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Association of ABCB1 and FLT3 Polymorphisms with Toxicities and Survival in Asian Patients Receiving Sunitinib for Renal Cell Carcinoma.

Chu YH, Li H, Tan HS, Koh V, Lai J, Phyo WM, Choudhury Y, Kanesvaran R, Chau NM, Toh CK, Ng QS, Tan PH, Chowbay B, Tan MH - PLoS ONE (2015)

Bottom Line: Primary resistance (OR=0.1, P=0.004) and inferior survival (progression-free: hazard ratio [HR]=5.5, P=0.001; overall: HR=5.0, P=0.005) were associated with the ABCB1 3435, 1236, 2677 TTT haplotype.In conclusion, ABCB1 and FLT3 polymorphisms may be helpful in predicting sunitinib toxicities, response and survival benefit in Asian mRCC patients.We have also validated the association between FLT3 738T and sunitinib-induced leucopenia previously reported in Caucasian populations, but have not validated other reported genetic associations.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioengineering and Nanotechnology, Singapore, Republic of Singapore.

ABSTRACT
Sunitinib is a tyrosine kinase inhibitor used as first-line treatment for metastatic renal cell carcinoma (mRCC). Asian ethnicity has been previously associated with lower clearance and greater toxicities for sunitinib treatment, relative to Caucasian ethnicity. Research focusing on identifying corresponding biomarkers of efficacy and toxicity has been hitherto conducted in Caucasian populations, and few of the reported associations have been externally validated. Our work thus aims to investigate candidate biomarkers in Asian patients receiving sunitinib, comparing the observed genotype effects with those reported in Caucasian populations. Using data from 97 Asian mRCC patients treated with sunitinib, we correlated 7 polymorphisms in FLT3, ABCB1, VEGFR2, ABCG2 and BIM with patient toxicities, response, and survival. We observed a stronger association of FLT3 738T genotype with leucopenia in our Asian dataset than that previously reported in Caucasian mRCC patients (odds ratio [OR]=8.0; P=0.03). We observed significant associations of FLT3 738T (OR=2.7), ABCB1 1236T (OR=0.3), ABCB1 3435T (OR=0.1), ABCB1 2677T (OR=0.4), ABCG2 421A (OR=0.3) alleles and ABCB1 3435, 1236, 2677 TTT haplotype (OR=0.1) on neutropenia. Primary resistance (OR=0.1, P=0.004) and inferior survival (progression-free: hazard ratio [HR]=5.5, P=0.001; overall: HR=5.0, P=0.005) were associated with the ABCB1 3435, 1236, 2677 TTT haplotype. In conclusion, ABCB1 and FLT3 polymorphisms may be helpful in predicting sunitinib toxicities, response and survival benefit in Asian mRCC patients. We have also validated the association between FLT3 738T and sunitinib-induced leucopenia previously reported in Caucasian populations, but have not validated other reported genetic associations.

No MeSH data available.


Related in: MedlinePlus

Survival curves.(A) Patients grouped according to the ABCB1 3435C/T, 1236C/T, 2677G/T haplotype; median PFS was 2.4 months for homozygous carriers of the TTT haplotype and 8.4 months for other cases (P = 0.001). (B) Patients grouped according to the ABCB1 3435C/T, 1236C/T, 2677G/TA haplotype; median OS was 4.6 months for homozygous carriers of the TTT haplotype and 19.6 months for other cases (P = 0.005).
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pone.0134102.g001: Survival curves.(A) Patients grouped according to the ABCB1 3435C/T, 1236C/T, 2677G/T haplotype; median PFS was 2.4 months for homozygous carriers of the TTT haplotype and 8.4 months for other cases (P = 0.001). (B) Patients grouped according to the ABCB1 3435C/T, 1236C/T, 2677G/TA haplotype; median OS was 4.6 months for homozygous carriers of the TTT haplotype and 19.6 months for other cases (P = 0.005).

Mentions: Primary sunitinib resistance, defined as the condition in which progressive disease is the best radiological response observed, was more common in carriers of the ABCB1 3435 TT genotype (P = 0.02), ABCB1 2677 TT genotype (P = 0.01) and the ABCB1 3435, 1236, 2677 TTT haplotype (P = 0.004) (Table 4). Median PFS of the 81 patients who received sunitinib as the first-line therapy was 8.1 months and median OS was 19.5 months. As shown in Table 5 (non-significant results are provided in S4 Table), after including starting dose as a covariate based on univariate P<0.05, the ABCB1 3435, 1236, 2677 TTT haplotype was correlated with inferior PFS (P = 0.001) and OS (P = 0.005) (survival curves are provided in Fig 1).


Association of ABCB1 and FLT3 Polymorphisms with Toxicities and Survival in Asian Patients Receiving Sunitinib for Renal Cell Carcinoma.

Chu YH, Li H, Tan HS, Koh V, Lai J, Phyo WM, Choudhury Y, Kanesvaran R, Chau NM, Toh CK, Ng QS, Tan PH, Chowbay B, Tan MH - PLoS ONE (2015)

Survival curves.(A) Patients grouped according to the ABCB1 3435C/T, 1236C/T, 2677G/T haplotype; median PFS was 2.4 months for homozygous carriers of the TTT haplotype and 8.4 months for other cases (P = 0.001). (B) Patients grouped according to the ABCB1 3435C/T, 1236C/T, 2677G/TA haplotype; median OS was 4.6 months for homozygous carriers of the TTT haplotype and 19.6 months for other cases (P = 0.005).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4526634&req=5

pone.0134102.g001: Survival curves.(A) Patients grouped according to the ABCB1 3435C/T, 1236C/T, 2677G/T haplotype; median PFS was 2.4 months for homozygous carriers of the TTT haplotype and 8.4 months for other cases (P = 0.001). (B) Patients grouped according to the ABCB1 3435C/T, 1236C/T, 2677G/TA haplotype; median OS was 4.6 months for homozygous carriers of the TTT haplotype and 19.6 months for other cases (P = 0.005).
Mentions: Primary sunitinib resistance, defined as the condition in which progressive disease is the best radiological response observed, was more common in carriers of the ABCB1 3435 TT genotype (P = 0.02), ABCB1 2677 TT genotype (P = 0.01) and the ABCB1 3435, 1236, 2677 TTT haplotype (P = 0.004) (Table 4). Median PFS of the 81 patients who received sunitinib as the first-line therapy was 8.1 months and median OS was 19.5 months. As shown in Table 5 (non-significant results are provided in S4 Table), after including starting dose as a covariate based on univariate P<0.05, the ABCB1 3435, 1236, 2677 TTT haplotype was correlated with inferior PFS (P = 0.001) and OS (P = 0.005) (survival curves are provided in Fig 1).

Bottom Line: Primary resistance (OR=0.1, P=0.004) and inferior survival (progression-free: hazard ratio [HR]=5.5, P=0.001; overall: HR=5.0, P=0.005) were associated with the ABCB1 3435, 1236, 2677 TTT haplotype.In conclusion, ABCB1 and FLT3 polymorphisms may be helpful in predicting sunitinib toxicities, response and survival benefit in Asian mRCC patients.We have also validated the association between FLT3 738T and sunitinib-induced leucopenia previously reported in Caucasian populations, but have not validated other reported genetic associations.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioengineering and Nanotechnology, Singapore, Republic of Singapore.

ABSTRACT
Sunitinib is a tyrosine kinase inhibitor used as first-line treatment for metastatic renal cell carcinoma (mRCC). Asian ethnicity has been previously associated with lower clearance and greater toxicities for sunitinib treatment, relative to Caucasian ethnicity. Research focusing on identifying corresponding biomarkers of efficacy and toxicity has been hitherto conducted in Caucasian populations, and few of the reported associations have been externally validated. Our work thus aims to investigate candidate biomarkers in Asian patients receiving sunitinib, comparing the observed genotype effects with those reported in Caucasian populations. Using data from 97 Asian mRCC patients treated with sunitinib, we correlated 7 polymorphisms in FLT3, ABCB1, VEGFR2, ABCG2 and BIM with patient toxicities, response, and survival. We observed a stronger association of FLT3 738T genotype with leucopenia in our Asian dataset than that previously reported in Caucasian mRCC patients (odds ratio [OR]=8.0; P=0.03). We observed significant associations of FLT3 738T (OR=2.7), ABCB1 1236T (OR=0.3), ABCB1 3435T (OR=0.1), ABCB1 2677T (OR=0.4), ABCG2 421A (OR=0.3) alleles and ABCB1 3435, 1236, 2677 TTT haplotype (OR=0.1) on neutropenia. Primary resistance (OR=0.1, P=0.004) and inferior survival (progression-free: hazard ratio [HR]=5.5, P=0.001; overall: HR=5.0, P=0.005) were associated with the ABCB1 3435, 1236, 2677 TTT haplotype. In conclusion, ABCB1 and FLT3 polymorphisms may be helpful in predicting sunitinib toxicities, response and survival benefit in Asian mRCC patients. We have also validated the association between FLT3 738T and sunitinib-induced leucopenia previously reported in Caucasian populations, but have not validated other reported genetic associations.

No MeSH data available.


Related in: MedlinePlus