Controversies in the adjuvant treatment of breast cancer: new adjuvant endocrine treatment strategies

Transcription

1 Annals of Oncology 15 (Supplement 4): iv23 iv29, 2004 doi: /annonc/mdh901 Controversies in the adjuvant treatment of breast cancer: new adjuvant endocrine treatment strategies V. D Hondt & M. Piccart Jules Bordet Institute, Brussels, Belgium Introduction The importance of endocrine therapy in the treatment of breast cancer has been known for more than a century. Approximately 75% of breast cancers are hormone responsive, and since the 1970 s, tamoxifen has been the most important drug prescribed, estimated to have saved the lives of women worldwide each year. Other endocrine therapies have been developed, initially for patients with tumors resistant to tamoxifen. Among them, third-generation aromatase inhibitors (AIs) (anastrozole, exemestane, letrozole) now challenge tamoxifen as the gold standard first-line endocrine therapy for postmenopausal women, and they are being studied in premenopausal women in combination with luteinizing hormone-releasing hormone LH-RH analogs. The purpose of this chapter devoted to early breast cancer is to review the recent and important data from studies investigating the role of AIs, the duration and the sequence of endocrine treatments and the future role of molecular biology in helping to define who might benefit from which endocrine therapy or which sequence of endocrine agents to use, and for how long. Postmenopausal endocrine treatment Postmenopausal women with hormone receptor-positive breast cancer constitute by far the largest demographic group of breast cancer patients. Adjuvant treatment Will an AI replace tamoxifen? It has been shown unequivocally that adjuvant endocrine therapy with tamoxifen decreases recurrence rate and prolongs survival in breast cancer. In the 1998 report of the Early Breast Cancer Trialists Collaborative Group (EBCTCG), the absolute improvements in 10-year survival for women treated with 5 years of adjuvant tamoxifen were 10.9% for patients with node-positive and 5.6% for those with node-negative estrogen receptor-positive (ER+) tumors [1]. In the last decade, third-generation AIs have shown equivalent or superior activity over tamoxifen in the first-line endocrine treatment of metastatic cancer. In the single but quite large randomized trial comparing letrozole with tamoxifen as first-line endocrine therapy, conducted in 916 postmenopausal women with locally advanced or metastatic breast cancer, a significant increase in time to progression was observed in the letrozole arm (9.4 versus 6 months), with a non-significant trend for a longer survival [2]. In the largest trial comparing anastrozole with tamoxifen, conducted in 668 postmenopausal women with locally advanced or metastatic breast cancer, no difference in efficacy was observed between the two arms [3]. Of note, for 55.8% of patients, receptor status of the tumor was unknown. In the second randomized study, including 353 postmenopausal women with advanced breast cancer, a significant increase in time to progression was observed in the anastrozole arm (11.1 versus 5.6 months) [4]. The phase III trial comparing exemestane with tamoxifen in 382 postmenopausal women with metastatic breast cancer was first reported at the Fourth European Breast Cancer Conference in March 2004 [5]. In this case also, an increase in progression-free survival was observed in the AI arm (9.9 versus 5.7 months). Adjuvant therapy trials with the third-generation AIs began 8 years ago, and there are several ongoing studies of these agents in postmenopausal women. The oldest trials are those comparing tamoxifen directly with an AI. In the first and largest of these studies, the ATAC (Arimidex and Tamoxifen Alone or in Combination) trail, 9366 postmenopausal patients were randomized to tamoxifen or anastrozole or to a combination of tamoxifen and anastrozole [6]. In this very large trial, 84% of patients had ER+ and/or progesterone receptor (PR)+ tumors. At a median 33 months follow-up, 87.4% of patients assigned to tamoxifen and 89.4% of patients assigned to anastrozole were disease-free (local, distant or contralateral disease). This absolute 2% reduction translates into a relative risk reduction of 17% (P = 0.013). The effect was seen only in patients whose tumors were known to be ER+ and/or PR+, and for these, the relative risk reduction was 22%. Interestingly, the risk reduction was greater for the ER+, PR tumors than for the ER+, PR+ ones [hazard ratio (HR) 0.48 versus 0.82] [7]. This retrospective analysis needs prospective confirmation, but the suggested difference in efficacy might be explained by a superior antitumor activity of the AI in comparison with tamoxifen in breast carcinomas expressing growth factor receptors, such as Her2, that co-segregate with PR negativity in ER+ tumors. This will be analyzed through further translational research efforts in the ATAC trial. So far, no difference in survival has emerged. Interestingly, the combination of tamoxifen and anastrozole is not superior to q 2004 European Society for Medical Oncology

2 iv24 tamoxifen alone, and this reminds us that a combination of two efficient drugs is not always better than their singleagent use. One of the main issues with AIs is their long-term sideeffects. Whereas tamoxifen has been shown to prevent bone loss and maintain appropriate lipid balance, AIs may affect bone turnover and lipid balance because they deprive the body of estrogens. In the anastrozole arm of the ATAC trial, the rate of fractures was significantly higher than in the tamoxifen group (5.9% versus 3.7%; P <0.0001). A similar difference was found for the musculoskeletal disorders (27.8% versus 21.3%; P <0.0001). However, thromboembolic events and hot flashes were less frequent in the anastrozole group (2.1% versus 3.5%, P = for thromboembolic events; and 34.3% versus 39.7%, P < for hot flashes). Other adverse effects were very similar in nature and frequency to those of tamoxifen: fatigue, headaches, mood disturbances and visual disturbances. The absence of estrogen s agonistic effect makes these new drugs safe for the uterus: endometrial malignancies are significantly less frequent in the anastrozole group as compared with tamoxifen. The ATAC trial results are maintained at a median followup of 47 months: an updated analysis has been reported with very similar data, i.e. 1.9% absolute difference in disease-free survival (DFS) [8]. However, in the absence of a difference in survival and without an increasing difference in either efficacy or toxicity, the ASCO Technology Panel, who reviewed the ATAC results after the first and the updated analysis, considered the data very promising but insufficient to change standard practice [9, 10]. Up to now, there are no other data supporting the use of AIs upfront in the adjuvant setting. However, several other trials compare an AI with tamoxifen in first-line adjuvant treatment (Figure 1): the International Breast Cancer Study Group (IBCSG) 18-98/Breast International Group (BIG) 1-98 trial using letrozole and the TEAM trial with exemestane. The recently launched National Cancer Institute of Canada (NCIC) CTG MA.27 study compares exemestane with anastrozole, with or without celecoxib. What is the optimal duration of endocrine treatment, and should an AI be used after or before tamoxifen? (i) Extending treatment beyond 5 years: the optimal duration of adjuvant tamoxifen treatment has been studied for several years. It is now clear that 5 years of tamoxifen is better than 2 years, but then arose the question of whether 10 years was better than 5 years, because even after 5 years of tamoxifen, women are still at risk for local recurrence, metastatic disease or a new contralateral tumor. The aggregate rate of these events is between 1% and 6% per year [11]. In the ongoing ATLAS (Adjuvant Tamoxifen Longer Against Shorter) trial, pre- or postmenopausal women treated with tamoxifen have already been randomized to continue for a further 5 years or to stop. A total accrual of women is expected in this trial, the primary end point of which is overall survival (OS). Another trial addressing the same question, the attom (adjuvant Tamoxifen Treatment offers more?) trial, has already randomized 5500 patients. The fact that neither of these studies has been interrupted predicts a small, if any, difference of efficacy between the two arms at this time. Interestingly, two smaller studies have suggested the absence of benefit of treating with tamoxifen beyond 5 years [12, 13], while a third [14], conducted by the Eastern Cooperative Oncology Group in a higher risk population, suggested the opposite. It is important to note, however, that all three studies were clearly underpowered. While there has been until now no strong rationale for pursuing tamoxifen treatment for longer than 5 years, two large, modern trials were designed to test whether extension of tamoxifen beyond 5 years with an AI could improve outcome. Indeed, it is known that resistance to tamoxifen develops over time, impairing its potential anticancer activity. Extension of the treatment with a non-cross-resistant drug therefore seemed to be a logical approach to take. In the recently published NCIC CTG MA.17/BIG 1-97 trial, 5187 postmenopausal women treated for 5 years (range 4.5 6) with tamoxifen were randomized to receive either letrozole or a placebo for 5 years [15]. A first planned interim analysis, at a median follow-up of 2.4 years, showed a significantly higher rate of DFS in the letrozole group: an absolute difference of 2.2% with an actuarial projection of an absolute difference of 6% in the rate of events over 4 years. The unexpected and robust difference in the rate of events led to the early termination of the study. The limited data on toxicity and the short follow-up (only 1% of women having received 4 years of letrozole) make this new treatment very interesting, but not applicable to all postmenopausal women. Instead, individualized treatment decisions are recommended, taking into account the residual risk of relapse, bone and joint health, menopausal symptoms, lipid profile and cardiovascular risk and the woman s preference. It should be noted that the National Surgical Adjuvant Breast and Bowel Project B33 study, which addressed the same question with exemestane instead of letrozole, had to be prematurely discontinued following the disclosure of the NCIC CTG MA.17/BIG 1-97 trial results (Figure 1). (ii) Sequencing of endocrine treatments within the first five post-operative years: several studies have addressed the questions of the optimal duration and sequence of tamoxifen and AIs in the first five post-operative years. The preliminary results of the Italian Tamoxifen Arimidex (ITA) trial were presented at the 2003 San Antonio meeting [16]. In this small trial, 426 patients on adjuvant treatment with tamoxifen for 2 years or more were randomized to continue with tamoxifen or to switch to anastrozole for a total of 5 years of endocrine therapy. At a median follow-up of 24 months, the risk of relapse was lower for the women who switched to anastrozole (HR 0.36; P = ). The much larger, ongoing, Austrian Breast and Colorectal Cancer Study Group study 8 addresses the same question,

3 iv25 Figure 1. Designs of ongoing or recently closed adjuvant studies with an aromatase inhibitor in postmenopausal women with endocrine responsive breast cancer. TEAM, tamoxifen and exemestane adjuvant multicenter trial; TAM, tamoxifen; EXE, exemestane; ABCSG, Austrian Breast Cancer Study Group; ANA, anastrozole; IBCSG, International Breast Cancer Study Group; BIG, Breast International Group; LET, letrozole; NSABP, National Surgical Adjuvant Breast Project; PLA, placebo; NCIC, National Cancer Institute of Canada; CELEC, celecoxib. and its results are needed before considering this particular sequence of endocrine agents as an option in daily clinical practice. In the recently published Intergroup Exemsestane Study (IES)/BIG 2-97, 4742 women on adjuvant treatment with tamoxifen for 2 3 years were randomized to continue tamoxifen for the remainder of 5 years or to switch to exemestane [17]. At a median follow-up of 30.6 months postrandomization, there was a 4.7% absolute benefit in DFS estimated at 3 years (91.5% for exemestane versus 86.8% for tamoxifen). The relative risk reduction is 32% (P = ). Interestingly, as in the ATAC trial, the risk reduction was somewhat higher for the ER+, PR tumors than for the ER+, PR+ ones (HR 0.58 versus 0.66, difference not significant). At the time the results were released, >90% of patients had completed their assigned treatment. In the tamoxifen group, gynecological symptoms as well as muscle cramps and thrombo-embolic events were more frequent. Arthralgia and diarrhea were more common in the exemestane group. Osteoporosis, visual disturbance and fractures were reported

4 iv26 more frequently in the exemestane group, but the differences were not statistically significant. Non-breast second primary cancers, specifically endometrium and lung cancers and melanoma, occurred less frequently in the exemestane arm (27 versus 53 cases, respectively; HR 0.51; P = 0.003, although the individual differences were not significant). It is not clear for cancers other than endometrium whether the observed differences in incidence of new primary tumors represent a protective effect of the AI or are chance findings. These provocative results need confirmation with longer follow-up. The IBCSG 18-98/BIG 1-98 trial compares (a) tamoxifen (5 years) with (b) letrozole (5 years), with (c) tamoxifen (2 years) + letrozole (3 years), with (d) letrozole (2 years) + tamoxifen (3 years). Accrual was completed in February 2003 with the inclusion of 8028 patients. This is the only study that compares both sequences of an AI and tamoxifen (AI! tamoxifen, tamoxifen! AI) with an AI alone given upfront; it is a very important trial in terms of establishing future standards of care for the use of AIs in the adjuvant setting. The optimal sequence and duration of adjuvant endocrine treatment have yet to be determined, but it is clear that AIs emerge as important partners in the early breast cancer treatment of postmenopausal women. The three main trials already published, ATAC, MA.17 and IES, have addressed three different questions with three different AIs (Table 1). In all these studies, a DFS benefit was obtained very early in the analysis (at the first or second interim analysis) [18]. It is unclear at this point which should be the preferred strategy: AI upfront, AI after 2 3 years of tamoxifen or AI after 5 years of tamoxifen. The very consistent results of these studies must be discussed with patients, who also need to be informed about the still limited data on toxicity, the short follow-up and the lack of survival benefit so far. The optimal duration of AI also remains to be defined, and re-randomization after 5 years of AI therapy is planned in the context of some of the above studies. Finally, because these trials show only a modest absolute increase in DFS, the financial burden (roughly evaluated by the number of patients to treat) remains high. This points to the crucial need for translational research efforts in the context of these trials, in order to identify subpopulations likely to show larger treatment benefits. Neo-adjuvant treatment The option of endocrine therapy instead of chemotherapy in the neo-adjuvant setting is attractive in older women, particularly if they wish conservative surgery and present with a large tumor. In small, non-randomized studies in older women (aged years) with large primary tumors (>3 cm), preoperative administration of anastrozole, letrozole or exemestane resulted in higher rates of regression than those observed earlier with tamoxifen [19 21]. In a randomized study, 337 postmenopausal women (median age 67 years) with large ER+ and/or PR+ tumors, not eligible for breast conserving surgery, received 4 months of neo-adjuvant tamoxifen or letrozole [22]. The objective clinical response rate was significantly higher with letrozole (55% versus 36%; P <0.001), as was the rate of breast conserving surgery (45% versus 35%; P = 0.022). Among the patients who underwent surgery (85%), too few pathological complete responses (pcr) were observed to allow a comparison between the two groups: only 1.5% of patients achieved a pcr. In addition, in the subgroup of patients overexpressing Her2 and/or epidermal growth factor receptor, 15 out of 17 showed a clinical objective response to letrozole, while only four out of 19 had a response to tamoxifen [23]. Table 1. Major published studies of adjuvant endocrine therapy with an AI in postmenopausal women ATAC MA.17 BIG 1-97 IES BIG 2-97 Question addressed Upfront AI for 5 years Extended treatment with AI after 5 years tamoxifen Sequential treatment tamoxifen! AI; total duration 5 years Design Anastrozole versus tamoxifen Letrozole versus placebo Tamoxifen versus tamoxifen! exemestane No. of women randomized 6241, excluding combination Ineligible (%) Percent of women completing 0 <1 >90 randomized treatment Withdrawal due to drug-related Anastrozole 5.1; tamoxifen, 7.2 Letrozole 4.5; placebo 3.6 Exemestane 5.8; tamoxifen 5 AE (%) Follow-up (months) No. of events Distant events [n (%)] 340 (49) 123 (54) 262 (58) DFS gain 2% at 3 years 2.2% at 2.4 years; projected 4.7% at 3 years 6% at 4 years Reduction in risk of contralateral breast cancer (%) NTT AI, aromatase inhibitor; ATAC, Arimidex and Tamoxifen Alone or in Combination; BIG, Breast International Group; IES, Intergroup Exemsestane Study; AE, adverse event; DFS, disease-free survival; NTT, number of patients to treat with the new treatment to avoid one event per year.

5 iv27 These results support the concept of cross-talk between the signal transduction pathways for steroids and those for epithelial growth factors. A higher efficacy of neo-adjuvant anastrozole over tamoxifen (more breast conserving surgery and greater antiproliferative effect) has also been suggested in the IMPACT trial presented at the 2003 San Antonio meeting [24, 25]. Because neo-adjuvant endocrine treatment has lower response rates than chemotherapy, it cannot presently be recommended as a standard of care. However, it can be considered for some women, such as those over the age of 70 years for whom neo-adjuvant treatment is an option; in these cases, an AI should be preferred over tamoxifen. Premenopausal endocrine treatment In premenopausal women, tamoxifen still remains the standard for those with endocrine-responsive tumors, even after completion of adjuvant chemotherapy. The debate over ovarian ablation remains open. In the EBCTCG meta-analysis, it was clear that ovarian ablation was associated with a positive effect on DFS and OS in node-positive and -negative tumors. In the most recent overview carried out in September 2000, information on 4900 women <50 years old from 15 trials was available. Only 1300 women were in trials of ovarian ablation in the absence of chemotherapy, while >3500 were in trials of ovarian ablation and chemotherapy. In the trials without chemotherapy, there was a clear benefit in overall survival (56.7% versus 46.3% at 15 years), while there was no significant difference in the trials of ovarian ablation plus chemotherapy [26]. Three large trials coordinated by the IBCSG under the BIG umbrella, SOFT (Suppression of Ovarian Function), TEXT (Tamoxifen and Exemestane) and PERCHE (Premenopausal Endocrine Responsive Chemotherapy) (Figure 2), were activated in 2003 to contribute to our understanding of the optimal treatment in young women with endocrine-responsive disease [27]. The SOFT trial addresses the question of ovarian Figure 2. Designs of ongoing adjuvant studies in premenopausal women with endocrine responsive breast cancer. SOFT, Suppression of Ovarian Function; IBCSG, International Breast Cancer Study Group; BIG, Breast International Group; GnRH, gonadotrophin-releasing hormone; TAM, tamoxifen; OFS, ovarian function suppression; EXE, exemestane; TEXT, Tamoxifen and Exemestane; PERCHE, Premenopausal Endocrine Responsive Chemotherapy; CT, chemotherapy.

6 iv28 ablation in addition to tamoxifen in young women who have not become amenorrheic within 6 months after chemotherapy or in premenopausal women for whom endocrine therapy alone is considered adequate treatment. Stratification is carried out for chemotherapy, number of nodes and method of ovarian function suppression. For women who should receive ovarian suppression, the TEXT trial compares gonadotrophin-releasing hormone (GnRH) analog + tamoxifen with GnRH analog + exemestane with or without chemotherapy as primary adjuvant treatment, and the PERCHE trial addresses the question of chemotherapy for women who have ovarian ablation randomly associated with tamoxifen or exemestane. In summary, tamoxifen remains the standard and should be administered in cases of an endocrine-responsive tumor. Ovarian ablation might represent an alternative to chemotherapy such as CMF (cyclophosphamide methotrexate 5-fluorouracil) or AC (doxorubicin cyclophosphamide), but strong data supporting the addition of ovarian ablation to adjuvant chemotherapy are still lacking. Many questions remain to be clarified about the best endocrine therapies and their association with chemotherapy in premenopausal women, but the appropriate studies have been launched and hopefully clear answers will be provided in the next 5 years. Tailored endocrine treatment sequences in 2010? Validation of new drugs in the clinic requires huge cohorts of patients, which nevertheless form a group of tumors with heterogeneous biological characteristics. In the adjuvant endocrine setting, every new drug or strategy described in this chapter provides a modest absolute benefit over the standard available treatment in the treated population taken as a whole. The challenge of the coming years will be to identify the women who are best treated with an AI upfront rather than a tamoxifen! AI sequence. Although only on the basis of retrospective analyses, evidence to date suggests that the benefit of the third-generation AIs is greater in ER+, PR and in Her2-overexpressing tumors. It is hoped that strong predictive data will one day be available from genomic and proteomic profiles to allow the best choice of endocrine treatments and their optimal sequence. The sequential use of non-cross-resistant endocrine therapies and the association of endocrine and biological therapies seem to be the way ahead, while much translational research needs to be carried out in parallel in order to understand which individual patients benefit from the incorporation of newer endocrine agents and more target-oriented approaches into their adjuvant therapy. In the greater picture, cost-effectiveness will also have to be considered, however, and could limit in part the indications of these expensive new strategies. Nevertheless, with three large positive trials, the replacement of tamoxifen by AIs or by sequences of tamoxifen/ais in postmenopausal women will receive a growing number of supporters. In daily clinical practice, the optimal adjuvant endocrine strategy for a patient has to be evaluated on a case by case basis, taking into account the expected benefits and toxic effects of each treatment option. References 1. Early Breast Cancer Trialists Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: Mouridsen H, Gershanovich M, Sun Y et al. 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 2001; 19: Bonneterre J, Thurlimann B, Robertson JFR et al. Anastrozole versus tamoxifen as first line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 2000; 18: Nabholtz JM, Buzdar A, Pollak M et al. Anastrozole is superior to tamoxifen as first line therapy for advanced breast carcinoma in postmenopauxsal women: results of a North American multicenter randomized trial. J Clin Oncol 2000; 18: Paridaens R, Therasse P, Dirix L et al. First results of a randomized phase III trial comparing exemestane versus tamoxifen as first-line hormone therapy (HT) for postmenopausal women with metastatic breast cancer (MBC) EORTC in collaboration with the exemestane working group and NCIC Clinical Trials Group. Eur J Cancer 2004; 2 (Suppl): 126(Abstr 241). 6. ATAC Trialists Group. 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 2002; 359: 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. Breast Cancer Res Treat 2003; 82 (Suppl 1): S7(Abstr 4). 8. Baum M, Budzar 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 2003; 98: Winer EP, Hudis C, Burstein HJ et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: Status report J Clin Oncol 2002; 20: Winer EP, Hudis C, Burstein HJ et al. American Society of Clinical Oncology technology assessment working group update: use of aromatase inhibitors in the adjuvant setting. J Clin Oncol 2003; 21: Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996; 14: 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:

7 iv Stewart HJ, Prescott RJ, Forrest PM. Scottisch adjuvant Tamoxifen trial: a randomised study updated to 15 years. J Natl Cancer Inst 2001; 93: Tormey DC, Gray R, Falkson HC. Post-chemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node positive breast cancer. J Natl Cancer Inst 1996; 88: Goss P, 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 2003; 349: Boccardo F, Rubagotti A, Amoroso D et al. on behalf of the Italian Tamoxifen Arimidex (ITA) trial. Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6(Abstr 3). 17. Coombes RC, Hall E, Gibson LJ et al. for the Intergroup Exemestane Study (IES). A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350: Piccart MJ. New stars in the sky of treatment for early breast cancer. N Engl J Med 2004; 350: Dixon JM. Neoadjuvant endocrine therapy. In Miller WR, Santen RJ (eds): Aromatase Inhibition and Breast Cancer. New York: Marcel Dekker 2000; Dixon JM, Love CDB, Bellamy COC et al. Letrozole as primary medical therapy for locally advanced and large operable breast cancer. Breast Cancer Res Treat 2001; 66: Miller WR, Dixon JM. Endocrine and clinical endpoints of exemestane as neoadjuvant therapy. Cancer Control 2002; 9 (Suppl): Eiermann W, Paepke S, Appfelstaedt J et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol 2001; 12: Ellis MJ, Coop A, Singh B et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB1 and/or Erb2 positive, estrogen receptor positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001; 19: Smith I, Dowsett M, on behalf of the IMPACT trialists. Comparison of anastrozole vs tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptor-positive (ER+) operable breast cancer in postmenopausal women: the IMPACT trial. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6(Abstr 1). 25. Dowsett M, Smith I, on behalf of the IMPACT trialists. Greater Ki67 response after 2 weeks neoadjuvant treatment with anastrozole (A) than with tamoxifen (T) or anastrozole plus tamoxifen (C) in the IMPACT trial: a potential predictor of relapse-free survival. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6(Abstr 2). 26. Pritchard KI. The best use of adjuvant endocrine treatments. Breast 2003; 12: Piccart MJ, Goldhirsch A, on behalf of the Breast International Group. An overview of recent and ongoing clinical trials for breast cancer. Straehle C (ed.): Breast International Group London, Greenwich Medical Media Ltd, 2003, 3rd edition.