Impact of<i>CYP2D6*4</i>genotype on progression free survival in tamoxifen breast cancer treatment

Stingl, Julia C.; Parmar, Sumit; Huber-Wechselberger, Ariana; Kainz, Alexander; Renner, Wilfried; Seeringer, Angela; Brockmöller, Jürgen; Langsenlehner, Uwe; Krippl, Peter; Haschke-Becher, Elisabeth

doi:10.1185/03007995.2010.518304

Cited by 35 publications

(22 citation statements)

References 24 publications

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“…The relationship between breast cancer and the CYP gene family was recently reported, including CYP1B1 (Economopoulos and Sergentanis, 2010;Ozbek et al, 2010), CYP2J2 (Jiang et al, 2007(Jiang et al, , 2009), CYP2D6 (Stingl et al, 2010;González-Tejera et al, 2010;Thompson et al, 2011), CYP2C8 (Knüpfer et al, 2004;Dixit, et al, 2007;Jernström et al, 2009), CYP2C9 (Ekhart et al, 2008;Jernström et al, 2009) and CYP2C19 (Justenhoven et al, 2009;Ruiter et al, 2010;Goetz and Suman, 2010). Several studies have reported different conclusions for the relationship with CYP2C19.…”

Section: Discussionmentioning

confidence: 99%

Association of CYP2C19*3 gene polymorphism with breast cancer in Chinese women

Gan¹,

Wang²,

Cao³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. Cytochrome P450 (CYP) 2C19 metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids, which significantly promote proliferation of cancer cells in vitro and in vivo. We looked for a possible association between human CYP2C19*3 gene polymorphism and breast cancer in the Chinese Han population. In a Chinese Han case-control study of breast cancer patients (N = 600) and age-and gender-matched healthy controls (N = 600), we investigated polymorphism in the CYP2C19 gene by PCR-RFLP analysis. The CYP2C19*3 AG + AA genotype was significantly more prevalent in breast cancer patients than in control subjects (6.67 vs 3.00%; P = 0.003). The odds ratio for carriers of AG + AA genotype for breast cancer was 2.31 (95% confidence interval = 1.27-4.43). Among patients, estrogen receptor, tumor size, histologic grade, presence of primary lymphonode metastases, progesterone receptor positivity, and age at diagnosis were not found to be significantly associated with CYP2C19*3 genotypes (all P > 0.05). We conclude that the CYP2C19*3 gene polymorphism is associated with breast cancer risk in Chinese Han women.

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Section: Discussionmentioning

confidence: 99%

Association of CYP2C19*3 gene polymorphism with breast cancer in Chinese women

Gan¹,

Wang²,

Cao³

et al. 2011

Genet. Mol. Res.

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“…No significant difference in recurrence-free survival was found in carriers of the *10 allele in 173 Japanese women with primary hormone receptor-positive breast cancer receiving adjuvant tamoxifen [66]. In an Austrian cohort of women with estrogen-positive BC and a history of previous chemotherapy, there were no differences in the time to progression or progression-free survival between carriers of the CYP2D6*4 and the wildtype allele in the overall study cohort [67]. However, in the subgroup of patients receiving adjuvant chemotherapy, homozygous carriers of the CYP2D6*4 allele had shorter time to progression (1.0 vs 6.3 and 5.0 years in *1/*4 and *1/*1 carriers; Wilcoxon p = 0.104) and significantly lower progression-free survival.…”

Section: The Clinical Relevance Of Cyp2d6 Polymorphism For Tamoxifen mentioning

confidence: 95%

Impact of CYP2D6 polymorphism on tamoxifen therapy: where are we?

Huber-Wechselberger

Niedetzky

Aigner

et al. 2012

Wien Med Wochenschr

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Tamoxifen is a mainstay in the treatment of hormone-receptor sensitive breast cancer. To be effective, it needs conversion into 4-hydroxy-tamoxifen and endoxifen. The key enzyme involved is encoded by the gene CYP2D6 of which several, sometimes population-specific alleles are known. Corresponding enzyme variants may result in poor, intermediate, and extensive metabolization and therefore different steady-state plasma levels of active metabolites. Those are hypothesized to be linked to clinical outcomes of tamoxifen therapy. However, a wealth of mostly retrospective cohort studies came up with conflicting results. Appraisal of these studies is difficult and a metaanalysis impossible due to heterogeneity of patient populations, disease factors, treatment modalities, and measured outcomes. As standardization would not overcome intrinsic limitations of retrospective analyses, prospective trials comparing genotype-guided versus unsighted tamoxifen treatment are required to prove whether routine CYP2D6 genotyping is clinically effective and cost-effective.

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“…Overall, no significant difference in tumour free survival was reported; however, a subgroup analysis of patients treated with concomitant chemotherapy showed that CYP2D6*4 poor metabolizers had a shorter mean time interval to disease progression. However, It has to be reported that information on comedication were not available [18] . The impact of CYP2D6 in the outcome of breast cancer was further studied in a population-based cohort trial of 313 women that were adherent to tamoxifen therapy for at least one year (Table 1).…”

Section: Researchmentioning

confidence: 99%

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Markopoulos

Kykalos

Mantas

2014

WJCO

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Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: CYP2D6; Tamoxifen; Breast cancer; Adjuvant treatment Core tip: Currently, routine cytochrome P450 (CYP)2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.Markopoulos C, Kykalos S, Mantas D. Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen.

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Impact ofCYP2D6*4genotype on progression free survival in tamoxifen breast cancer treatment

Abstract: While earlier data on CYP2D6 and tamoxifen excluded women with prior chemotherapy, the present analysis suggests that CYP2D64 genotype might be particularly crucial in this group of high-risk patients. Key limitations are restriction to the CYP2D64 allele and missing data of comedication.

Cited by 35 publications

References 24 publications

Association of CYP2C19*3 gene polymorphism with breast cancer in Chinese women

Association of CYP2C19*3 gene polymorphism with breast cancer in Chinese women

Impact of CYP2D6 polymorphism on tamoxifen therapy: where are we?

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

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