breast cancer who received tamoxifen adjuvant therapy. CYP3A5 (6986A>G), CYP2D6 (100C>T), ABCB1 (3435C>T), and ABCC2 (-24C>T) were genotyped using allelic discrimination real-time polymerase chain reaction assays. The impacts of prognostic clinical factors and genetic variants on disease-free survival were analyzed using the Kaplan-Meier method and Cox regression analysis.

Results: In the univariate analysis, primary tumor size >5 cm was significantly associated with increased risk of distant metastasis (P=0.004; hazard ratio [HR] =3.05; 95% confidence interval [CI], 1.44-6.47). In the multivariate analysis, tumor size >5 cm remained predictive of distant metastasis (P<0.001; HR=5.49; 95% CI, 2.30-13.10). ABCC2 -24CC were shown to be associated with increased risk of distant metastasis (P=0.040; adjusted HR=2.34; 95% CI, 1.04-5.27). The combined genotype of ABCC2 -24CC - ABCB1 3435 CT+TT was associated with increased risk of distant and bone metastasis (P=0.020; adjusted HR=2.46; 95% CI, 1.15-5.26 and P=0.040; adjusted HR=3.70; 95% CI, 1.06-12.89, respectively).

Conclusion: This study indicates that polymorphisms of ABCC2 and ABCB1 are independently associated with bone metastasis. Further prospective studies with larger sample sizes are needed to verify this finding.

No MeSH data available.


Related in: MedlinePlus

The Kaplan–Meier survival curve compares 16 patients carrying ABCB1 3435CT or TT and ABCC2−24CC to 36 patients carrying other combined genotypes of ABCC2 and ABCB1 in bone metastasis with respect to disease-free survival (DFS).
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f2-ott-9-2121: The Kaplan–Meier survival curve compares 16 patients carrying ABCB1 3435CT or TT and ABCC2−24CC to 36 patients carrying other combined genotypes of ABCC2 and ABCB1 in bone metastasis with respect to disease-free survival (DFS).

Mentions: ABCB1 3435C>T, ABCC2 −24C>T, CYP3A5 6986A>G, and CYP2D6 100C>T were successfully genotyped in all patients. The genotype frequencies of these variants were compared between non-metastasis and metastasis groups according to first dominant site of metastasis as shown in Table 2. There was no significant difference between genotype frequency and first dominant site of metastasis. Regardless of any first dominant site of metastasis, Kaplan–Meier analysis indicated that patients carrying ABCC2 −24CC had significantly shorter DFS than those who carry −24CT (log-rank test, P=0.044; Figure 1). Regarding bone metastasis, patients carrying ABCC2 −24CC and ABCB1 3435CT or TT genotypes had significantly shorter DFS time than those who carry ABCB1 3435CC and ABCC2 −24CC or ABCC2 −24CT (log-rank test, P=0.040; Figure 2 and Table S1). No such variants of CYP3A5 6986A>G and CYP2D6 100C>T were found to be associated with tamoxifen treatment outcomes.


ABCB1 and ABCC2 and the risk of distant metastasis in Thai breast cancer patients treated with tamoxifen.

Sensorn I, Sukasem C, Sirachainan E, Chamnanphon M, Pasomsub E, Trachu N, Supavilai P, Pinthong D, Wongwaisayawan S - Onco Targets Ther (2016)

The Kaplan–Meier survival curve compares 16 patients carrying ABCB1 3435CT or TT and ABCC2−24CC to 36 patients carrying other combined genotypes of ABCC2 and ABCB1 in bone metastasis with respect to disease-free survival (DFS).
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835128&req=5

f2-ott-9-2121: The Kaplan–Meier survival curve compares 16 patients carrying ABCB1 3435CT or TT and ABCC2−24CC to 36 patients carrying other combined genotypes of ABCC2 and ABCB1 in bone metastasis with respect to disease-free survival (DFS).
Mentions: ABCB1 3435C>T, ABCC2 −24C>T, CYP3A5 6986A>G, and CYP2D6 100C>T were successfully genotyped in all patients. The genotype frequencies of these variants were compared between non-metastasis and metastasis groups according to first dominant site of metastasis as shown in Table 2. There was no significant difference between genotype frequency and first dominant site of metastasis. Regardless of any first dominant site of metastasis, Kaplan–Meier analysis indicated that patients carrying ABCC2 −24CC had significantly shorter DFS than those who carry −24CT (log-rank test, P=0.044; Figure 1). Regarding bone metastasis, patients carrying ABCC2 −24CC and ABCB1 3435CT or TT genotypes had significantly shorter DFS time than those who carry ABCB1 3435CC and ABCC2 −24CC or ABCC2 −24CT (log-rank test, P=0.040; Figure 2 and Table S1). No such variants of CYP3A5 6986A>G and CYP2D6 100C>T were found to be associated with tamoxifen treatment outcomes.

Bottom Line: However, the results are inconclusive.The combined genotype of ABCC2 -24CC - ABCB1 3435 CT+TT was associated with increased risk of distant and bone metastasis (P=0.020; adjusted HR=2.46; 95% CI, 1.15-5.26 and P=0.040; adjusted HR=3.70; 95% CI, 1.06-12.89, respectively).This study indicates that polymorphisms of ABCC2 and ABCB1 are independently associated with bone metastasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.

ABSTRACT

Background: Genetic polymorphisms of drug-metabolizing enzymes and transporters have been extensively studied with regard to tamoxifen treatment outcomes. However, the results are inconclusive. Analysis of organ-specific metastasis may reveal the association of these pharmacogenetic factors. The aim of this study is to investigate the impact of CYP3A5, CYP2D6, ABCB1, and ABCC2 polymorphisms on the risk of all distant and organ-specific metastases in Thai patients who received tamoxifen adjuvant therapy.

Methods: Genomic DNA was extracted from blood samples of 73 patients with breast cancer who received tamoxifen adjuvant therapy. CYP3A5 (6986A>G), CYP2D6 (100C>T), ABCB1 (3435C>T), and ABCC2 (-24C>T) were genotyped using allelic discrimination real-time polymerase chain reaction assays. The impacts of prognostic clinical factors and genetic variants on disease-free survival were analyzed using the Kaplan-Meier method and Cox regression analysis.

Results: In the univariate analysis, primary tumor size >5 cm was significantly associated with increased risk of distant metastasis (P=0.004; hazard ratio [HR] =3.05; 95% confidence interval [CI], 1.44-6.47). In the multivariate analysis, tumor size >5 cm remained predictive of distant metastasis (P<0.001; HR=5.49; 95% CI, 2.30-13.10). ABCC2 -24CC were shown to be associated with increased risk of distant metastasis (P=0.040; adjusted HR=2.34; 95% CI, 1.04-5.27). The combined genotype of ABCC2 -24CC - ABCB1 3435 CT+TT was associated with increased risk of distant and bone metastasis (P=0.020; adjusted HR=2.46; 95% CI, 1.15-5.26 and P=0.040; adjusted HR=3.70; 95% CI, 1.06-12.89, respectively).

Conclusion: This study indicates that polymorphisms of ABCC2 and ABCB1 are independently associated with bone metastasis. Further prospective studies with larger sample sizes are needed to verify this finding.

No MeSH data available.


Related in: MedlinePlus