Association of the ABCB1 gene polymorphisms 2677G&gt;T/A and 3435C&gt;T with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients

Chang, Hang Seok; Rha, Sun Young; Jeung, Hei‐Cheul; Im, Chang‐Hwan; Ahn, Joong Bae; Kwon, Woo Sun; Yoo, Nae Choon; Roh, Jae Kyung; Chung, Hyun Cheol

doi:10.1093/annonc/mdn624

Cited by 97 publications

(89 citation statements)

References 24 publications

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“…This result was relevant with several studies that showed there was no association between polymorphism of MDR1 C3435T with leukocytopenia event [26]. This result was contradictive with other study in 58 cancer patient who get docetaxel monotherapy that there was an association between homozygous variant (TT) of MDR1 C3435T with grade III leukocytopenia.…”

Section: Kruskal-wallis Testcontrasting

confidence: 55%

Association of Multi-Drug Resistance-1 (MDR1) Gene Polymorphism with Leukocytopenia in Breast Cancer Patients treated with Chemotherapy

Syarifah¹,

Widyawati²,

Siregar³

et al. 2017

Proceedings of the 1st Public Health International Conference (PHICo 2016)

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Abstract-Breast cancer incidence rates tend to increase in Indonesia and worldwide. Chemotherapy is an important breast cancer treatment which improve survival rate but also has many side effects. Leukocytopenia is one of the most common side effects that can be life-threatening due to opportunistic infection. Genetic polymorphism has been linked to inter-individual variations in terms of toxicity response of anticancer drugs. C3435T polymorphism in exon 26 of Multi-Drug Resistance 1 (MDR-1) gene which encodes P-glycoprotein (P-gp) is considered to be associated with increase of leukocytopenia incidence during chemotherapy. This study aim to investigate the association between MDR1 C3435T polymorphism with the grading of leukocytopenia in breast cancer patients treated with chemotherapy. 72 Indonesian female breast cancer patients from Haji Adam Malik Hospital who received chemotherapy containing doxorubicin-paclitaxel were selected for this cohort study. DNA was extracted from peripheral leukocytes and MDR1 C3435T polymorphism was analyzed with polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Patient data were collected for 3 cycles of chemotherapy. Association between MDR1 C3435T polymorphism with the grading of leukocytopenia was assessed using Kruskal-Wallis test. Decline of absolute leucocyte count during 3 cycles of chemotherapy was assessed using Wilcoxon test. Genotype deviation and allele frequencies were also determined by HardyWeinberg Equilibrium. Patients were divided into 4 ethnics: Bataknese, Minangkabau, Javanese and Acehnese. Distribution of MDR1 C3435T polymorphism was varied among these ethnics. The frequencies of MDR1 C3435T genotype for wildtype (CC) was 22 (30,6%), heterozygous (CT) was 38 (52,8%) and homozygous mutant (TT) was 12 (16,7%). There was no association between MDR1 C3435T polymorphism and the grading of leukocytopenia (p>0,05). The average of absolute leukocyte count was differ after the second chemotherapy and after the third chemotherapy (p<0,05). The allele and genotype frequency from Hardy-Weinberg Equilibrium showed no significant deviation. MDR1 C3435T polymorphism had no association with leukocytopenia in breast cancer patients treated with doxorubicin-taxan regimen, meanwhile there was a trend of absolute leukocyte count declining post chemotherapy cycle 2.

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Section: Kruskal-wallis Testcontrasting

confidence: 55%

Association of Multi-Drug Resistance-1 (MDR1) Gene Polymorphism with Leukocytopenia in Breast Cancer Patients treated with Chemotherapy

Syarifah¹,

Widyawati²,

Siregar³

et al. 2017

Proceedings of the 1st Public Health International Conference (PHICo 2016)

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“…38 The MRP expression profile of CTCs allowed us to trace a sort of ''chemotherapy-biogram,'' specific for each patient in a precise time of disease, to be correlated to clinical response. This biogram is easy to perform in a short time and with low costs of execution because of the use of a basic test such as relative RT-PCR.…”

Section: Discussionmentioning

confidence: 99%

Chemosensitivity profile assay of circulating cancer cells: prognostic and predictive value in epithelial tumors

Gazzaniga

Naso

Gradilone

et al. 2010

Intl Journal of Cancer

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The prognostic value associated with the detection of circulating tumor cells (CTCs) in metastatic breast cancer by the CellSearch TM technology raise additional issues regarding the biological value of this information. We postulated that a drugresistance profile of CTCs may predict response to chemotherapy in cancer patients and therefore could be used for patient selection. One hundred 5 patients with diagnosis of carcinoma were enrolled in a prospective trial. CTCs were isolated from peripheral blood, and positive samples were evaluated for the expression of a panel of genes involved in anticancer drugs resistance. The drug-resistance profile was correlated with disease-free survival (DFS; patients in adjuvant setting) and time to progression (TTP; metastatic patients) in a 24-months follow-up. Objective response correlation was a secondary end point. Fifty-one percent of patients were found positive for CTCs while all blood samples from healthy donors were negative. The drug-resistance profile correlates with DFS and TTP (p < 0.001 in both). Sensitivity of the test: able to predict treatment response in 98% of patients. Specificity of the test: 100%; no sample from healthy subject was positive for the presence of CTCs. Positive and negative predictive values were found to be 96.5 and 100%, respectively. We identified a drug-resistance profile of CTCs, which is predictive of response to chemotherapy, independent of tumor type and stage of disease. This approach may represent a first step toward the individualization of chemotherapy in cancer patients.In 2007, cancer killed 7.6 million people (about 20,000 cancer deaths a day), despite the extended use of chemotherapy. 1Excluding skin malignancies, $85% of solid tumors are of epithelial origin. The main cause of death of our cancer patients is undoubtedly the appearance of metastasis, a subset of cancer cells that, detaching from the primary mass, survive in blood and bone marrow eluding immune surveillance and apoptosis. 2 This is the demonstration that systemic chemotherapy is often ineffective, particularly in controlling the metastatic process, and that in $50% of patients with solid tumors, the treatment will be palliative, associated with modest benefit and extremely toxic.3 Therefore, it is important to develop novel models that would allow the proper selection of systemic treatment and predict the outcome in the individual patient. This could lead to achieving the goal of truly personalized therapy.Prospective studies have demonstrated that the number of these circulating tumor cells (CTCs) is predictive of progression-free survival and overall survival [4][5][6] ; this led to the Food and Drug Administration (FDA) approval of the CellSearch TM as the 1st platform used as a counter of CTCs in the peripheral blood of patients with advanced epithelial cancers, which provides prognostic information and is useful to monitor treatment efficacy. [7][8][9] The prognostic value of CTCs in different epithelial malignancies suggests a common biological backgrou...

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“…2, 11, and [16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Any studies investigating genetic variations only associated with pharmacokinetic, outcome, or taxane resistance endpoints but not sensory peripheral neuropathy/neurotoxicity were excluded.…”

Section: Candidate Gene Selection For Assessment In Pgsnpsmentioning

confidence: 99%

“…Several SNPs in ABCB1 have previously been commonly reported to be associated with TRSN (16)(17)(18)(19)(20)(22)(23)(24)(25)(26). Two of such SNPs are ABCB1, rs1045642 (P ¼ 0.03), and rs2032582 (P ¼ 0.02).…”

Section: We Identified 17 Relevant Publications (Supplementarymentioning

confidence: 99%

Replication of Genetic Polymorphisms Reported to Be Associated with Taxane-Related Sensory Neuropathy in Patients with Early Breast Cancer Treated with Paclitaxel

Abraham

Guo

Dorling

et al. 2014

Clinical Cancer Research

100

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Purpose: Associations between taxane-related sensory neuropathy (TRSN) and single-nucleotide polymorphisms (SNP) have previously been reported, but few have been replicated in large, independent validation studies. This study evaluates the association between previously investigated SNPs and TRSN, using genotype data from a study of chemotherapy-related toxicity in patients with breast cancer.Experimental Design: We investigated 73 SNPs in 50 genes for their contribution to TRSN risk, using genotype data from 1,303 European patients. TRSN was assessed using National Cancer Institute common toxicity criteria for adverse events classification. Unconditional logistic regression evaluated the association between each SNP and TRSN risk (primary analysis). Cox regression analysis assessed the association between each SNP and cumulative taxane dose causing the first reported moderate/severe TRSN (secondary analysis). The admixture likelihood (AML) test, which considers all SNPs with a prior probability of association with TRSN together, tested the hypothesis that certain SNPs are truly associated.Results: The AML test provided strong evidence for the association of some SNPs with TRSN (P ¼ 0.023). The two most significantly associated SNPs were rs3213619(ABCB1) [OR ¼ 0.47; 95% confidence interval (CI), 0.28-0.79; P ¼ 0.004] and rs9501929(TUBB2A) (OR ¼ 1.80; 95% CI, 1.20-2.72; P ¼ 0.005). A further 9 SNPs were significant at P-value 0.05.Conclusion: This is currently the largest study investigating SNPs associated with TRSN. We found strong evidence that SNPs within genes in taxane pharmacokinetic and pharmacodynamic pathways contribute to TRSN risk. However, a large proportion of the inter-individual variability in TRSN remains unexplained. Further validated results from GWAS will help to identify new pathways, genes, and SNPs involved in TRSN susceptibility. Clin Cancer Res; 20(9); 2466-75. Ó2014 AACR.

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Association of the ABCB1 gene polymorphisms 2677G>T/A and 3435C>T with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients

Abstract: ABCB1 genotypes may be a predictor of paclitaxel activity as well as a prognostic factor in metastatic breast cancer patients.

Cited by 97 publications

References 24 publications

Association of Multi-Drug Resistance-1 (MDR1) Gene Polymorphism with Leukocytopenia in Breast Cancer Patients treated with Chemotherapy

Association of Multi-Drug Resistance-1 (MDR1) Gene Polymorphism with Leukocytopenia in Breast Cancer Patients treated with Chemotherapy

Chemosensitivity profile assay of circulating cancer cells: prognostic and predictive value in epithelial tumors

Replication of Genetic Polymorphisms Reported to Be Associated with Taxane-Related Sensory Neuropathy in Patients with Early Breast Cancer Treated with Paclitaxel

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