Breast Cancer Research and Treatment

, Volume 159, Issue 1, pp 97–108 | Cite as

A pooled analysis of CYP2D6 genotype in breast cancer prevention trials of low-dose tamoxifen

  • Harriet Johansson
  • Sara Gandini
  • Davide Serrano
  • Jennifer Gjerde
  • Monia Lattanzi
  • Debora Macis
  • Aliana Guerrieri-Gonzaga
  • Valentina Aristarco
  • Gunnar Mellgren
  • Ernst Lien
  • Andrea DeCensi
  • Bernardo Bonanni
Clinical trial


Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low-dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. DNA from 367 subjects was genotyped for CYP2D6 alleles associated with absent (PM allele: *3, *4, *5, *6, *7, *8, *12, and *14), reduced (IM allele: *9, *10, *17, *29, *41), normal (EM allele), or increased (UM: *XN) enzyme activity. Associations of tamoxifen, metabolites, activity biomarkers, and event-free survival with rapid (UM/EM, UM/IM, EM/EM, EM/IM, or EM/PM alleles) versus slow metabolizers (PM/IM or PM/PM) were investigated through random effects models, with ‘study’ as the random factor, and Cox regression models, adjusting for confounders. Rapid metabolizers had higher endoxifen levels than slow metabolizers: 15.3 versus 12.2 ng/mL (P = 0.018) with 5 mg/day, and 3.8 versus 2.8 ng/mL (P = 0.004) with 1 mg/day or 10 mg/week tamoxifen. The IGF-I decrease correlated with endoxifen (P = 0.002) and 4-hydroxytamoxifen levels, demonstrating steeper decreases at higher metabolite levels (P = 0.001). After a median follow-up of 12 years, rapid metabolizers with prior history of breast neoplasms allocated to tamoxifen 5 mg/day had a 60 % reduction of risk of recurrences (HR = 0.40, 95 % CI: 0.16–0.99) compared to slow metabolizers. CYP2D6 genotype may have an impact on tamoxifen efficacy at low doses. Trials investigating tamoxifen dose adjustments based on the woman’s hormonal context and CYP2D6 genotype are warranted.


Breast cancer Tamoxifen Prevention CYP2D6 Biomarkers IGF-I Pharmacogenetics 





4-hydroxy-N-desmethyltamoxifen, or endoxifen


Body mass index


Extensive metabolizers


Hormone replacement therapy


Insulin-like growth factor


Intermediate metabolizers


Interquartile ranges






Poor metabolizers


Sex hormone-binding globulin


Ultrarapid metabolizers



We thank Medical Systems S.p.A. (Genoa, Italy) for providing instruments for CYP analysis and Tiziana Chiesa for her technical assistance.


Lega Italiana per la Lotta contro i Tumori, Italian Foundation for Cancer Research, National Cancer Institute (Grant No CA-77188), A regional Grant (1068/2005) on second tumors from the Italian Association for Cancer Research, Susan Komen Breast Cancer Foundation (Grant No. BCTR01-00537), Italian Health Ministry (Ricerca Finalizzata 2004/86), Gruppo Bancario Credito Valtellinese (Research Fellowship), European Institute of Oncology Foundation, Western Norway Regional Health Authority.

Author contribution

HJ, SG, and DS contributed to the conception and design of the study. For the clinical interpretation of the data, HJ was assisted by DS and ADC. SG performed the statistical analysis. AGG assisted with her expertise in data management and coordination of clinical trial reporting. JG performed tamoxifen metabolite measurements. DM and VA performed DNA extraction and genotyping of CYP2D6, assisted by ML at Medical System S.p.A. (Genoa, Italy). HJ gave technical support for laboratory measurements and quality check of lab analysis. GM and EAL participated in the trial design as experts in the field of tamoxifen pharmacokinetics studies. BB and ADC are PIs of the four chemoprevention trials and Senior coauthors of this manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare they have no competing interests.

Supplementary material

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Supplementary material 1 (DOCX 16 kb)
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Supplementary material 2 (DOCX 17 kb)
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Supplementary material 3 (DOCX 18 kb)
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Supplementary material 4 (DOCX 14 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Harriet Johansson
    • 1
  • Sara Gandini
    • 2
  • Davide Serrano
    • 1
  • Jennifer Gjerde
    • 3
    • 4
  • Monia Lattanzi
    • 5
  • Debora Macis
    • 1
  • Aliana Guerrieri-Gonzaga
    • 1
  • Valentina Aristarco
    • 1
  • Gunnar Mellgren
    • 3
    • 4
  • Ernst Lien
    • 3
    • 4
  • Andrea DeCensi
    • 6
    • 7
  • Bernardo Bonanni
    • 1
  1. 1.Division of Cancer Prevention and GeneticsEuropean Institute of OncologyMilanItaly
  2. 2.Division of Epidemiology and BiostatisticsEuropean Institute of OncologyMilanItaly
  3. 3.Department of Clinical ScienceUniversity of BergenBergenNorway
  4. 4.Hormone LaboratoryHaukeland University HospitalBergenNorway
  5. 5.Medical Systems S.p.A.GenoaItaly
  6. 6.Division of Medical OncologyE.O. Ospedali GallieraGenoaItaly
  7. 7.Wolfson Institute of Preventive MedicineQueen Mary University of LondonLondonUK

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