Commentary (Carraway/Wolff): Selecting Adjuvant Endocrine Therapy for Breast Cancer

Our understanding of the biology of breast cancer has undoubtedly improved in the past decade, and remarkable progress has been achieved in its treatment. Those caring for these patients have long realized that breast cancer is a disease with an extremely diverse natural history, and much remains to be learned about the interaction among known predictive and prognostic factors. Not long ago, the "more is better" strategy exemplified by high-dose chemotherapy (often resulting in high-dose toxicity) dominated the research agenda and clinical practices of many institutions. Although a minimum chemotherapy dose intensity is required[1] and increasing the frequency of specific regimens is advantageous,[2] further dose intensification with[3] or without stem cell rescue[4-6] offers no meaningful benefit in the adjuvant setting. Pathologic response after preoperative chemotherapy appears to be a prognostic marker of outcome pending the upcoming results of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27.[7] Early studies suggest that gene-expression profiling of tumor samples at baseline may predict those likely to respond to specific chemotherapy regimens,[8,9] but our ability to identify those likely to benefit from different chemotherapy options among patients with similar clinicopathologic features is limited. Still, chemotherapy has had a major impact in reducing the odds of recurrence and death in early-stage disease,[ 10] and its role in patients with moderate- and high-risk disease will remain unchallenged for the foreseeable future. Over the past 10 years, adjuvant endocrine therapy has taken center stage in this setting, and it is now accepted as effective therapy in patients with hormone-receptor-positive disease, regardless of age or nodal status.[ 11] In this issue of ONCOLOGY, Eneman et al present us with an extensive review of available adjuvant endocrine therapy options and remind us of important ongoing clinical trials. They also created four hypothetical didactic clinical scenarios to illustrate how to best integrate available prognostic and predictive factors. Two topics described in their review are worth highlighting: the resurgence of interest in ovarian ablation/suppression for premenopausal women and the growing body of evidence confirming the clinical benefit offered by aromatase inhibitors in postmenopausal women. Ovarian Suppression
Long identified as an effective therapy in patients with advanced disease,[ 12] ovarian suppression was recently shown to be an effective riskreduction strategy in high-risk women carrying mutations in BRCA1 or BRCA2.[13] Interest in its role in early-stage disease was rekindled by long-term follow-up data comparing ovarian suppression vs no therapy in premenopausal women.[14] Several early-generation trials have since been reported.[15] Some of these trials compared ovarian suppression with nonanthracycline regimens, while others examined the role of combining ovarian suppression with chemotherapy and tamoxifen. These data suggest that much of the chemotherapy benefit observed in premenopausal women is due to the suppressive effects on ovarian function.

Surgical ablation (ie, bilateral oophorectomy) and chemical inhibition (ie, luteinizing hormone-releasing hormone [LHRH] analogs) are the most commonly used methods of ovarian suppression, and recent data suggest a possible direct antitumor effect of LHRH agonists in addition to their known endocrine effects.[16] Ovarian irradiation is also feasible if careful attention is paid to its delivery and to monitoring of efficacy.[17] The available evidence supports the statement from the 2000 National Institutes of Health Consensus Development Conference on adjuvant therapy indicating that ovarian suppression may be considered an alternative to chemotherapy in premenopausal women.[18] Quality-of-life studies favor the adjuvant use of ovarian suppression over chemotherapy in pre-/perimenopausal patients with endocrineresponsive, node-positive breast cancer. Quality-of-life scores in the Zoladex Early Breast Cancer Research Association (ZEBRA) trial[19] favored the LHRH agonist during the first 3 to 6 months of therapy due to side effects from CMF chemotherapy (cyclophosphamide [Cytoxan, Neosar], methotrexate, fluorouracil [5-FU]).[20] No significant differences in overall quality of life were observed during and after the 2 years of goserelin (Zoladex), aside from worse scores for hormonal symptoms during the period of ovarian suppression. A similar survival outcome was seen among 1,063 patients with nodenegative disease treated in the International Breast Cancer Study Group (IBCSG) Trial VIII with goserelin for 24 months, classic CMF for six cycles, or both in sequence for 24 months.[21] Perhaps of greater significance, most patients treated with ovarian suppression alone resumed menses once goserelin was discontinued, whereas most treated with CMF did not. This suggests that permanent induction of menopause is not necessary for the antitumor effect, an observation with a potential beneficial long-term impact on the overall health of these patients. Questions remain about the optimal use and duration of ovarian suppression (2 to 3 years vs longer), and on its beneficial effects in premenopausal women treated with anthracyclinecontaining regimens[10] and tamoxifen.[ 11] The role of ovarian suppression in addition to tamoxifen in patients who remain premenopausal after chemotherapy is being addressed by the IBCSG 24-02 Suppression of Ovarian Function Trial (SOFT). Aromatase Inhibitors
In an ironic twist following the release of major trial results, patients and their doctors find themselves in a period of uncertainty regarding how to best use aromatase inhibitors in the adjuvant care of postmenopausal women. Since 2002, three large prospective randomized, placebo-controlled trials have been published examining the role of the commercially available third-generation aromatase inhibitors vs tamoxifen in postmenopausal women.[22-25] These data clearly show a disease-free survival benefit favoring those who received an aromatase inhibitor immediately after local therapy or after a few years of tamoxifen. In addition, a recent update of the MA.17 trial presented at the 2004 meeting of the American Society of Clinical Oncology demonstrated an overall survival benefit favoring aromatase inhibitors in patients with node-positive disease. Many questions remain, and some are the subject of ongoing or recently completed trials (Table 1).[23-27] Conclusions
It has taken a long time for endocrine therapy-arguably among the best examples of "targeted" therapy- to be fully accepted as one of the most important tools in the treatment of breast cancer. Many questions remain regarding its optimal use. In the notso- distant future, we hope to be able to integrate hallmark biologic markers of each patient's tumor to customize individual therapies. Specifically, characterization of multiple breast cancer phenotypes[28,29] may help identify tumors with specific natural histories that are likely to respond to a given therapy. Preliminary clinical data suggesting that aromatase inhibitors may have greater efficacy than tamoxifen in cancers expressing the growth factor receptor HER2[30] indicate that continued research is necessary to guide us in designing optimal therapies. Future research will focus on understanding the interactions among signal transduction pathways and the application of genetic and proteomic profiling techniques to better identify a responsive disease profile. Incorporating these markers into the selection of optimal therapy will push the concept of directed therapy to a new frontier.

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. Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330:1253-1259, 1994.
2. Citron ML, Berry DA, Cirrincione C, et al: A randomized trial of dose dense vs conventionally scheduled and sequential vs concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup C9741-CALGB 9741. J Clin Oncol 21:1431- 1439, 2003.
3. Hortobagyi GN: What is the role of highdose chemotherapy in the era of targeted therapies? J Clin Oncol 22:2263-2266, 2004.
4. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003.
5. Fisher B, Anderson S, Wickerham DL, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 15:1858-1869, 1997.
6. Fisher B, Anderson S, DeCillis A, et al: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17:3374-3388, 1999.
7. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998
8. Ayers M, Symmans WF, Stec J, et al: Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol 22:2284-2293, 2004.
9. Ellis M, Ballman K: Trawling for genes that predict response to breast cancer adjuvant therapy. J Clin Oncol 22:2267-2269, 2004.
10. Polychemotherapy for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 352:930-942, 1998.
11. Tamoxifen for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group (see comments). Lancet 351:1451-1467, 1998.
12. Beatson G: On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment with illustrative cases. Lancet 2:104-107, 1896.
13. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609-1615, 2002.
14. Ovarian ablation in early breast cancer: Overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group (see comments). Lancet 348:1189-1196, 1996.
15. Emens LA, Davidson NE: Adjuvant hormonal therapy for premenopausal women with breast cancer. Clin Cancer Res 9:486S-494S, 2003.
16. Limonta P, Montagnani Marelli M, Moretti RM: LHRH analogues as anticancer agents: Pituitary and extrapituitary sites of action. Expert Opin Investig Drugs 10:709-720, 2001.
17. Hughes LL, Gray RJ, Solin LJ, et al: Efficacy of radiotherapy for ovarian ablation: Results of a Breast Intergroup study. Cancer 101:969-972, 2004.
18. National Institutes of Health Consensus Development Panel: National Institutes of Health Consensus Development Conference statement: Adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 93:979-989, 2001.
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. de Haes H, Olschewski M, Kaufmann M, et al: Quality of life in goserelin-treated versus cyclophosphamide + methotrexate + fluorouracil-treated premenopausal and perimenopausal patients with node-positive, early breast cancer: The Zoladex Early Breast Cancer Research Association Trialists Group. J Clin Oncol 21:4510-4516, 2003.
21. Castiglione-Gertsch M, O•fNeill A, Price KN, et al: Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: A randomized trial. J Natl Cancer Inst 95:1833-1846, 2003.
22. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002.
23. Baum M, Buzdar A, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802-1810, 2003.
24. 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.
25. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004.
26. Dowsett M, on Behalf of the ATAC Trialists Group: Analysis of time to recurrence in the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial according to estrogen receptor and progesterone receptor status (abstract 4). Breast Cancer Res Treat 82(suppl 1):S7, 2003.
27. Gnant M, Hausmaninger H, Samonigg H, et al: Changes in bone mineral density caused by anastrozole or tamoxifen in combination with goserelin (zoledronate) as adjuvant treatment for hormone receptor-positive premenopausal breast cancer: Results of a randomized multicenter trial (abstract 12). Breast Cancer Res Treat 76(suppl 1):S31, 2002.
28. Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406:747-752, 2000.
29. Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418-8423, 2003.
30. Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 19:3808-3816, 2001.