Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients

Autor: Jan Terje Kvaløy, Steinar Hustad, Vessela N. Kristensen, Ersilia Bifulco, Timothy L. Lash, Thomas Helland, Bjørn Naume, Gunnar Mellgren, Håvard Søiland, Emiel A. M. Janssen, Nina Henne, Ron H.N. van Schaik, Grethe I. Grenaker Alnæs, Elin Borgen, Ernst A. Lien
Přispěvatelé: Clinical Chemistry
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Oncology
Pharmacogenomic Variants
Survival
Endoxifen
Breast cancer
0302 clinical medicine
Surgical oncology
Medicine
skin and connective tissue diseases
Adjuvant
Aged
80 and over
tamoxifen
CYP2D6
Hazard ratio
Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762 [VDP]
Middle Aged
Prognosis
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
overlevelse
prognose
4OHtam
Cytochrome P-450 CYP2D6
Chemotherapy
Adjuvant
Midical sciences: 700 [VDP]
030220 oncology & carcinogenesis
Cohort
Female
Medisinske fag: 700 [VDP]
medicine.drug
Adult
Evaluering av behandlinger og terapeutiske intervensjoner [Kreft]
medicine.medical_specialty
Antineoplastic Agents
Hormonal
helsefag
Breast Neoplasms
lcsh:RC254-282
03 medical and health sciences
SDG 3 - Good Health and Well-being
brystkreft
Internal medicine
Humans
Aged
Retrospective Studies
Gynecology
business.industry
Research
metabolisme
Antiestrogen
medicine.disease
Confidence interval
Tamoxifen
Metabolism
030104 developmental biology
endoxifen
Evaluation of Treatments and Therapeutic Interventions [Cancer]
Neoplasm Grading
business
Zdroj: Breast Cancer Research
Breast Cancer Research, 19:125. BioMed Central Ltd.
Breast Cancer Research, Vol 19, Iss 1, Pp 1-13 (2017)
Breast Cancer Research : BCR
ISSN: 1465-5411
Popis: Background Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients. Methods From an original observational study comprising 817 breast cancer patients, 99 women with operable breast cancer were retrospectively included in the present study. This cohort of patients were adjuvantly treated with tamoxifen, had provided serum samples suitable for measuring tamoxifen metabolites, and were relapse-free at 3 years after the primary treatment commenced. The median follow-up time from this entry point to breast cancer death was 13.9 years. Patients were CYP2D6 genotyped and grouped into four CYP2D6 phenotype groups (Ultra rapid, extensive, intermediate, and poor metabolizers). Tamoxifen and nine metabolites were quantified in serum (n = 86) and compared with CYP2D6 phenotype groups and outcome. Results Breast cancer patients with low concentrations of Z-4-hydroxy-tamoxifen (Z-4OHtam; ≤ 3.26 nM) had a breast cancer-specific survival (BCSS) of 60% compared to 84% in patients with Z-4OHtam concentrations > 3.26 nM (p = 0.020, log-rank hazard ratio (HR) = 3.56, 95% confidence interval (CI) = 1.14–11.07). For patients with Z-4-hydroxy-N-desmethyl-tamoxifen (Z-endoxifen) levels ≤ 9.00 nM BCSS was 57% compared to 84% for patients with concentrations > 9.00 nM (p = 0.029, HR = 3.73, 95% CI = 1.05–13.22). Low concentrations of Z-4OHtam and Z-endoxifen were associated with poorer survival also after adjusting for clinically relevant variables (HR = 4.27, 95% CI = 1.35–13.58, and HR = 3.70, 95% CI = 1.03–13.25, respectively). Overall survival analysis showed similar survival differences for both active metabolites. The Antiestrogen Activity Score showed comparable effects, but did not improve the prognostic information. Conclusions Patients with Z-4OHtam and Z-endoxifen concentrations lower than 3.26 nM or 9.00 nM, respectively, showed an adverse outcome. Our results suggest that direct measurement of active tamoxifen metabolite concentrations could be of clinical value. Validation in larger study cohorts is warranted.
Databáze: OpenAIRE
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