J Breast Cancer.  2010 Sep;13(3):242-249.

Adjuvant Hormonal Therapy: Current Standard and Practical Issues

• Park BW
• Park HS

Abstract

Adjuvant hormonal therapy is used as the first target-specific approach in curing breast cancers due to its high efficacy and mild side effects. Five years of tamoxifen therapy has been the gold standard for women with estrogen receptor-positive breast cancer irrespective of age or menopausal and nodal status. After the emergence of 3rd generation aromatase inhibitors (AI), the use of either tamoxifen or tamoxifen plus ovarian function suppression for 5 years has been proposed as an acceptable standard for premenopausal women while AI should form part of standard endocrine therapy for the postmenopausal women as established at the St. Gallen Concensus Conference. The addition of luteinizing-hormone-releasing hormone (LHRH) analogs might be beneficial for the younger patients who remain premenopausal after chemotherapy, however controversies over the addition of LHRH analogs remains. Further, it has been suggested that CYP2D6 polymorphisms and concomitant use of CYP2D6 inhibitors which reduce CYP2D6 activity may influence the clinical outcomes of adjuvant tamoxifen therapy. The androgen receptor has been evaluated as a prognostic or predictive marker for endocrine responsiveness in a few studies; however, there are many issues to be answered and ongoing clinical trials will provide the answers. Until then, it would be important for clinicians to carefully evaluate the risk factors of patients, monitor the compliance of those patients who are under endocrine therapy, and take care in selecting antidepressants when coprescription with tamoxifen is necessary. In the future, tailored therapy will be designed based on the target molecular profiling of the tumors, pharmacogenomics, and improved understanding of receptor signaling biology. More attention should be given to explore molecular markers that could differentiate the subsets for tailoring.

Keyword

Aromatase inhibitors; Breast Neoplasms; Hormonal antineoplastic agents; Tamoxifen

MeSH Terms

Antidepressive Agents
Antineoplastic Agents, Hormonal
Aromatase Inhibitors
Biology
Breast
Breast Neoplasms
Compliance
Cytochrome P-450 CYP2D6
Estrogens
Female
Gonadotropin-Releasing Hormone
Humans
Organothiophosphorus Compounds
Pharmacogenetics
Receptors, Androgen
Risk Factors
Tamoxifen
Antidepressive Agents
Antineoplastic Agents, Hormonal
Aromatase Inhibitors
Cytochrome P-450 CYP2D6
Estrogens
Gonadotropin-Releasing Hormone
Organothiophosphorus Compounds
Receptors, Androgen
Tamoxifen

Reference

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005. 365:1687–1717.

2. Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 2009. 20:1319–1329.

3. Coates AS, Keshaviah A, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007. 25:486–492.

4. Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008. 9:45–53.

5. Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007. 369:559–570.

6. Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005. 366:455–462.

7. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005. 97:1262–1271.

8. Jonat W, Gnant M, Boccardo F, Kaufmann M, Rubagotti A, Zuna I, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis. Lancet Oncol. 2006. 7:991–996.

9. Ingle JN, Dowsett M, Cuzick J, Davies C. Aromatase inhibitors versus tamoxifen as adjuvant therapy for postmenopausal women with estrogen receptor positive breast cancer: meta-analyses of randomized trials of monotherapy and switching strategies. Cancer Res. 2009. 69:2 Suppl. abstract #12.

10. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. National Comprehensive Cancer Network. 2007. accessed January 4th 2007. v.1: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

11. Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thurlimann B, Paridaens R, Smith I, et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009. 361:766–776.

12. Jakesz R, Gnant M, Greil R, Tausch C, Samonigg H, Kwasny W, et al. The benefits of sequencing adjuvant tamoxifen and anastrozole in postmenopausal women with hormone-responsive early breast cancer: 5 year-analysis of the ABCSG Trial 8. Breast Cancer Res Treat. 2005. 94:Suppl 1. S10. abstract #13.

13. Mouridsen HT, Giobbie-Hurder A, Mauriac L, Paridaens R, Colleoni M, Thuerlimann B, et al. BIG 1-98: A randomized double-blind phase III study evaluating letrozole and tamoxifen given in sequence as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Cancer Res. 2009. 69:2 Suppl. abstract #13.

14. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol. 1996. 14:2738–2746.

15. Elder EE, Kennedy CW, Gluch L, Carmalt HL, Janu NC, Joseph MG, et al. Patterns of breast cancer relapse. Eur J Surg Oncol. 2006. 32:922–927.

16. De Boer R Sr, Burris HA, Monnier A, Mouridsen H, O'Shaughnessy JA, McIntyre K, et al. The Head to Head trial: Letrozole vs anastrozole as adjuvant treatment of postmenopausal patients with node positive breast cancer. J Clin Oncol. 2006. 24:18 Suppl. S582. abstract #10672.

17. Moy B, Elliott CR, Chapman J-AW, Pater JL, Ding Z, Goss PE. NCIC CTG MA.27: menopausal symptoms of ethnic minority women. Breast Cancer Res Treat. 2006. 100:Suppl 1. S144. abstract #3059.

18. Breast density, hormone levels, and anticancer drug levels in women with invasive breast cancer who are receiving exemestane or anastrozole. North Central Cancer Treatment Group, National Cancer Institute and National Cancer Institute of Canada. accessed June 27th, 2007. http://www.clinicaltrials.gov.

19. Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001. 93:684–690.

20. Tormey DC, Gray R, Falkson HC. Eastern Cooperative Oncology Group. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. J Natl Cancer Inst. 1996. 88:1828–1833.

21. ATLAS: Adjuvant Tamoxifen Longer Against Shorter. University of Oxford Clinical Trial Service Unit and Epidemiological Studies Unit. accessed July 25th 2007. Oxford: University of Oxford;http://www.ctsu.ox.ac.uk/projects/atlas.

22. Peto R, Davies C. ATLAS (Adjuvant Tamoxifen, Longer Against Shotrer): international randomized trial of 10 versus 5 years of adjuvanr tamoxifen among 11500 women-preliminary results. The 30th Annual San Antonio Breast Cancer Symposium. 2007. abstract #48.

23. Adjuvant treatment tamoxifen offers more. National Cancer Research Network. accessed June 27th, 2007. http://www.ncrn.org.uk/portfolio/data.

24. Gray RG, Rea DW, Handley K, Marshall A, Pritchard MG, Perry P, et al. aTTom (adjuvant Tamoxifen-To offer more): Randomized trial of 10 versus 5 years of adjuvant tamoxifen among 6,934 women with estrogen receptor-positive (ER+) or ER untested breast cancer-Preliminary results. J Clin Oncol. 2008. 26:15 Suppl. S10. abstract #513.

25. Cuzick J, Ambroisine L, Davidson N, Jakesz R, Kaufmann M, Regan M, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet. 2007. 369:1711–1723.

26. Davidson NE, O'Neill AM, Vukov AM, Osborne CK, Martino S, White DR, et al. Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol. 2005. 23:5973–5982.

27. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003. 348:2431–2442.

28. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril. 2001. 75:305–309.

29. Smith IE, Dowsett M, Yap YS, Walsh G, Lonning PE, Santen RJ, et al. Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. J Clin Oncol. 2006. 24:2444–2447.

30. Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol. 2005. 23:619–629.

31. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1996. 14:1718–1729.

32. Goodwin PJ, Ennis M, Pritchard KI, Trudeau M, Hood N. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol. 1999. 17:2365–2370.

33. Bianco AR, Del Mastro L, Gallo C, Perrone F, Matano E, Pagliarulo C, et al. Prognostic role of amenorrhea induced by adjuvant chemotherapy in premenopausal patients with early breast cancer. Br J Cancer. 1991. 63:799–803.

34. Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009. 360:679–691.

35. Francis P, Fleming G, Nasi ML, Pagani O, Perez E, Walley B. Tailored treatment investigations for premenopausal women with endocrine responsive (ER and/or PgR) breast cancer: The SOFT, TEXT, and PERCHE trials. Breast. 2003. 12:Suppl 1. S44. abstract #104.

36. Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004. 85:151–159.

37. Lim YC, Li L, Desta Z, Zhao Q, Rae JM, Flockhart DA, et al. Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther. 2006. 318:503–512.

38. Borgna JL, Rochefort H. Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem. 1981. 256:859–868.

39. Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol. 2005. 55:471–478.

40. Lee SJ, Lee SS, Jung HJ, Kim HS, Park SJ, Yeo CW, et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos. 2009. 37:1464–1470.

41. Li H, Feng L, Xu Y, Yao L, Ouyang T, Li J, et al. The association of CYP2D6 *10 polymorphism with breast cancer risk and clinicopathologic characteristics in Chinese women. Acta Oncol. 2006. 45:597–601.

42. Sachse C, Brockmoller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet. 1997. 60:284–295.

43. Kubota T, Yamaura Y, Ohkawa N, Hara H, Chiba K. Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes. Br J Clin Pharmacol. 2000. 50:31–34.

44. Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005. 23:9312–9318.

45. Lim HS, Ju Lee H, Seok Lee K, Sook Lee E, Jang IJ, Ro J. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol. 2007. 25:3837–3845.

46. Xu Y, Sun Y, Yao L, Shi L, Wu Y, Ouyang T, et al. Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol. 2008. 19:1423–1429.

47. Kiyotani K, Mushiroda T, Imamura CK, Hosono N, Tsunoda T, Kubo M, et al. Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J Clin Oncol. 2010. 28:1287–1293.

48. Okishiro M, Taguchi T, Jin Kim S, Shimazu K, Tamaki Y, Noguchi S. Genetic polymorphisms of CYP2D6 10 and CYP2C19 2, 3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer. 2009. 115:952–961.

49. Seruga B, Amir E. Cytochrome P450 2D6 and outcomes of adjuvant tamoxifen therapy: results of a meta-analysis. Breast Cancer Res Treat. 2010. 122:609–617.

50. Chubak J, Buist DS, Boudreau DM, Rossing MA, Lumley T, Weiss NS. Breast cancer recurrence risk in relation to antidepressant use after diagnosis. Breast Cancer Res Treat. 2008. 112:123–132.

51. Coyne JC, Palmer SC, Shapiro PJ, Thompson R, DeMichele A. Distress, psychiatric morbidity, and prescriptions for psychotropic medication in a breast cancer waiting room sample. Gen Hosp Psychiatry. 2004. 26:121–128.

52. Loprinzi CL, Barton DL, Sloan JA, Novotny PJ, Dakhil SR, Verdirame JD, et al. Mayo Clinic and North Central Cancer Treatment Group hot flash studies: a 20-year experience. Menopause. 2008. 15:655–660.

53. Reich M, Lesur A, Perdrizet-Chevallier C. Depression, quality of life and breast cancer: a review of the literature. Breast Cancer Res Treat. 2008. 110:9–17.

54. Bertelsen KM, Venkatakrishnan K, Von Moltke LL, Obach RS, Greenblatt DJ. Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab Dispos. 2003. 31:289–293.

55. Venkatakrishnan K, Obach RS. In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude. Drug Metab Dispos. 2005. 33:845–852.

56. Venkatakrishnan K, Obach RS, Rostami-Hodjegan A. Mechanism-based inactivation of human cytochrome P450 enzymes: strategies for diagnosis and drug-drug interaction risk assessment. Xenobiotica. 2007. 37:1225–1256.

57. Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ. 2010. 340:c693.

58. Dezentje VO, van Blijderveen NJ, Gelderblom H, Putter H, van Herk-Sukel MP, Casparie MK, et al. Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer. J Clin Oncol. 2010. 28:2423–2429.

59. Park S, Koo J, Park HS, Kim JH, Choi SY, Lee JH, et al. Expression of androgen receptors in primary breast cancer. Ann Oncol. 2010. 21:488–492.

60. Castellano I, Allia E, Accortanzo V, Vandone AM, Chiusa L, Arisio R, et al. Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers. Breast Cancer Res Treat. Epub 2010 Feb 3. DOI: 10.1007/s10549-010-0761-y.