Prognostic Value of Two Polymorphisms, rs1045642 and rs1128503, in ABCB1 Following Taxane-based Chemotherapy: A Meta-Analysis

Chen, Quanyao; Lin, Wei-Hsin; Yang, Jianhui; Lin, Min; Lin, Xiuxian; Weng, Yiyin; Chen, Yao

doi:10.31557/apjcp.2021.22.1.3

Cited by 10 publications

(8 citation statements)

References 44 publications

(41 reference statements)

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“…Another meta-analysis including case–control studies did not detect such associations in breast cancer patients, but had limited precision [ 42 ]. In the study by Chen et al [ 12 ], no overall associations were found for ABCB1 rs1045642, but poor overall survival was found in European populations homozygote for the variant allele, consistent with the increased mortality observed in our study.…”

Section: Discussionsupporting

confidence: 92%

“…A meta-analysis by Chen et al [ 12 ], including prospective studies of taxane-treated breast, lung, ovarian, gastric, and head/neck cancer patients, reported better survival in ABCB1 rs1128503 variant carriers, consistent with our findings [ 12 ]. Another meta-analysis including case–control studies did not detect such associations in breast cancer patients, but had limited precision [ 42 ].…”

Section: Discussionsupporting

confidence: 91%

“…Research suggests that clinical outcomes (survival, progression-free survival, and tumor response) in cancer patients treated with taxanes may depend on genetic differences in taxane transporters [ 12 , 13 ] and/or metabolizing enzymes [ 13 , 14 ]. However, findings are rarely replicated [ 15 , 16 ] and available studies have several limitations—including small sample size, population stratification, and different treatment schedules.…”

Section: Introductionmentioning

confidence: 99%

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Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark

Hjorth

Damkier

Stage

et al. 2022

Breast Cancer Res Treat

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Purpose Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer. Methods We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes. Results Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98–1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98). Conclusion Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark

Hjorth

Damkier

Stage

et al. 2022

Breast Cancer Res Treat

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“…The patients administered with platinum‐based docetaxel‐containing chemotherapy with a mutant genotype for ABCB1C 1236 T showed a better survival than those with a wild‐type genotype. Chen et al 39 reported that ABCB1 C 1236 T had prognostic significance for OS in patients who received taxane‐containing chemotherapy. The impact of genetic mutations on survival could be attributed to polymorphisms that induce alterations in the encoded amino acids, disrupting the normal function of particular drug transporters and reducing P‐gp expression.…”

Section: Discussionmentioning

confidence: 99%

Impact of ABCB1, ABCC1, ABCC2, and ABCG2 variants in predicting prognosis and clinical outcomes of north Indian lung cancer patients undergoing platinum‐based doublet chemotherapy

Sharma

Singh

Sharma

2022

The Journal of Gene Medicine

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Background ABC transporters are membrane proteins expressed in the lungs and are crucial for efflux of various chemotherapeutic agents. Polymorphisms of ABC transporters have a certain impact on the transporter activity because their expression levels may influence the extent and longevity of chemotherapeutic drug outflow, affecting patient outcomes. The present study aimed to assess the impact of ABCB1, ABCC1/2, and ABCG2 gene variants in predicting prognosis and clinical outcomes in lung carcinoma patients. Methods In total, 502 lung cancer patients undergoing platinum‐based chemotherapy were recruited in this prospective study. Genotyping of ABCB1 (C1236T, C3435T, and G2677T/A), ABCC1 (G3173A and G2168A), ABCC2 (G4544A), and ABCG2 (C421A) polymorphisms in Northern Indian lung carcinoma patients were evaluated using polymerase chain reaction‐restriction fragment length polymorphism analysis. Results Poor survival outcomes were noted in patients carrying a heterozygous genotype (CT) for the ABCB1 C1236T polymorphism compared to the wild‐type genotype (CC) (p = 0.04). The mutant genotype (AA) for ABCC1 G3173A exhibited a lower median survival time compared to the reference genotype (GG) (p = 0.009). Lower survival was observed in individuals carrying a heterozygous genotype (GA) for ABCC2 G4544A polymorphism compared to the wild‐type genotype (GG) (p = 0.017). Small cell lung cancer patients with the ABCB1 G2677A polymorphism having a heterozygous genotype (GA) showed poor survival compared to the wild‐type genotype (GG) (p = 0.03). For ABCC1 G3173A, adenocarcinoma patients having a mutant genotype (AA) had reduced survival compared to the wild‐type (GG) genotype (p = 0.03). For ABCB1 C3435T, individuals carrying a heterozygous (CT) (p = 0.018) and mutant (TT) genotype (p = 0.007) had poor survival compared to the wild‐type (CC) genotype in patients treated with pemetrexed and cisplatin. The patients administered cisplatin and irinotecan and having mutant alleles (AA) for the ABCB1 G2677A polymorphism showed a lower survival compared to the individuals carrying wild‐type alleles (GG) (p = 0.009). Conclusions Our findings suggest that ABCB1 C1236T, ABCB1 C3435T, ABCB1 G2677A, ABCC1 G3173A, and ABCC2 G4544A are involved in predicting prognosis. Genotyping of the ABC polymorphism is essential for predicting prognosis in lung carcinoma patients.

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“…Cancer resistance reduces the outcome of therapy and is a cause of treatment failure (Pilotto Heming et al 2022). ABCB1 transporter is one of the most important proteins involved in transporter-dependent resistance and plays a signi cant role in cancer resistance against taxanes, Vinca alkaloids, and anthracyclines (Krause 2019; Chen et al 2021). Modulation of ABCB1 activity is considered a potential therapeutic approach to sensitize cells against cytotoxic agents; however, all P-glycoprotein inhibitors, despite their activity in preclinical models, failed during clinical investigations.…”

Section: Introductionmentioning

confidence: 99%

Comparative study on ABCB1-dependent efflux of anthracyclines and their metabolites: consequences for cancer resistance

Piska

Koczurkiewicz-Adamczyk

Jamrozik

et al. 2023

Preprint

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Purpose ABC transporters are transmembrane proteins involved in ATP-dependent translocation of organic compounds across cellular membranes. Among them, ABCB1 (P-glycoprotein, MDR1) transporter is one of the most important involved in cancer multi-drug resistance. It also plays a significant role in cancer resistance against anthracyclines, an anticancer group of drugs, including doxorubicin and daunorubicin. Carbonyl reductases and aldo-keto reductases metabolize anthracyclines to carbonyl-reduced, hydroxy metabolites, which have impaired cytotoxic properties. However, metabolites efflux by ABCB1 transporter is not well characterized, while it may be the mechanism responsible for the metabolites' lack of activity. Methods In this study recombinant ABCB1 ATPase transporter assay; anthracyclines accumulation assay in resistant cells overexpressing ABCB1; and molecular modeling were used to investigate anthracyclines: doxorubicin and daunorubicin and their carbonyl-reduced metabolites (doxorubicinol, daunorubicinol) susceptibility for ABCB1-dependent efflux. Results Based on the kinetics parameters of ATPase activity of ABCB1, it was found that daunorubicinol exerted an exceptionally high potential for being effluxed by the ABCB1 transporter. ABCB1 was found to significantly affect the accumulation pattern of studied chemicals in resistant cancer cells. Doxorubicin and daunorubicin accumulation was influenced by the activity of ABCB1 modulator – valspodar. Conclusions Results indicate that ABCB1 activity affects not only anthracyclines but also their metabolites. The effect of ABCB1 on metabolites may be even higher than for parent anthracyclines. Therefore crosstalk between the process of anthracyclines metabolism and metabolites efflux may be the mechanism of impairing anticancer properties of anthracyclines metabolites.

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Prognostic Value of Two Polymorphisms, rs1045642 and rs1128503, in ABCB1 Following Taxane-based Chemotherapy: A Meta-Analysis

Abstract: Several genetic polymorphisms have been shown to affect the activity of taxanes. The most common gene reportedly associated with these effects is ATP-binding cassette transporter B subfamily member 1 (ABCB1), also

Cited by 10 publications

References 44 publications

Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark

Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark

Impact of ABCB1, ABCC1, ABCC2, and ABCG2 variants in predicting prognosis and clinical outcomes of north Indian lung cancer patients undergoing platinum‐based doublet chemotherapy

Comparative study on ABCB1-dependent efflux of anthracyclines and their metabolites: consequences for cancer resistance

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