La responsabilidad administrativa del juez por sus actos jurisdiccionales

Diseño del Consejo de la Judicatura y sus atribuciones disciplinarias

2) En febrero de 2008, fueron destituidos los tres miembros del Tribunal Primero de lo Penal del Azuay, doctores Nelson Pesántez, Tomás Aguilar y Rodrigo Dávila, por las mismas

3.3.2 La responsabilidad administrativa del juez por sus actos jurisdiccionales

• The cytochrome P450 2D6 (CYP2D6) enzyme is involved in

metabolizing tamoxifen into endoxifen, which is 30-100 times more effective than tamoxifen and considered to be primarily responsible for the pharmacologic effects of tamoxifen.1

• Studies suggest that certain variations (polymorphisms) in the

CYP2D6 gene result in reduced or absent enzyme function, which may lead to lower levels of active tamoxifen metabolites and reduced treatment efficacy.2-4 • CYP2D6 testing has, therefore, been proposed to

guide adjuvant therapy decisions in some circumstances.

o Postmenopausal women considering tamoxifen have a choice between tamoxifen and aromatase inhibitors.5 Results of CYP2D6 testing could influence that decision, although data about the utility of testing has been mixed (see Guidelines/Evidence below for details).

o Testing is not indicated for perimenopausal and premenopausal women with hormone-positive breast cancer. Tamoxifen is the current standard of care for these patients,5 and no alternative treatment plans have been approved.

o Testing is not recommended for patients considering tamoxifen in the preventative setting.6

Test Information

• CYP2D6 testing is usually performed on a buccal swab or blood sample using polymerase chain reaction (PCR) to look for certain common variants.

• More than 75 variants of the CYP2D6 gene have been noted to date.7

Variants most commonly included in available test panels are: *2, *3, *4. *5, *6, *7, *8, *9, *10, *11, *12, *14, *15, *17, *41, *1XN, *2XN, *4XN, *10XN, *17XN, *41XN. • Genotype results are generally assigned a metabolizer phenotype:

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Phenotype Genotype(s)8

Poor Metabolizer (PM) Two CYP2D6 inactive variants Intermediate Metabolizer (IM)

One normal and one inactivevariant

One inactive and one reduced-activity variant Two reduced-activity variants

Extensive Metabolizer (EM) Two normal CYP2D6 alleles

Ultrarapid Metabolizer (UM) More than two copies of the normal CYP2D6 allele

• The frequency of the CYP2D6 metabolizer phenotypes varies with ethnicity. About 5-10% of Caucasians are poor metabolizers, while the frequency is much lower in Africans and Asians.7

Guidelines and Evidence

• Evidence-based guidelines from the National Comprehensive Cancer Network (NCCN, 2012) state: "At this time, based on current data the [NCCN Breast Cancer] panel recommends against CYP2D6 testing for women being

considered for tamoxifen therapy."5 (category 2A: The recommendation is based on lower level evidence and there is uniform NCCN consensus)

• Practice guidelines from the American Society of Clinical Oncologists (ASCO, 2009) state: "Given the limited evidence, CYP2D6 testing is currently not

recommended in the preventive setting."6

• Two important large clinical trials have most directly addressed clinical utility of CYP2D6 testing for tamoxifen response.9,10 Both found that CYP2D6 genotype did not predict long-term outcome among tamoxifen users.

o Regan et al. performed CYP2D6 variant testing on tumor tissue from 4393 patients enrolled in the BIG 1-98 trial and evaluated the association with breast cancer recurrence. BIG 1-98 was an international, randomized double-blind trial that compared tamoxifen monotherapy, letrozole (an aromatase inhibitor) monotherapy, and sequential therapy (2 years of one and 3 years of another). Patients were mostly Caucasian and all had postmenopausal, hormone receptor-positive, operable breast cancer. Results found a non-statistically significant association between

metabolizer phenotype and recurrence (poor metabolizer vs. extensive metabolizer HR = 0.58, 95% CI = 0.28 to 1.21). The authors concluded "The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen."9 o Similarly, Rae et al. found no association between CYP2D6 genotype and

breast cancer recurrence in people treated with tamoxifen from the randomized double-blind Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (n=1203; poor metabolizer vs. extensive metabolizer HR = 1.25, 95% CI = 0.55 to 3.15). The authors conclude "The results do not

Lab Management Guidelines V1.0.2016

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support the hypothesis that CYP2D6 genotype predicts clinical benefit of adjuvant tamoxifen treatment among postmenopausal breast cancer patients."10

Criteria

This test is considered investigational and/or experimental.

o Investigational and experimental (I&E) molecular and genomic (MolGen) tests refer to assays involving chromosomes, DNA, RNA, or gene

products that have insufficient data to determine the net health impact, which typically means there is insufficient data to support that a test accurately assesses the outcome of interest (analytical and clinical validity), significantly improves health outcomes (clinical utility), and/or performs better than an existing standard of care medical management option. Such tests are also not generally accepted as standard of care in the evaluation or management of a particular condition.

o In the case of MolGen testing, FDA clearance is not a reliable standard given the number of laboratory developed tests that currently fall outside of FDA oversight and FDA clearance often does not assess clinical utility.

References

1. Fleeman N, Martin Saborido C, Payne K, et al. The clinical effectiveness and cost-

effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review. Health Technol Assess. 2011 Sep;15(33):1-102. 2. Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant

tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007;25(33):5187-93.

3. Goetz MP, Knox SK, Suman VJ, et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat. 2007;101:113-21.

4. Newman WG, Hadfield KD, Latif A, et al. Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res. 2008;14(18):5913-8.

5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 1.2012. Available

at http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf.

6. Visvanathan K, Lippman SM, Hurley P, Temin S. American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. Gynecol

Oncol. 2009;115(1):132-4.

7. Zhou S. Polymorphism of human CYP450 2D6 and its clinical significance: Part I. Clin

Pharamcokinet. 2009;48(11):689-723.

8. Higgins MC, Rae JM, Flockhart DA, et al. Pharmacogenetics of tamoxifen: who should undergo CYP2D6 genetic testing? J NCCN. 2009;7(2):203-13.

9. Regan MM, Leyland-Jones B, Bouzyk M, et al.; Breast International Group (BIG) 1-98 Collaborative Group. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl

Cancer Inst. 2012 Mar 21;104(6):441-51.

10. Rae JM, Drury S, Hayes DF, et al.; ATAC trialists. CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012 Mar 21;104(6):452-60.

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