Commentary (Wong/Pritchard): Adjuvant Hormonal Therapy in Early Breast Cancer

Breast cancer is a systemic disease with 10-year relapse risks after surgery alone ranging between 30% and 50%.[1] About 60% to 75% of breast cancers are hormonereceptor- positive[2] and are potentially responsive to endocrine therapy, which remains a cornerstone in the adjuvant therapy of such tumors in this era of targeted therapy and genomics. The article by Kumar and Leonard provides a broad overview of adjuvant endocrine therapy and highlights the surrounding controversies. In this review, we will emphasize key developments and discuss ongoing trials that seek to address these controversies. Tamoxifen in Pre- and Postmenopausal Women
In the 2000 overview by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), 5 years of adjuvant tamoxifen reduced annual relapse by 41%, annual breast cancer mortality by 34%, and contralateral breast cancer by one-third in women with estrogen-receptor (ER)-positive tumors.[ 3] These benefits are largely irrespective of age at study entry, nodal status, and use of chemotherapy, and persist during years 5 to 9 of follow-up, indicating a protective carryover effect. There are, however, limited data for adding tamoxifen to chemotherapy in premenopausal women compared to chemotherapy alone. Only 205 women in this category were included in the 2000 EBCTCG overview (personal communication, R. Peto) in whom a small but significant reduction in relapse and a trend toward improved overall survival was observed with the addition of tamoxifen. Results from individual trials are conflicting but, in aggregate, point toward a small benefit in this setting.[ 4-7] We await information from two completed trials-the European Organization for Research and Treatment of Cancer (EORTC) 01901 trial, which randomized women to 3 years of tamoxifen or not after completion of six cycles of adjuvant chemotherapy and which has been presented but not with subgroup analysis by menopausal status,[8] and the National Cancer Institute of Canada (NCIC) MA.12 trial, which randomized women after adjuvant chemotherapy to tamoxifen or placebo for 5 years. Duration of Therapy
Early adjuvant tamoxifen trials tested 2 years of therapy compared to no treatment.[ 9-11] Subsequent trials compared 5 years of therapy to no treatment[11,12] and led to randomized comparisons of 2 vs 5 years and 5 vs 10 years of tamoxifen.[ 7,13-16] These studies provide conclusive evidence that 5 years is superior to 2 years of therapy.[13,14] In contrast, there is uncertainty regarding the extension of tamoxifen therapy beyond 5 years.[7,15,16] An Eastern Cooperative Oncology Group (ECOG) study did find improved time to relapse in ER-positive women, but this was a very small trial involving only 194 patients.[16] Two large studies under way will hopefully provide definitive information concerning extended tamoxifen therapy. The Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial comparing 5 vs 10 years of tamoxifen has completed accrual and is in the follow-up phase, while the Adjuvant Tamoxifen Treatment Offer More (aTTom) trial is a UK counterpart to ATLAS with a similar trial design. Ovarian Ablation in Premenopausal Women
Adjuvant ovarian ablation either with or without tamoxifen has been compared against no treatment or chemotherapy alone. Studies have also examined the value of adding ovarian ablation to chemotherapy. As Kumar and Leonard have pointed out, the overall evidence suggests that ovarian ablation improves disease-free and overall survival in the absence of chemotherapy.[ 3,17] Multiple studies have shown the equivalence or superiority of ovarian ablation with or without tamoxifen compared to CMF (cyclophosphamide, methotrexate, fluorouracil) or FEC50 (fluorouracil, epirubicin at 50 mg/m², and cyclophosphamide).[ 18-21] These studies have limited generalizability because of the increasing use of superior second- and third-generation regimens. Neither data from the 2000 EBCTCG overview nor from individual trials demonstrate improvement in outcomes when ovarian ablation is added to chemotherapy,[ 3,22-25] although exploratory subset analysis in one trial showed a trend toward improved disease-free survival in women younger than age 40 and women who do not become menopausal after chemotherapy.[ 22] In contrast, the addition of ovarian ablation plus tamoxifen to chemotherapy compared to chemotherapy alone has been found to improve disease-free survival.[22,26]

Three complementary randomized studies examining the optimal combination of endocrine therapy for premenopausal women are ongoing. The Suppression of Ovarian Function Trial (SOFT) compares ovarian ablation plus either tamoxifen or exemestane (Aromasin) to the current standard of tamoxifen alone for women who are not candidates for chemotherapy or who remain premenopausal after completion of adjuvant chemotherapy. The Tamoxifen and Exemestane Trial (TEXT) compares the relative benefit of adding tamoxifen vs exemestane to upfront ovarian ablation. The Premenopausal Endocrine Responsive Chemotherapy (PERCHE) study is examining the merit of adding chemotherapy to complete estrogen blockade by ovarian ablation plus either tamoxifen or exemestane. Aromatase Inhibitors in Postmenopausal Women
Data from multiple large randomized trials support the use of aromatase inhibitors in hormone-receptor-positive postmenopausal women in the adjuvant setting (see Table 1)[27-34] and have been synthesized in an American Society of Clinical Oncology (ASCO) Technology Assessment.[35] These studies have demonstrated improvements in disease-free and distant disease- free survival as well as a reduction in contralateral breast cancer. No overall survival advantage has emerged, except in a subset analysis of node-positive women in the MA.17 trial presented at the 2004 ASCO meeting.[29] Full publication of these data is awaited. These studies have also highlighted the impact of long-term aromatase inhibitors on bone and cardiovascular health. Fracture incidence is increased in patients who receive an aromatase inhibitor,[27-33] significantly so in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (BIG 1-98) trials. Numerically, more cardiovascular events occurred in the Intergroup Exemestane Study (IES) and significantly more serious cardiac events were noted in the BIG 1-98 study with aromatase inhibitor therapy.[ 31,33] It is interesting to note that in MA.17-the only trial to compare an aromatase inhibitor with placebo- no increase in cardiac events was seen in the letrozole (Femara) arm.[29] Hence, it is plausible that the difference in cardiac event rates between patients who received an aromatase inhibitor and those who received tamoxifen in BIG 1-98 and IES could have resulted not from a negative effect of an aromastase inhibitor but from a positive effect of tamoxifen, a drug that may have cardioprotective effects.[36-38] Kumar and Leonard have pointed to the controversy arising from early termination of MA.17-a move that was recommended by an independent data and safety monitoring committee based on data from protocol-specified interim analysis indicating a larger than unexpected benefit from letrozole. There were concerns that the crossover of patients would lead to loss of information regarding any overall survival and distant disease- free survival benefits, and that the findings could not be used to support 5 years of letrozole treatment because none of the patients had received the drug for that long. Further follow-up of MA.17, however, has shown a persistent disease-free survival advantage. In addition, patients who have completed 5 years of letrozole therapy are being offered re-randomization to a further 5 years of therapy vs placebo to determine the optimal duration of treatment. Sequence and Type of Aromatase Inhibitor
BIG 1-98 addresses the issue of the optimal sequence of adjuvant aromatase inhibitor therapy. This study randomized 8,010 postmenopausal women with endocrine-responsive early-stage breast cancer to one of four arms: tamoxifen for 5 years, letrozole for 5 years, tamoxifen for 2 years followed by letrozole for 3 years, or the reverse sequence. Preliminary results with a median follow-up of 25.8 months comparing upfront tamoxifen vs letrozole demonstrated improved disease-free and distant relapse-free survival for those receiving letrozole, but as yet, no significant difference in overall survival.[33] A higher 5-year incidence of death without recurrence on the letrozole arm (3.1% vs 1.8%, P = .08) due to more cerebrovascular accidents (7 vs 1) and cardiac events (13 vs 6) was observed. Another important ongoing study is NCIC MA.27, which is comparing adjuvant exemestane to anastrozole (Arimidex), each for 5 years, and seeks to answer whether a steroidal or nonsteroidal aromatase inhibitor is superior. Because the crossover results of BIG 1-98 will not be available for some years, different groups have proposed mathematical models to estimate clinical outcomes from initial, sequential, or extended aromatase therapy.[39,40] Burstein et al developed Markov models incorporating disease-free survival hazard ratios from published trials to derive recurrence probabilities in hypothetical cohorts of women. They suggest that disease-free survival was best with initial aromatase inhibitor therapy in patients with ER-positive, PR-negative tumors, whereas patients with ER-positive, PR-positive tumors have the best disease-free survival when given tamoxifen for 2.5 years followed by an aromatase inhibitor. Conclusions
Progress has been made in adjuvant endocrine therapy for early breast cancer. The challenge remaining is to determine the optimal incorporation of new and existing treatment modalities into everyday patient care.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Fisher B, Redmond C, Fisher ER, et al: Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 312:674-681, 1985.
2. Anderson WF, Chatterjee N, Ershler WB, et al: Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat 76:27-36, 2002.
3. 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 randomized trials. Lancet 365:1687-1717, 2005.
4. Andersson M, Kamby C, Jensen MB, et al: Tamoxifen in high risk premenopausal women with primary breast cancer receiving adjuvant chemotherapy. Eur J Cancer 35:1659- 1666, 1999.
5. Hutchins L, Green S, Ravdin P, et al: CMF versus CAF ± tamoxifen in high-risk node-negative patients and a natural history follow-up study in low-risk node negative patients: Update of tamoxifen results (abstract 1). Breast Cancer Res Treat 57:25, 1999.
6. Colleoni M, Gelber S, Snyder R, et al: Randomized comparison of adjuvant tamoxifen (Tam) versus no hormonal treatment for premenopausal women with node-positive (N+), early stage breast cancer: First results of International Breast Cancer Study Group Trial 13- 93 (abstract 532). Proc Am Soc Clin Oncol 22(14S):10, 2004.
7. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 88:1529-1542, 1996.
8. Paridaens R, Dyczka J, Rutgers EJT, et al: Postoperative adjuvant chemotherapy followed by adjuvant tamoxifen versus nil for patients with operable breast cancer. First results of a randomized phase III trial EORTC 10901 (abstract 70). Eur J Cancer 2(suppl 3):A-49, 2004.
9. NATO: Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer. Interim analysis at four years by Nolvadex Adjuvant Trial Organisation. Lancet 1:257-261, 1983.
10. NATO: Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Nolvadex Adjuvant Trial Organisation. Br J Cancer 57:608-611, 1988.
11. Rutqvist LE, Cedermark B, Glas U, et al: Randomized trial of adjuvant tamoxifen in node negative postmenopausal breast cancer. Stockholm Breast Cancer Study Group. Acta Oncol 31:265-270, 1992.
12. Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC): Adjuvant tamoxifen in the management of operable breast cancer: The Scottish Trial. Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC), Edinburgh. Lancet 2:171-175, 1987.
13. Swedish Breast Cancer Cooperative Group: Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. Swedish Breast Cancer Cooperative Group. J Natl Cancer Inst 88:1543-1549, 1996.
14. Current Trials Working Party of the Cancer Research Campaign Breast Cancer Trials Group: Preliminary results from the cancer research campaign trial evaluating tamoxifen duration in women aged fifty years or older with breast cancer. Current Trials Working Party of the Cancer Research Campaign Breast Cancer Trials Group. J Natl Cancer Inst 88:1834-1839, 1996.
15. Stewart HJ, Forrest AP, Everington D, et al: Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group. Br J Cancer 74:297-299, 1996.
16. Tormey DC, Gray R, Falkson HC: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph nodepositive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 88:1828-1833, 1996.
17. Love RR, Duc NB, Havighurst TC, et al: Her-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer. J Clin Oncol 21:453-457, 2003.
18. Scottish Cancer Trials Breast Group: Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: The Scottish trial. Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy’s Hospital, London. Lancet 341:1293-1298, 1993.
19. Jonat W, Kaufmann M, Sauerbrei W, et al: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20:4628-4635, 2002.
20. Jakesz R, Hausmaninger H, Kubista E, et al: Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: Evidence for the superiority of treatment with endocrine blockade in pre menopausal patients with hormone-responsive breast cancer-Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 20:4621-4627, 2002.
21. Roche H, Kerbrat P, Bonneterre J, et al: Complete hormonal blockade versus chemotherapy in premenopausal early-stage breast cancer patients (Pts) with positive hormone-receptor (HR+) and 1-3 node-positive (N+) tumor: Results of the FASG 06 trial (abstract 279). Proc Am Soc Clin Oncol 19:72a, 2000.
22. Davidson N, O’Neill A, Vukov A, et al: Effect of chemohormonal therapy in premenopausal, node (+), receptor (+) breast cancer: An Eastern Cooperative Oncology Group phase III Intergroup Trial (E5188, INT-0101) (abstract 249). Proc Am Soc Clin Oncol 18:67a, 1999.
23. Houghton J, Baum M, Rutqvist LE, et al: The ZIPP trial of adjuvant zoladex in premenopausal patients with early breast cancer: An update at five years (abstract 359). Proc Am Soc Clin Oncol 19:93a, 2000.
24. Baum M, Houghton J, Sawyer W, et al: Management of premenopausal women with early breast cancer: Is there a role for goserelin? (abstract 103) Proc Am Soc Clin Oncol 21:38a, 2001.
25. Castiglione-Gertsch M, O’Neill A, Gelber RD, et al: Is the addition of adjuvant chemotherapy always necessary in node negative (N-) pre/perimenopausal breast cancer patients (pts) who receive goserelin? First results of IBCSG trial VIII (abstract 149). Proc Am Soc Clin Oncol 21:38a, 2002.
26. De Placido S, De Laurentiis M, De Lena M, et al: A randomised factorial trial of sequential doxorubicin and CMF vs CMF and chemotherapy alone vs chemotherapy followed by goserelin plus tamoxifen as adjuvant treatment of node-positive breast cancer. Br J Cancer 92:467-474, 2005.
27. Howell A, Cuzick J, Baum M: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60-62, 2005.
28. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003.
29. Goss PE, Ingle JN, Martino S, et al: Updated analysis of the NCIC CTG MA.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer (abstract 847). Proc Am Soc Clin Oncol 22(14S):88s, 2004.
30. Coombes RC, Hall E, Gibson LJ, et al: A randomised trial of exemestane after two or three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004.
31. Coombes RC, Hall E, Snowdon CF, et al: The Intergroup Exemestane Study: A randomized trial in postmenopausal patients with early breast cancer who remain disease-free after two to three years of tamoxifen-updated survival analysis (abstract 3). Breast Cancer Res Treat 88(suppl 1):S7, 2004.
32. Jakesz R, Kaufmann M, Gnant M, et al: Benefits of switching postmenopausal women with hormone-sensitive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: Combined results from 3,123 women enrolled in the ABCSG Trial 8 and the ARNO 95 Trial (abstract 2). Breast Cancer Res Treat 88(suppl 1):S7, 2004.
33. Thurlimann BJ, Keshaviah A, Mouridsen H, et al: BIG 1-98: Randomized double blind phase III study to evaluate letrozole (L) vs tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer (abstract 511). Proc Am Soc Clin Oncol 23:6s, 2005.
34. Boccardo F, Rubagotti A, Amoroso D, et al: Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment (abstract 3). Breast Cancer Res Treat 82:S6, 2003.
35. Winer EP, Hudis C, Burnstein HJ, 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 23:619- 629, 2005.
36. McDonald CC, Alexander FE, Whyte BW, et al: Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group. Br Med J 311:977-980, 1995.
37. Costantino JP, Kuller LH, Ives DG, et al: Coronary heart disease mortality and adjuvant tamoxifen therapy. J Natl Cancer Inst 89:776-782, 1997.
38. Rutqvist LE, Mattsson A: Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 85:1398-1406, 1993.
39. Burstein HJ, Winer EP, Kuntz KM, et al: Optimizing endocrine therapy in postmenopausal women with early stage breast cancer: A decision analysis for biological subsets of tumors (abstract 259). Proc Am Soc Clin Oncol 23:11s, 2005.
40. Cuzick J, Howell A: Optimal timing of the use of an aromatase inhibitor in the adjuvant treatment of postmenopausal hormone receptor- positive breast cancer (abstract 658). Proc Am Soc Clin Oncol 23:43s, 2005.