title: Association of ABCB1 and FLT3 Polymorphisms with Toxicities and Survival in Asian Patients Receiving Sunitinib for Renal Cell Carcinoma.
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.
authors.affiliation: Institute of Bioengineering and Nanotechnology, Singapore, Republic of Singapore.
authors.forename: Ying-Hsia
authors.initials: YH
authors.lastname: Chu
authors.affiliation: Health Services Research, Singapore General Hospital, Singapore, Republic of Singapore.
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.
authors.forename: Hui Shan
authors.initials: HS
authors.lastname: Tan
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore, Republic of Singapore.
authors.forename: Valerie
authors.initials: V
authors.lastname: Koh
authors.affiliation: Institute of Bioengineering and Nanotechnology, Singapore, Republic of Singapore.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Lai
authors.affiliation: Institute of Bioengineering and Nanotechnology, Singapore, Republic of Singapore.
authors.forename: Wai Min
authors.initials: WM
authors.lastname: Phyo
authors.affiliation: Institute of Bioengineering and Nanotechnology, Singapore, Republic of Singapore.
authors.forename: Yukti
authors.initials: Y
authors.lastname: Choudhury
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.
authors.forename: Ravindran
authors.initials: R
authors.lastname: Kanesvaran
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.
authors.forename: Noan Minh
authors.initials: NM
authors.lastname: Chau
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.
authors.forename: Chee Keong
authors.initials: CK
authors.lastname: Toh
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.
authors.forename: Quan Sing
authors.initials: QS
authors.lastname: Ng
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore, Republic of Singapore.
authors.forename: Puay Hoon
authors.initials: PH
authors.lastname: Tan
authors.affiliation: Laboratory of Clinical Pharmacology, Division Medical Sciences, National Cancer Centre Singapore, Singapore, Republic of Singapore; Clinical Pharmacology Core, SingHealth, Singapore, Republic of Singapore; Clinical Sciences, Duke-NUS Graduate Medical School, Singapore, Republic of Singapore.
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
authors.affiliation: Institute of Bioengineering and Nanotechnology, Singapore, Republic of Singapore; Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.
authors.forename: Min-Han
authors.initials: MH
authors.lastname: Tan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D012846:Singapore; D000077210:Sunitinib; D016896:Treatment Outcome; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D000077210:Sunitinib