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

Abstract

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.

Keywords

Breast cancer Tamoxifen Prevention CYP2D6 Biomarkers IGF-I Pharmacogenetics 

Abbreviation

4OHTam

4-hydroxytamoxifen

4OHNdesTam

4-hydroxy-N-desmethyltamoxifen, or endoxifen

BMI

Body mass index

EM

Extensive metabolizers

HRT

Hormone replacement therapy

IGF

Insulin-like growth factor

IM

Intermediate metabolizers

IQR

Interquartile ranges

NDDTam

N-desdimethyltamoxifen

NDTam

N-desmethyltamoxifen

PM

Poor metabolizers

SHBG

Sex hormone-binding globulin

UM

Ultrarapid metabolizers

Notes

Acknowledgments

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

Funding

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

10549_2016_3932_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 16 kb)
10549_2016_3932_MOESM2_ESM.docx (17 kb)
Supplementary material 2 (DOCX 17 kb)
10549_2016_3932_MOESM3_ESM.docx (18 kb)
Supplementary material 3 (DOCX 18 kb)
10549_2016_3932_MOESM4_ESM.docx (15 kb)
Supplementary material 4 (DOCX 14 kb)

References

  1. 1.
    Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S et al (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378:771–784CrossRefPubMedGoogle Scholar
  2. 2.
    Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S, Decensi A et al (2013) Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet 381:1827–1834CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Rutqvist LE, Johansson H, Signomklao T, Johansson U, Fornander T, Wilking N (1995) Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast Cancer Study Group. J Natl Cancer Inst 87:645–651CrossRefPubMedGoogle Scholar
  4. 4.
    Early Breast Cancer Trialists’ Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351:1451–1467CrossRefGoogle Scholar
  5. 5.
    Decensi A, Robertson C, Viale G, Pigatto F, Johansson H, Kisanga ER et al (2003) A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst 95:779–790CrossRefPubMedGoogle Scholar
  6. 6.
    Decensi A, Gandini S, Serrano D, Cazzaniga M, Pizzamiglio M, Maffini F et al (2007) Randomized dose-ranging trial of tamoxifen at low doses in hormone replacement therapy users. J Clin Oncol 25:4201–4209CrossRefPubMedGoogle Scholar
  7. 7.
    Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE (2013) PharmGKB summary: tamoxifen pathway, pharmacokinetics. Pharmacogenet Genomics 23:643–647CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kiyotani K, Mushiroda T, Imamura CK, Hosono N, Tsunoda T, Kubo M et al (2010) Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J Clin Oncol 28:1287–1293CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW et al (2011) Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther 89:718–725CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Margolin S, Lindh JD, Thoren L, Xie H, Koukel L, Dahl ML et al (2013) CYP2D6 and adjuvant tamoxifen: possible differences of outcome in pre- and post-menopausal patients. Pharmacogenomics 14:613–622CrossRefPubMedGoogle Scholar
  11. 11.
    Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S et al (2009) Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA 302:1429–1436CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Newman WG, Hadfield KD, Latif A, Roberts SA, Shenton A, McHague C et al (2008) Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res 14:5913–5918CrossRefPubMedGoogle Scholar
  13. 13.
    Xu Y, Sun Y, Yao L, Shi L, Wu Y, Ouyang T et al (2008) Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol 19:1423–1429CrossRefPubMedGoogle Scholar
  14. 14.
    Bijl MJ, van Schaik RH, Lammers LA, Hofman A, Vulto AG, van GT et al (2009) The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users. Breast Cancer Res Treat 118:125–130CrossRefPubMedGoogle Scholar
  15. 15.
    Cajal T, Altes A, Pare L, del RE, Alonso C, Barnadas A et al (2010) Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment. Breast Cancer Res Treat 119:33–38CrossRefGoogle Scholar
  16. 16.
    Park HS, Choi JY, Lee MJ, Park S, Yeo CW, Lee SS et al (2011) Association between genetic polymorphisms of CYP2D6 and outcomes in breast cancer patients with tamoxifen treatment. J Korean Med Sci 26:1007–1013CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Teh LK, Mohamed NI, Salleh MZ, Rohaizak M, Shahrun NS, Saladina JJ et al (2012) The risk of recurrence in breast cancer patients treated with tamoxifen: polymorphisms of CYP2D6 and ABCB1. AAPS J 14:52–59CrossRefPubMedGoogle Scholar
  18. 18.
    Sukasem C, Sirachainan E, Chamnanphon M, Pechatanan K, Sirisinha T, Ativitavas T et al (2012) Impact of CYP2D6 polymorphisms on tamoxifen responses of women with breast cancer: a microarray-based study in Thailand. Asian Pac J Cancer Prev 13:4549–4553CrossRefPubMedGoogle Scholar
  19. 19.
    Damodaran SE, Pradhan SC, Umamaheswaran G, Kadambari D, Reddy KS, Adithan C (2012) Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy. Cancer Chemother Pharmacol 70:75–81CrossRefPubMedGoogle Scholar
  20. 20.
    Goetz MP, Suman VJ, Hoskin TL, Gnant M, Filipits M, Safgren SL et al (2013) CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res 19:500–507CrossRefPubMedGoogle Scholar
  21. 21.
    Bonanni B, Macis D, Maisonneuve P, Johansson H, Gucciardo G, Oliviero P et al (2006) Polymorphism in the CYP2D6 Tamoxifen-Metabolizing Gene Influences Clinical Effect but Not Hot Flashes: data From the Italian Tamoxifen Trial. J Clin Oncol 24:3708–3709CrossRefPubMedGoogle Scholar
  22. 22.
    Goetz MP, Schaid DJ, Wickerham DL, Safgren S, Mushiroda T, Kubo M et al (2011) Evaluation of CYP2D6 and Efficacy of Tamoxifen and Raloxifene in Women Treated for Breast Cancer Chemoprevention: results from the NSABP P1 and P2 Clinical Trials. Clin Cancer Res 17:6944–6951CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP et al (2012) CYP2D6 and UGT2B7 Genotype and Risk of Recurrence in Tamoxifen-Treated Breast Cancer Patients. J Natl Cancer Inst 104:452–460CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R et al (2012) CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl Cancer Inst 104:441–451CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sestak I, Kealy R, Nikoloff M, Fontecha M, Forbes JF, Howell A et al (2012) Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial. Br J Cancer 107:230–233CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kiyotani K, Mushiroda T, Zembutsu H, Nakamura Y (2013) Important and critical scientific aspects in pharmacogenomics analysis: lessons from controversial results of tamoxifen and CYP2D6 studies. J Hum Genet 58:327–333CrossRefPubMedGoogle Scholar
  27. 27.
    Lien EA, Soiland H, Lundgren S, Aas T, Steen VM, Mellgren G et al (2013) Serum concentrations of tamoxifen and its metabolites increase with age during steady-state treatment. Breast Cancer Res Treat 141:243–248CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bonanni B, Serrano D, Gandini S, Guerrieri-Gonzaga A, Johansson H, Macis D et al (2009) Randomized biomarker trial of anastrozole or low-dose tamoxifen or their combination in subjects with breast intraepithelial neoplasia. Clin Cancer Res 15:7053–7060CrossRefPubMedGoogle Scholar
  29. 29.
    Decensi A, Robertson C, Guerrieri-Gonzaga A, Serrano D, Cazzaniga M, Mora S et al (2009) Randomized double-blind 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk premenopausal women. J Clin Oncol 27:3749–3756CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Johansson H, Bonanni B, Gandini S, Guerrieri-Gonzaga A, Cazzaniga M, Serrano D et al (2013) Circulating hormones and breast cancer risk in premenopausal women: a randomized trial of low-dose tamoxifen and fenretinide. Breast Cancer Res Treat 142:569–578CrossRefPubMedGoogle Scholar
  31. 31.
    Serrano D, Lazzeroni M, Gandini S, Macis D, Johansson H, Gjerde J et al (2013) A randomized phase II pre-surgical trial of weekly low-dose tamoxifen versus raloxifene versus placebo in premenopausal women with estrogen receptor positive breast cancer. Breast Cancer Res 15:R47CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Serrano D, Lazzeroni M, Zambon CF, Macis D, Maisonneuve P, Johansson H et al (2011) Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial. Pharmacogenomics J 11:100–107CrossRefPubMedGoogle Scholar
  33. 33.
    Gjerde J, Kisanga ER, Hauglid M, Holm PI, Mellgren G, Lien EA (2005) Identification and quantification of tamoxifen and four metabolites in serum by liquid chromatography-tandem mass spectrometry. J Chromatogr A 1082:6–14CrossRefPubMedGoogle Scholar
  34. 34.
    Gjerde J, Hauglid M, Breilid H, Lundgren S, Varhaug JE, Kisanga ER et al (2008) Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. Ann Oncol 19:56–61CrossRefPubMedGoogle Scholar
  35. 35.
    Jager NGL, Rosing H, Linn SC, Schellens JHM, Beijnen JH (2012) Importance of highly selective LC-MS/MS analysis for the accurate quantification of tamoxifen and its metabolites: focus on endoxifen and 4-hydroxytamoxifen. Breast Cancer Res Treat 133:793–798CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Murdter TE, Schroth W, Bacchus-Gerybadze L, Winter S, Heinkele G, Simon W et al (2011) Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther 89:708–717CrossRefPubMedGoogle Scholar
  37. 37.
    Kisanga ER, Gjerde J, Guerrieri-Gonzaga A, Pigatto F, Pesci-Feltri A, Robertson C et al (2004) Tamoxifen and metabolite concentrations in serum and breast cancer tissue during three dose regimens in a randomized preoperative trial. Clin Cancer Res 10:2336–2343CrossRefPubMedGoogle Scholar
  38. 38.
    Guerrieri-Gonzaga A, Botteri E, Lazzeroni M, Rotmensz N, Goldhirsch A, Varricchio C et al (2010) Low-dose tamoxifen in the treatment of breast ductal intraepithelial neoplasia: results of a large observational study. Ann Oncol 21:949–954CrossRefPubMedGoogle Scholar
  39. 39.
    Johansson H, Baglietto L, Guerrieri-Gonzaga A, Bonanni B, Mariette F, Macis D et al (2004) Factors associated with circulating levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in 740 women at risk for breast cancer. Breast Cancer Res Treat 88:63–73CrossRefPubMedGoogle Scholar
  40. 40.
    Johansson H, Gandini S, Bonanni B, Mariette F, Guerrieri-Gonzaga A, Serrano D et al (2008) Relationships between circulating hormone levels, mammographic percent density and breast cancer risk factors in postmenopausal women. Breast Cancer Res Treat 108:57–67CrossRefPubMedGoogle Scholar
  41. 41.
    Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C et al (1998) Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 352:93–97CrossRefPubMedGoogle Scholar
  42. 42.
    Veronesi U, Maisonneuve P, Rotmensz N, Bonanni B, Boyle P, Viale G et al (2007) Tamoxifen for the Prevention of Breast Cancer: late Results of the Italian Randomized Tamoxifen Prevention Trial Among Women With Hysterectomy. J Natl Cancer Inst 99:727–737CrossRefPubMedGoogle Scholar
  43. 43.
    Decensi A, Bonanni B, Maisonneuve P, Serrano D, Omodei U, Varricchio C et al (2013) A phase-III prevention trial of low-dose tamoxifen in postmenopausal hormone replacement therapy users: the HOT study. Ann Oncol 24:2753–2760CrossRefPubMedGoogle Scholar
  44. 44.
    Iqbal J, Ginsburg OM, Wijeratne TD, Howell A, Evans G, Sestak I et al (2012) Endometrial cancer and venous thromboembolism in women under age 50 who take tamoxifen for prevention of breast cancer: a systematic review. Cancer Treat Rev 38:318–328CrossRefPubMedGoogle Scholar
  45. 45.
    Zanardi S, Branchi D, Ponti A, Cruciani G, D’Amico C, Cortesi L et al (2011) Abstract A56: randomized, placebo-controlled, phase III trial of low-dose tamoxifen in women with intraepithelial neoplasia. Cancer Prev Res 4:A56CrossRefGoogle Scholar

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

Personalised recommendations