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.

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.