Neoadjuvant chemotherapy for breast cancer is indicated for tumors that are not suitable for modified radical mastectomy or to increase the chance of breast-conserving surgery for tumors considered operable only with modified radical mastectomy. However, neoadjuvant therapy has several further advantages besides the potential to improve surgical outcomes in patients with large tumors. First, the response of the primary tumor provides an in vivo test of drug sensitivity, which might be of value in identifying patients at high risk of relapse despite a course of standard adjuvant chemotherapy. Second, repeat sampling of the tumor before and after treatment enables research on the mechanisms of drug action and predictive biomarkers. Unfortunately, however, the theoretical advantage of improved long-term systemic control as a result of neoadjuvant chemotherapy[1] has never been demonstrated in large randomized studies.[2,3] Thus, neoadjuvant chemotherapy remains a largely optional aspect of breast cancer therapy, except in patients who truly have locally advanced disease. The use of neoadjuvant endocrine therapy is fairly uncontroversial among patients too unfit to receive chemotherapy or who choose not to undergo this more toxic form of treatment. However, for patients who could be reasonably treated with either approach, the knowledge base for the neoadjuvant use of aromatase inhibitors is still too limited for many physicians to accept the routine application of this treatment. For example, an international expert panel convened recently to consider neoadjuvant treatment concluded that hormonal manipulation is not currently a standard of care for preoperative treatment of operable breast cancer but is a "second choice" for selected patients including the elderly, women with impaired organ function, poor performance status, or those who are considered a poor surgical risk, as well as women who are unwilling to accept the side effects associated with chemotherapy.[4] Nonetheless, the panel encouraged research and recommended trials to optimize the neoadjuvant treatment of estrogenreceptor (ER)-positive, locally advanced disease. Historical Experience With Tamoxifen(Drug information on tamoxifen) Early studies of the use of endocrine therapy for the treatment of primary carcinomas of the intact breast were mostly small, phase II trials of tamoxifen alone without surgery in elderly or unfit, poor surgical candidates.[ 5] The majority of patients in these studies did not undergo definitive surgery, and hormone-receptor expression analysis was not an eligibility criterion. These issues probably account for the poor long-term results and contributed to the misconception that endocrine treatment of primary breast cancer is not efficacious. For example, in one study, more than 60% of patients treated with primary tamoxifen therapy developed progressive disease after 5 years, although almost 50% initially responded to treatment.[6] It was, therefore, no surprise that a meta-analysis of the long-term results of two trials comparing primary tamoxifen to initial surgery followed by tamoxifen demonstrated that primary tamoxifen therapy was associated with an increased risk of death from breast cancer.[7] Clearly, primary tamoxifen therapy is a suboptimal therapeutic approach that can almost never be recommended. It is fair to argue that a similar result would have been achieved with chemotherapy alone because, in follow-up, patients with good initial responses to neoadjuvant chemotherapy also show poor local control without definitive surgery.[8] Unquestionably, surgery remains an indispensable aspect of the management of breast cancer regardless of the nature of the neoadjuvant therapy. Although interest in primary tamoxifen therapy waned as a result of these data, interest persisted in the use of tamoxifen for a few months as neoadjuvant therapy in older patients with ER-positive disease. For example, a study in Edinburgh treated 100 patients over the age of 70 with ERrich breast cancers.[9] Using volume reductions determined by ultrasound as a measure of response, 73 patients experienced significant tumor regression. Similar conclusions regarding an acceptable level of efficacy for neoadjuvant tamoxifen therapy in older patients were drawn from a smaller study conducted at the M. D. Anderson Cancer Center.[10] Neoadjuvant Aromatase Inhibitor Therapy The introduction of third-generation aromatase inhibitors encouraged further research on neoadjuvant endocrine treatment. An initial phase II experience with neoadjuvant letrozole(Drug information on letrozole) (Femara) in Edinburgh was encouraging, with a response rate of 92% documented in 24 postmenopausal women with ER-positive, locally advanced breast cancer treated for 3 months prior to surgery.[11] All 15 patients who initially required mastectomy were subsequently able to undergo breast conservation. The same investigators recently reviewed their phase II experiences in more than 100 patients treated with 3 months of tamoxifen, letrozole, anastrozole(Drug information on anastrozole) (Arimidex), or exemestane(Drug information on exemestane) (Aromasin).[12] Their conclusion that aromatase inhibitors were likely to be more effective neoadjuvant therapy than tamoxifen stimulated the activation of several randomized controlled trials to confirm this hypothesis. Letrozole
The first and currently only adequately powered study to report to date was a randomized, double-blind, multicenter study (Letrozole 024) that compared the activity of 4 months of preoperative letrozole vs tamoxifen in 337 postmenopausal women with ER- and/or progesterone(Drug information on progesterone) receptor (PR)-positive breast cancer.[13] At baseline, none of the patients were eligible for breast-conserving surgery, with 14% considered inoperable. The letrozole group had a significantly higher objective clinical response rate compared to the tamoxifen group (55% vs 36%, P < .001). Secondary end points that supported this conclusion included ultrasound response (35% vs 25%, P = .042), mammographic response (34% vs 16%, P < .001), and breast-conserving surgery rates (45% vs 35%, P = .022). In a prospective central analysis of hormone-receptor status, a small number of ER- and PR-negative tumors were detected. This led investigators to modestly underestimate the value of neoadjuvant endocrine treatment, and the adjusted analysis is presented in Table 1. This study also illustrated the strong relationship between ERexpression levels (determined by the Allred score) and the likelihood of response (Figure 1). As long as ER is expressed at high levels (Allred score of 7 and 8), response rates of 60% to 70% can be expected. Anastrozole
Preliminary data on neoadjuvant anastrozole have also been reported. Only one of these studies has been published in the peer-reviewed literature,[ 14] and most of the ongoing investigations carry caveats associated with abstract presentations and single- institution experiences. A recently reported Russian study randomized 87 postmenopausal women with ER-rich tumors to anastrozole, tamoxifen, or the combination of anastrozole and tamoxifen for 3 months.[15] Anastrozole was superior to both tamoxifen and the combination in overall response rates by clinical palpation, mammography, and ultrasound (70% vs 44% vs 49%, P = .048; 55% vs 36% vs 40%, P = .058; 44% vs 30% vs 32%, P = .072, respectively) with a trend toward higher breast-conservation rates (42% vs 28% vs 30%, P = .056). The ongoing Immediate Preoperative Arimidex Compared to Tamoxifen (IMPACT) trial is evaluating anastrozole, tamoxifen, and the combination in 330 postmenopausal women with ER-positive operable breast cancer.[16-18] Updated results of this study were reported at the San Antonio Breast Cancer Symposium in December 2003. In terms of response rates, anastrozole and tamoxifen were no different, although suppression of Ki67 and rates of breast-conserving surgery were greater with anastrozole. One important feature of the IMPACT trial is that inoperable breast tumors are excluded (unlike the Letrozole 024 study). As a result, crosstrial comparisons of response rates may be misleading. Exemestane
The efficacy of exemestane was evaluated in 13 postmenopausal women with untreated large or locally advanced ER-rich tumors after a 3-month treatment period. Treatment was associated with a marked reduction in aromatization in nonmalignant breast tissue in every patient and in breast tumor tissue in all but one patient. The median reduction in tumor volume by clinical examination, ultrasound, and mammography was 85.5%, 82.5%, and 84%, respectively. Of 10 patients who initially required mastectomy, 8 were able to undergo breast-conserving surgery after treatment.[19] A Spanish multicenter study recently evaluated the efficacy of 6 months of exemestane in 33 women over 65 years old with ER-rich tumors larger than 3 cm and reported a response rate of 50% in the first 28 patients.[20] These preliminary data support further studies of exemestane as neoadjuvant therapy. Summary of Findings
In conclusion, the promising randomized data on letrozole will soon be supplemented by peer-reviewed information on anastrozole and exemestane. An outstanding question concerns the optimal duration of preoperative endocrine therapy. Interestingly, preliminary data on patients given a maximum of 8 months of preoperative letrozole showed a response rate of 90% vs 57% for those receiving 4 months of treatment.[21] Larger randomized studies will be necessary to determine the optimal duration of aromatase inhibitor therapy for tumors that have responded by 4 months, but the tamoxifen experience would suggest that for nonresponding tumors further delays in surgery are inappropriate. Indirect Comparison of Neoadjuvant Endocrine Therapy and Chemotherapy Postmenopausal women with hormone- receptor-positive breast cancer derive most adjuvant benefit from en-docrine treatment rather than chemotherapy.[ 22,23] On this basis, neoadjuvant endocrine therapy is a logical approach to investigate in this patient subpopulation. The design of a practice- setting trial that would compare neoadjuvant therapy with an aromatase inhibitor (investigational arm) to chemotherapy (standard therapy arm) requires an estimate of the efficacy of neoadjuvant chemotherapy. Data on this issue are difficult to compile, however, because the results of trials of neoadjuvant chemotherapy are not often reported according to age, hormone-receptor status, and age. In addition, neoadjuvant chemotherapy studies, like breast cancer studies in general, enroll very few women over age 70. Arguably, robust data on the effectiveness of neoadjuvant chemotherapy in postmenopausal women with strongly ER-positive disease simply do not exist. Side Effects
One of the most striking advantages of neoadjuvant therapy with aromatase inhibitors over chemotherapy is the lower toxicity level. Aside from short-term reversible side effects, chemotherapyassociated leukemia and cardiomyopathy are more common in older patients and should be taken into account when considering the risk-benefit ratio for the administration of cytotoxic drugs in postmenopausal women. A hypothetical advantage of neoadjuvant endocrine therapy is that it can be regarded as an in vivo sensitivity test of endocrine therapy. Patients who achieve a response might have a better chance of survival and could perhaps avoid chemotherapy. Although preliminary data support the hypothesis that patients with primary tumors that respond to tamoxifen survive longer than nonresponders (Figure 2),[6] large-scale studies will be required to generate more confident predictions regarding the relationship between response to neoadjuvant aromatase inhibitor therapy and survival from breast cancer. Neoadjuvant Anthracycline-Based Chemotherapy in ER-Positive Disease
In unselected patients, anthracycline- based neoadjuvant chemothera-py is associated with a high response rate. However, evidence shows that responsiveness is attenuated (to < 5%) in ER-positive disease. For example, in an M. D. Anderson Cancer Center study of neoadjuvant chemotherapy with FAC (fluorouracil [5-FU], doxorubicin(Drug information on doxorubicin) [Adriamycin], and cyclophosphamide(Drug information on cyclophosphamide) [Cytoxan, Neosar]), of 43 patients who achieved a complete pathologic response after four cycles, only 3 had ER-positive disease. Since the total number of known ER-positive tumors in this data set was 106, the pathologic complete response rate can be calculated to be only 2.8% with this regimen.[24] This low pathologic complete response rate is comparable to the response rate observed with 4 months of letrozole (1.3%). Other studies have reported decreased objective response rates to neoadjuvant chemotherapy in patients with ER-positive disease.[ 25,26] These results reflect the results of the Oxford overview, in which the proportional reduction in recurrence with chemotherapy among women aged 50 to 69 years with ER-poor disease (30%) appeared to be nearly twice that of women with ER-positive disease (18%)-a difference that was statistically significant.[23] Thus, it is reasonable to conclude that chemotherapy responsiveness is attenuated in ER-positive disease, and research to improve neoadjuvant therapy in this subset of patients is highly justifiable. Several approaches could be considered- for example, incorporation of a taxane. However, questions remain regarding the benefits of adjuvant regimens incorporating paclitaxel(Drug information on paclitaxel) in ER-positive disease,[27] and the addition of further cytotoxic agents is not necessarily the correct investigational approach to take in older patients. Another approach that has been fairly well investigated is to combine tamoxifen with chemotherapy. Unfortunately, no evidence demonstrates that neoadjuvant chemoendocrine therapy is superior to chemotherapy alone,[28,29] and in the adjuvant setting, tamoxifen actually antagonizes the therapeutic benefits of adjuvant CAF (cyclophosphamide, doxorubicin, 5-FU).[30] Improvements in Surgical Outcomes
Even though the pathologic complete response rate is low, the degree of tumor regression with neoadjuvant aromatase inhibitor therapy is unquestionably sufficient to improve surgical outcomes. In the Letrozole 024 study, all patients were either ineligible for breast-conserving surgery or were deemed inoperable at baseline. T2 tumors were included only if they were considered ineligible for an initial attempt at breast-conserving surgery. After treatment with letrozole, 45% of patients underwent successful breast-conserving surgery, with the rate increasing to 61% among patients with T2 tumors. Comparable estimates with neoadjuvant chemotherapy are difficult to make because the rate of conversion to breast-conserving surgery is not usually reported according to ER status, age, or menopausal status. In addition, many neoadjuvant chemotherapy trials, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial, included a large number of small tumors eligible for lumpectomy at baseline. Table 2 compares the intended and actual surgical outcomes in NSABP B-18 and Letrozole 024. This comparison must exclude T1 tumors, which were not studied in the Letrozole 024 trial, and arguably T2 tumors as well, because NSABP B-18 allowed the entry of T2 tumors that were eligible for breast conservation at presentation. Only 3% of patients with > T2 tumors were considered eligible for breast-conserving surgery in NSABP B-18, but 22% of these individuals underwent breast conservation after four cycles of neoadjuvant AC (doxorubicin, cyclophosphamide) chemotherapy.[31] In the comparable group of > T2 tumors in the Letro-zole 024 study, 29% were eligible for breast conservation. One can therefore argue that four cycles of AC in unselected patients and 4 months of letrozole in postmenopausal women with ER-positive disease are broadly similar in efficacy, in terms of improvements in surgical outcomes.