CYP2D6 Inhibition and Breast Cancer Recurrence in a Population-Based Study in Denmark

Lash, Timothy L.; Cronin‐Fenton, Deirdre; Ahern, Thomas P.; Rosenberg, Carol L.; Lunetta, Kathryn L.; Silliman, Rebecca A.; Garne, Jens Peter; Sørensen, Henrik Toft; Hellberg, Ylva; Christensen, Mariann; Pedersen, Lars; Hamilton-Dutoit, Stephen

doi:10.1093/jnci/djr010

Cited by 79 publications

(76 citation statements)

References 66 publications

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“…1,16 In our study 5.4% of the NM group and 9.1% of the IM group developed metastasis. No metastasis was observed in the PM and UM groups and no statistical significance was detected (p= 0.87).…”

Section: Discussionsupporting

confidence: 48%

Evaluation of CYP2D6 Polymorphic Types and Their Effect on Tamoxifen Efficacy Among Turkish Tamoxifen Users with Breast Cancer

Günaldı¹

2014

UHOD

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In this study we investigated the role of the polymorphic types of CYP2D6 in the Turkish population for therapeutic efficacy among patients with early stage breast cancer who treated with tamoxifen. CYP2D6 plays an important role in tamoxifen metabolism. CYP2D6 genotypes were determined of 115 patients treated with adjuvant tamoxifen using the AmpliChip CYP450 test. Genotypes were classified by metabolizer groups and evaluated by the diagnostic and clinical characteristics of the patients and the recurrences of the disease. To create an intergroup comparison of the categorical measurements, the Chi-Square test was used. The most common CYP2D6 gene polymorphism was *1/*2 with a percentage of 19.9% (n= 19). In the Turkish population, among patients with early stage breast cancer, the normal metabolizer group was the largest with a percentage of 77.1% (n= 74). The percentage rates were determined to be 11.5% (n= 11) for intermediate metabolizers, 5.2% (n= 5) for ultrarapid metabolizers and 2.1% (n= 2) for poor metabolizers. In patients with early stage breast cancer treated with adjuvant tamoxifen. no significant correlation was detected between CYP2D6 types and recurrence and metastasis rates. This study was the first study to determine CYP2D6 genotypes and characteristics of Turkish patients with early stage breast cancer. Although no correlation was demonstrated between CYP2D6 genotype polymorphism and disease recurrence in the earlier period, long-term follow-ups seem to be warranted. Keywords: Breast cancer, CYP2D6, Tamoxifen ÖZET Tamoksifen Kullanan Meme Kanserli Türk Hastalarda CYP2D6 Gen Polimorfizm Tiplerinin Tamoksifen Etkinliğine Etkinliklerinin DeğerlendirilmesiBiz bu çalışmada, erken evre meme kanseri tedavisinde tamoksifen kullanan Türk hastalarda CYP2D6 gen polimorfizmleri ile tedavi etkinliği arasındaki ilişkiyi araştırdık. Adjuvant tamoksifen kullanan 115 hastanın CYP2D6 genotipleri AmpliChip CYP450 test kullanılarak belirlendi. Metaboze edici gruplar genotiplere gore sınıflandırılarak tanı, klinik ve hastalığın tekrarı ile değerlendirildi. Sınıflandırılan ölçümlerin karşılaştırılmasında Ki-kare testi kullanıldı. En sık CYP2D6 gen polimorfizmi 19.9% (n= 19) ile *1/*2 idi. Erken evre meme kanserli Türk hastalarda 77.1% (n= 74) normal metabolize edici grup en büyük grubu oluşturdu. Orta metabolize edici grup 11.5% (n= 11), 5.2% (n= 5) hızlı metabolize edici grup, 2.1% (n= 2) yavaş metabolize edici grup olarak saptandı. Tamoksifenle tedavi edilen erken evre meme kanserli hastalarda CYP2D6 gen polimorfizmleri ile hastalık tekrarı ve metastazı arasında anlamlı bir ilişki saptanmadı. Erken evre meme kanserli Türk hastalarda CYP2D6 genotipleri ve özelliklerini saptayan ilk çalışmadır. CYP2D6 genotip polimorfizmleri ve hastalık tekrarı arasında erken dönemde bir ilişki saptanmasa da uzun dönem takibe ihtiyaç olduğu görünmektedir.

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Section: Discussionsupporting

confidence: 48%

Evaluation of CYP2D6 Polymorphic Types and Their Effect on Tamoxifen Efficacy Among Turkish Tamoxifen Users with Breast Cancer

Günaldı¹

2014

UHOD

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“…Other studies found no association between CYP2D6 metabolizer status and outcomes of tamoxifen therapy [19][20][21][22][23][24]. The effect of genetic polymorphisms can vary across populations due to genetic and environmental factors.…”

Section: Discussionmentioning

confidence: 98%

Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy

Damodaran

Pradhan

Umamaheswaran

et al. 2012

Cancer Chemother Pharmacol

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“…Neither study found a positive association between reduced CYP2D6 function and breast cancer recurrence. In a large case-control study, Lash et al (28) also reported a near-null association between CYP2D6 genotype and recurrence risk. On the basis of current evidence, 3 independent guideline panels have explicitly recommend against implementing CYP2D6 genotype testing for patients who are candidates for tamoxifen therapy (6,8,29).…”

mentioning

confidence: 95%

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

Ahern¹,

Hertz²,

Damkier³

et al. 2016

Am. J. Epidemiol.

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Tamoxifen therapy for estrogen receptor-positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (CYP2D6), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-Ndesmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Thirty-one studies of the association of CYP2D6 genotype with breast cancer survival have yielded heterogeneous results. Some influential studies genotyped DNA from tumorinfiltrated tissues, and their results may have been susceptible to germline genotype misclassification from loss of heterozygosity at the CYP2D6 locus. We systematically reviewed 6 studies of concordance between genotypes obtained from paired nonneoplastic and breast tumor-infiltrated tissues, all of which showed excellent CYP2D6 genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association. The bias analysis showed negligible bias by discordant genotypes. Summary estimates of association, with or without bias adjustment, indicated no clinically important association between CYP2D6 genotype and breast cancer survival in tamoxifen-treated women. breast neoplasms; cytochrome P-450 2D6; tamoxifen Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination; BIG 1-98, Breast International Group 1-98; CI, confidence interval; CYP2D6, cytochrome P-450 2D6; FFPE, formalin-fixed, paraffin-embedded; FFPE-T, formalin-fixed, paraffinembedded tumor tissue; FFPE-TN, formalin-fixed, paraffin-embedded tumor tissue with nonneoplastic tissue; HWE, HardyWeinberg equilibrium; LOH, loss of heterozygosity; RR, relative risk.

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CYP2D6 Inhibition and Breast Cancer Recurrence in a Population-Based Study in Denmark

Abstract: The association between CYP2D6 inhibition and recurrence in tamoxifen-treated patients is likely null or small.

Cited by 79 publications

References 66 publications

Evaluation of CYP2D6 Polymorphic Types and Their Effect on Tamoxifen Efficacy Among Turkish Tamoxifen Users with Breast Cancer

Evaluation of CYP2D6 Polymorphic Types and Their Effect on Tamoxifen Efficacy Among Turkish Tamoxifen Users with Breast Cancer

Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

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