Skip to main content

Advertisement

SpringerLink
Log in

Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The CYP19A1 gene encodes the aromatase enzyme involved in the peripheral conversion of androgen to estrogen. We evaluated the efficacy of the aromatase inhibitor letrozole in patients with metastatic breast cancer (MBC) as related to DNA polymorphisms of CYP19A1.

Patients and methods

One hundred and nine patients with hormone receptor–positive MBC were treated with letrozole alone or in combination with a GnRH agonist. DNA was isolated from peripheral blood and genotyped for 46 single nucleotide polymorphisms (SNPs) of CYP19A1.

Results

Among 46 SNPs examined, rs700518, rs10459592, and rs4775936 were significantly associated with higher clinical benefit rate (CBR, CR + PR + SD ≥ 6 months) (OR = 2.61 [95% CI; 1.13–6.03], P = 0.025; OR = 2.45 [95% CI; 1.06–5.65], P = 0.036; OR = 2.60 [95% CI; 1.12–6.02], P = 0.026, respectively). Median time to progression (TTP) was improved without statistical significance in patients having an over-dominant form of rs700518. In haplotype analysis, the specific haplotypes M_1_3 and M_2_1 showed a strong association with CBR (OR = 3.37 [95% CI 1.43–7.90], P = 0.005; OR = 5.33 [95% CI 1.63–17.45], P = 0.006, respectively). There was a statistically significant difference in TTP in patients with haplotype M_1_3 (5.61 months [95% CI 0.00–11.45] vs. 11.08 months [95% CI 6.75–15.42], P = 0.040) and M_2_1 (7.31 months [95% CI 4.63–9.99] vs. 12.95 months [95% CI 9.27–16.63], P = 0.038). Haplotypes M_3_5 (OR = 11.25 [95% CI 1.17–108.28], P = 0.01) and M_5_3 (OR = 4.12, [95% CI 1.09–15.61], P = 0.03) were associated with side effects of arthralgia and hot flash, respectively.

Conclusion

The genetic variations of CYP19A1 were significantly associated with clinical efficacy, suggesting potential predictive markers for letrozole treatment in patients with metastatic breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI et al (2003) A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349(19):1793–1802

    Article  PubMed  CAS  Google Scholar 

  2. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350(11):1081–1092

    Article  PubMed  CAS  Google Scholar 

  3. Mouridsen H, Gershanovich M (2003) The role of aromatase inhibitors in the treatment of metastatic breast cancer. Semin Oncol 30(4 Suppl 14):33–45

    Article  PubMed  CAS  Google Scholar 

  4. Park IH, Ro J, Lee KS, Kim EA, Kwon Y, Nam BH, Jung SY, Lee S, Kim SW, Kang HS (2010) Phase II parallel group study showing comparable efficacy between premenopausal metastatic breast cancer patients treated with letrozole plus goserelin and postmenopausal patients treated with letrozole alone as first-line hormone therapy. J Clin Oncol 28(16):2705–2711

    Article  PubMed  CAS  Google Scholar 

  5. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F et al (2001) Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the international Letrozole breast cancer group. J Clin Oncol 19(10):2596–2606

    PubMed  CAS  Google Scholar 

  6. Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M (2000) Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex study group. J Clin Oncol 18(22):3758–3767

    PubMed  CAS  Google Scholar 

  7. Bedard PL, Freedman OC, Howell A, Clemons M (2008) Overcoming endocrine resistance in breast cancer: are signal transduction inhibitors the answer? Breast Cancer Res Treat 108(3):307–317

    Article  PubMed  CAS  Google Scholar 

  8. Bulun SE, Lin Z, Zhao H, Lu M, Amin S, Reierstad S, Chen D (2009) Regulation of aromatase expression in breast cancer tissue. Ann NY Acad Sci 1155:121–131

    Article  PubMed  CAS  Google Scholar 

  9. Cai Q, Kataoka N, Li C, Wen W, Smith JR, Gao YT, Shu XO, Zheng W (2008) Haplotype analyses of CYP19A1 gene variants and breast cancer risk: results from the Shanghai breast cancer study. Cancer Epidemiol Biomarkers Prev 17(1):27–32

    Article  PubMed  CAS  Google Scholar 

  10. Miyoshi Y, Ando A, Hasegawa S, Ishitobi M, Yamamura J, Irahara N, Tanji Y, Taguchi T, Tamaki Y, Noguchi S (2003) Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk. Eur J Cancer 39(17):2531–2537

    Article  PubMed  CAS  Google Scholar 

  11. Fasching PA, Loehberg CR, Strissel PL, Lux MP, Bani MR, Schrauder M, Geiler S, Ringleff K, Oeser S, Weihbrecht S et al (2008) Single nucleotide polymorphisms of the aromatase gene (CYP19A1), HER2/neu status, and prognosis in breast cancer patients. Breast Cancer Res Treat 112(1):89–98

    Article  PubMed  CAS  Google Scholar 

  12. Long JR, Kataoka N, Shu XO, Wen W, Gao YT, Cai Q, Zheng W (2006) Genetic polymorphisms of the CYP19A1 gene and breast cancer survival. Cancer Epidemiol Biomarkers Prev 15(11):2115–2122

    Article  PubMed  CAS  Google Scholar 

  13. Ma CX, Adjei AA, Salavaggione OE, Coronel J, Pelleymounter L, Wang L, Eckloff BW, Schaid D, Wieben ED, Weinshilboum RM (2005) Human aromatase: gene resequencing and functional genomics. Cancer Res 65(23):11071–11082

    Article  PubMed  CAS  Google Scholar 

  14. Colomer R, Monzo M, Tusquets I, Rifa J, Baena JM, Barnadas A, Calvo L, Carabantes F, Crespo C, Munoz M et al (2008) A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma. Clin Cancer Res 14(3):811–816

    Article  PubMed  CAS  Google Scholar 

  15. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  PubMed  CAS  Google Scholar 

  16. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN et al (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13(3):176–181

    Article  PubMed  Google Scholar 

  17. Gabriel S, Ziaugra L, Tabbaa D (2009) SNP genotyping using the Sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet 60:2.12.1–2.12.16

  18. Devlin B, Risch N (1995) A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 29(2):311–322

    Article  PubMed  CAS  Google Scholar 

  19. Niu T, Qin ZS, Xu X, Liu JS (2002) Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am J Hum Genet 70(1):157–169

    Article  PubMed  CAS  Google Scholar 

  20. Garcia-Casado Z, Guerrero-Zotano A, Llombart-Cussac A, Calatrava A, Fernandez-Serra A, Ruiz-Simon A, Gavila J, Climent MA, Almenar S, Cervera-Deval J et al (2010) A polymorphism at the 3′-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole. BMC Cancer 10:36

    Google Scholar 

  21. Moy B, Tu D, Pater JL, Ingle JN, Shepherd LE, Whelan TJ, Goss PE (2006) Clinical outcomes of ethnic minority women in MA.17: a trial of letrozole after 5 years of tamoxifen in postmenopausal women with early stage breast cancer. Ann Oncol 17(11):1637–1643

    Article  PubMed  CAS  Google Scholar 

  22. Enjuanes A, Garcia-Giralt N, Supervia A, Nogues X, Mellibovsky L, Carbonell J, Grinberg D, Balcells S, Diez-Perez A (2003) Regulation of CYP19 gene expression in primary human osteoblasts: effects of vitamin D and other treatments. Eur J Endocrinol 148(5):519–526

    Article  PubMed  CAS  Google Scholar 

  23. Enjuanes A, Garcia-Giralt N, Supervia A, Nogues X, Ruiz-Gaspa S, Bustamante M, Mellibovsky L, Grinberg D, Balcells S, Diez-Perez A (2005) Functional analysis of the I.3, I.6, pII and I.4 promoters of CYP19 (aromatase) gene in human osteoblasts and their role in vitamin D and dexamethasone stimulation. Eur J Endocrinol 153(6):981–988

    Article  PubMed  CAS  Google Scholar 

  24. Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E, Novik KL, Kelemen L, Ogata S, Pharoah PD (2004) Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 96(12):936–945

    Article  PubMed  CAS  Google Scholar 

  25. Tworoger SS, Chubak J, Aiello EJ, Ulrich CM, Atkinson C, Potter JD, Yasui Y, Stapleton PL, Lampe JW, Farin FM (2004) Association of CYP17, CYP19, CYP1B1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women. Cancer Epidemiol Biomarkers Prev 13(1):94–101

    Article  PubMed  CAS  Google Scholar 

  26. Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE (2002) Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 20(3):751–757

    Article  PubMed  CAS  Google Scholar 

  27. Dixon JM, Renshaw L, Young O, Murray J, Macaskill EJ, McHugh M, Folkerd E, Cameron DA, A’Hern RP, Dowsett M (2008) Letrozole suppresses plasma estradiol and estrone sulphate more completely than anastrozole in postmenopausal women with breast cancer. J Clin Oncol 26(10):1671–1676

    Article  PubMed  CAS  Google Scholar 

  28. Utsumi T, Harada N, Maruta M, Takagi Y (1996) Presence of alternatively spliced transcripts of aromatase gene in human breast cancer. J Clin Endocrinol Metab 81(6):2344–2349

    Article  PubMed  CAS  Google Scholar 

  29. Zhou C, Zhou D, Esteban J, Murai J, Siiteri PK, Wilczynski S, Chen S (1996) Aromatase gene expression and its exon I usage in human breast tumors. Detection of aromatase messenger RNA by reverse transcription-polymerase chain reaction. J Steroid Biochem Mol Biol 59(2):163–171

    Article  PubMed  CAS  Google Scholar 

  30. Wang L, Ellsworth KA, Moon I, Pelleymounter LL, Eckloff BW, Martin YN, Fridley BL, Jenkins GD, Batzler A, Suman VJ et al (2010) Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors. Cancer Res 70(1):319–328

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by NCC grant 0910320.

Author information

Authors and Affiliations

  1. Center for Breast Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Korea

    In Hae Park, Keun Seok Lee & Jungsil Ro

  2. Functional Genomics Branch, National Cancer Center, Goyang-si, Korea

    Yeon-Su Lee, Sook-young Kim & Seung-Hyun Hong

  3. Center for Clinical Trials, National Cancer Center, Goyang-si, Korea

    Jaeheon Jeong, Hyewon Lee & Byung-Ho Nam

Authors
  1. In Hae Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yeon-Su Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keun Seok Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sook-young Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seung-Hyun Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jaeheon Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hyewon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jungsil Ro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Byung-Ho Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jungsil Ro.

Additional information

In Hae Park, Yeon-Su Lee contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLS 320 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, I.H., Lee, YS., Lee, K.S. et al. Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer. Cancer Chemother Pharmacol 68, 1263–1271 (2011). https://doi.org/10.1007/s00280-011-1615-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-011-1615-y

Keywords

Search

Navigation