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Adjuvant Endocrine Therapy for Postmenopausal Women with Early Breast Cancer

Author's Affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota

Requests for reprints: James N. Ingle, Division of Medical Oncology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-2511; Fax: 507-284-1803; E-mail: ingle.james{at}mayo.edu.

	Abstract

Top Abstract Aromatase Inhibitors as Extended... Switching to Aromatase... Initial Adjuvant Endocrine... Conclusions Open Discussion References

 
Results from multiple clinical trials involving aromatase inhibitors have added to the knowledge base relating to endocrine therapy of postmenopausal women with hormone receptor–positive early breast cancer. In the extended adjuvant setting, data from the Austrian Breast and Colorectal Cancer Study Group 6a trial showed an advantage for anastrozole following 5 years of tamoxifen treatment, consistent with the more robust MA.17 trial that examined letrozole versus placebo following 5 years of tamoxifen treatment. The combined analysis of the Austrian Breast and Colorectal Cancer Study Group 8 trial and the German Arimidex Nolvadex 95 trial, plus the Italian Tamoxifen Anastrozole trial, have shown the advantage of switching to anastrozole over continuing the tamoxifen to complete the full 5 years of adjuvant therapy. These trials support the previously reported larger and double-blind Intergroup Exemestane Study. The Arimidex, Tamoxifen, Alone or in Combination trial now has data out to 68 months of median follow-up showing the maintenance of a significant advantage of anastrozole over tamoxifen for disease-free survival. In this initial treatment setting, the Breast International Group 1-98 trial recently showed a significant advantage for letrozole over tamoxifen. The current debate is centered on whether the optimal strategy is to give an aromatase inhibitor initially or after several years of tamoxifen treatment. Multiple important questions remain, including the predictive value of molecular markers such as progesterone receptor, the optimal duration of aromatase inhibitor therapy, the long-term adverse effects, and the relative efficacy and toxicity of the different aromatase inhibitors.

Data are now available from seven prospective randomized clinical trials (Figs. 1 and 2), which together provide a large body of data on the aromatase inhibitors as adjuvant endocrine therapy in postmenopausal women. These seven trials comprise three clinical settings: (a) extended adjuvant therapy in which the aromatase inhibitor is administered after 5 years of tamoxifen treatment, (b) a "switching" approach in which the aromatase inhibitor is given after several years of tamoxifen treatment, and (c) the initial adjuvant therapy setting in which the aromatase inhibitor is administered rather than tamoxifen. The three different settings involve populations of patients at different time points relative to the diagnosis of their disease. The population of patients entered in the extended adjuvant studies would be expected to include a lower proportion of patients with hormone-insensitive breast cancer than in the switching setting, which in turn would be expected to have a lower proportion of such patients than those entered in the initial therapy setting. Each of these settings is superimposed on a recurrence-free survival curve estimated from the Oxford Overview data (2) in Fig. 2, illustrating that the population of patients differed in terms of prior tamoxifen exposure and thus location on the natural history continuum of patients so treated. Direct cross-setting comparisons are confounded by the fact that the populations are substantially different in terms of tumor characteristics, particularly hormonal sensitivity. Despite these differences, a review of the available data from the extended adjuvant, switching, and initial therapy settings is necessary to develop proposals for patient management, identify issues that need attention, and develop hypotheses for future study. The results from the trials in the three settings will be considered along with implications for patient management.

View larger version (17K): [in this window] [in a new window]   Fig. 1. Schemata for the clinical trials which have reported results on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with early breast cancer (R, randomization).

View larger version (14K): [in this window] [in a new window]   Fig. 2. Clinical trials that have reported results on the use of aromatase inhibitors as adjuvant therapy in postmenopausal women with early breast cancer superimposed on a recurrence-free survival curve estimated from the Oxford Overview data (8) for patients treated with tamoxifen for 5 years. Arrow, points of randomization.

	Aromatase Inhibitors as Extended Adjuvant Therapy

Top Abstract Aromatase Inhibitors as Extended... Switching to Aromatase... Initial Adjuvant Endocrine... Conclusions Open Discussion References

MA.17. MA.17 (5) is a large trial conducted by the Breast Cancer Intergroup of North America involving 5,187 postmenopausal patients who, after 4.5 to 6 years of tamoxifen treatment, were randomized in a double-blind fashion to either letrozole or placebo for a planned 5-year period. The primary end point was disease-free survival, in which death without either recurrence of breast cancer or new diagnosis of a contralateral breast cancer was not considered an event. The initial report of this trial (5) has been updated (6), with the update based on a median follow-up of 30 months. Disease-free survival was significantly superior for those who received letrozole, with the hazard ratio (HR; letrozole/placebo) being 0.58 [95% confidence interval (CI); 0.45-0.76; P < 0.001]. Thus, the use of letrozole was associated with a 42% reduction in risk of an event compared with those who received placebo. Distant disease-free survival was also significantly better for women who received letrozole (HR, 0.60; 95% CI, 0.43-0.84; P = 0.002), but there was no significant difference in overall survival. Additional preplanned analyses were done in node-positive and node-negative cohorts. Letrozole use was associated with a significant improvement in disease-free survival for both node-negative and node-positive patients and with a significant improvement in distant disease-free survival and overall survival for node-positive but not node-negative patients. Letrozole was also associated with a 37.5% reduction in the risk of a contralateral new primary breast cancer, but this did not reach statistical significance. Higher incidences of joint and muscle complaints, hot flushes, and patient-reported new diagnoses of osteoporosis were seen in the letrozole arm, but vaginal bleeding was less frequent. The rates of bone fractures and cardiovascular events were similar.

Three substudies associated with MA.17 evaluating quality of life, bone, and lipids have been reported. Whelan et al. (7) evaluated quality of life in 3,612 women, representing almost 70% of the entire study population, using the Medical Outcomes Study Short Form 36-item (SF-36) general health questionnaire and the menopause-specific quality of life questionnaire. This study, the largest thus far involving aromatase inhibitors, revealed that letrozole use was associated with statistically significant worsening but small differences in the SF-36 domains of physical function, bodily pain, and vitality, and in the menopause-specific quality of life questionnaire with vasomotor and sexual domains at various time points. However, letrozole did not have an adverse effect on overall quality of life, and the findings of small effects were considered by the investigators to be consistent with a minority of patients having important changes in several specific domains. This large study, with a high level of compliance among the participants, provides additional support for the conclusion that letrozole is well tolerated in the extended adjuvant setting.

Wasan et al. (8) did a study to examine the effect of letrozole on serum lipid concentrations in a subset of 347 women entered on MA.17. The lipid variables examined were total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and lipoprotein (a), and these were measured at baseline, 6 months, 12 months, and annually thereafter. Marginally significant differences between letrozole-treated patients and those who received placebo were found in terms of percentage change from baseline in high-density lipoprotein cholesterol at 6 months, low-density lipoprotein cholesterol at 12 months, and triglycerides at 24 months with all of the changes being adverse for letrozole. Importantly, there was no significant difference between the letrozole and placebo groups with respect to the numbers of patients exceeding the thresholds defined for the lipid variables. These findings support the safety of letrozole in the extended adjuvant setting and are consistent with the finding of no difference in cardiovascular events between patients treated with letrozole or placebo in the entire population entered on MA.17.

Perez et al. (9) evaluated the effect of letrozole on bone mineral density and markers of bone turnover in 226 women entered on MA.17. The variables examined included bone mineral density in the hip and lumbar spine (L2-4), serum bone alkaline phosphatase as a marker of bone formation, and serum C-teleopeptide and urinary N-teleopeptide as markers of bone resorption. Measurements were taken at baseline, 6 months, 12 months, and annually thereafter. Letrozole administration, relative to placebo, was associated with significant decreases in hip and lumbar spine bone mineral density at 24 months, and increases in the bone resorption marker urinary N-teleopeptide. These findings indicate the need to monitor bone density in women receiving aromatase inhibitors as recommended by the American Society of Clinical Oncology (ASCO) Expert Panel on Bisphosphonates in Breast Cancer (10).

ABCSG6a trial. Jakesz et al. (11) reported the only other study, ABCSG6a, that has addressed the issue of extended adjuvant therapy following 5 years of tamoxifen treatment. This trial involved women who had been entered on ABCSG6 (12), which randomized patients to either tamoxifen alone for 5 years or tamoxifen plus the first-generation aromatase inhibitor aminoglutethimide for the first 2 years. Patients on ABCSG6 were randomized at 54 months to either observation or anastrozole for 3 years beginning at the time of completion of 5 years of tamoxifen treatment. ABCSG6a included 387 women on anastrozole and 469 women on observation, the imbalance was due to the refusal by some women to take anastrozole. The results were reported based on the women who accepted the randomization and showed that anastrozole use was associated with a decrease in recurrence with a HR of 0.64 (95% CI, 0.41-0.99; P = 0.047). The pattern of decrease in recurrence was consistent for local to regional disease, distant metastasis, and contralateral disease.

Patient management implications of trials of extended adjuvant therapy. The findings of ABCSG6a are consistent with those of MA.17, but the latter study must be considered substantially more robust based on its double-blind approach and a sample size that was six times as large. Collectively, the studies support the consideration of extended adjuvant therapy in women with early breast cancer who have completed 5 years of tamoxifen treatment. The fact that both MA.17 and ABCSG6a showed reductions in risk of recurrence clearly illustrated that there is a residual risk of recurrence in women following 5 years of tamoxifen treatment. The most recent publication from the Oxford Overview (3) contains a curve for disease recurrence for women who underwent 5 years of tamoxifen treatment [Fig. 8 in ref. (3)] that shows the recurrences continuing out to 15 years without a plateau. Ravdin and Davis (13) have used the Overview data (2) to estimate residual risk of relapse in patients completing 5 years of tamoxifen treatment and found the average annual risk of relapse from years 6 through 10 is 2.0% for node-negative patients and 4.4% for women with node-positive disease. Clinicians should be aware of these levels of residual risk when considering extended adjuvant therapy.

	Switching to Aromatase Inhibitors after 2 Years of Tamoxifen Treatment

Top Abstract Aromatase Inhibitors as Extended... Switching to Aromatase... Initial Adjuvant Endocrine... Conclusions Open Discussion References

 
At present, results are available for three clinical trials that have examined the value of switching to an aromatase inhibitor after 2 years of tamoxifen treatment. The largest and most robust trial, based on its double-blind approach, is the Intergroup Exemestane Study (IES). The combined ABCSG8/German Arimidex Nolvadex (ARNO) 95 trials and the Italian Tamoxifen Anastrozole (ITA) trial have recently been published.

IES. The IES (14) was published and updated at the San Antonio Breast Cancer Symposium in December of 2004 (15). The publication (14) has been previously considered in some detail (16) and the findings from the update will be considered here. Coombes et al. (15) provided an update on the 4,742 women who had already undergone 2 to 3 years of adjuvant tamoxifen and were randomized to receive, in a double-blind fashion, either tamoxifen or the steroidal aromatase inhibitor exemestane to complete a 5-year course of therapy. Disease-free survival was the primary end point with an event defined as recurrence of breast cancer at any site, a second primary breast cancer, or death from any cause. Approximately 81% of the patients were known to have estrogen receptor–positive status with most of the remainder being estrogen receptor–unknown. The updated report was based on a median follow-up of 42 months compared with 30.6 months in the original publication. Disease-free survival remained significantly superior for those women switched to exemestane with an adjusted HR (exemestane/tamoxifen) of 0.72 (95% CI, 0.62-0.85; P = 0.00006). This HR indicates that switching a woman from tamoxifen to exemestane was associated with a 28% reduction in the risk of an event compared with continuing the tamoxifen. Switching to exemestane was also associated with a significant improvement in breast cancer–free survival and time to contralateral breast cancer. The toxicity profiles differed between the exemestane and tamoxifen arms of the study. Exemestane was associated with a significantly higher incidence of arthralgias, myalgias, diarrhea, and myocardial infarction with this latter adverse event occurring in 0.9% of patients on exemestane compared with 0.5% on tamoxifen. Tamoxifen was associated with a significantly higher incidence of thromboembolic disease and gynecologic symptoms.

ABCSG8/ARNO95. Jakesz et al. (17) reported the results from the planned combined analysis of these two trials. The design of these trials involved women with 2 years of tamoxifen adjuvant therapy who were randomized to tamoxifen or anastrozole for 3 additional years. This report involved 3,224 patients with resected hormone receptor–positive breast cancer and a medium follow-up of 28 months. Switching to anastrozole was associated with a significantly better event-free survival (HR, 0.60; 95% CI, 0.44-0.81; P = 0.0009) and distant recurrence-free survival (HR, 0.61, 95% CI 0.42-0.87; P = 0.0067). More bone fractures and fewer thromboses were seen in women who were switched to anastrozole.

ITA trial. Despite being the smallest of the three trials evaluating the switching approach with 448 patients, 10% of the sample size for IES and 14% of that for ABCSG8/ARNO95, the ITA trial could be viewed as a positive study in terms of showing the value of switching from tamoxifen to an aromatase inhibitor. Boccardo et al. (18) reported the results of ITA with 36 months' median follow-up. All patients entered on this trial had undergone 2 to 3 years of tamoxifen treatment for node-positive and estrogen receptor–positive disease and then were randomized to complete their 5 years of adjuvant endocrine therapy with either tamoxifen or anastrozole. Switching to anastrozole was associated with a significantly better event-free survival (HR, 0.35; 95% CI, 0.20-0.63; P = 0.0002), recurrence-free survival (HR, 0.35; 95% CI, 0.18-0.68; P = 0.001), local recurrence-free survival (HR, 0.15; 95% CI, 0.03-0.65; P = 0.003), and distant metastasis–free survival (HR, 0.49; 95% CI, 0.22-1.05; P = 0.06). Thus, despite the relatively small sample size, impressive differences were identified, which may have been facilitated by the inclusion of only node-positive patients, a group with high event rates.

Patient management implications of trials of switching from tamoxifen to an aromatase inhibitor. For postmenopausal women with early breast cancer initially treated with tamoxifen, the three trials discussed above, i.e., the IES, ABCSG8/ARNO95, and ITA, show with clear consistency that switching to either exemestane or anastrozole is associated with higher antitumor efficacy. There are differences in the toxicity profiles of switching to exemestane versus continuing with tamoxifen, but these do not seem to outweigh the therapeutic value of switching to an aromatase inhibitor. Patients should be informed of the potential benefits of switching to an aromatase inhibitor after several years of tamoxifen treatment and the adverse events associated with each approach. An important consideration in the patient being considered for a switch to an aromatase inhibitor is the assessment and monitoring of bone mineral density because of the increased risk of fractures with aromatase inhibitor therapy.

	Initial Adjuvant Endocrine Therapy: Aromatase Inhibitors versus Tamoxifen

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Two major clinical trials comparing tamoxifen with a third-generation aromatase inhibitor have been reported. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was the first of the major adjuvant aromatase inhibitor trials to be reported (19, 20), and an update with 68 months' median follow-up has recently been made available (21). ATAC will be considered in-depth in an accompanying article in this issue but will be briefly summarized here as background for consideration of the other major trial, the Breast International Group (BIG) 1-98 trial, which compared letrozole with tamoxifen.

ATAC. This important trial showed that anastrozole, compared with tamoxifen, significantly improved disease-free survival (HR, 0.87; 95% CI, 0.78-0.97; P = 0.01) and time to recurrence (HR, 0.79; 95% CI, 0.70-0.90; P = 0.0005) and significantly reduced distant metastases (HR, 0.86; 95% CI, 0.74-0.99; P = 0.04) and contralateral breast cancers (42% reduction; 95% CI, 12-62%; P = 0.01; ref. 21). Toxicity profiles were different between the two agents. Anastrozole was associated with significant reductions in the incidence of thromboembolic events, ischemic cerebrovascular events, endometrial cancer, vaginal bleeding, hot flushes, and vaginal discharge, whereas tamoxifen was associated with a significantly lower incidence of fractures and arthralgias. There was no significant difference in ischemic cardiovascular disease (21). Fallowfield et al. (22) did a quality of life subprotocol in 1,021 women entered on the ATAC trial and concluded that these agents had a similar overall effect on quality of life.

BIG 1-98. BIG 1-98 is a four-arm clinical trial consisting of two monotherapy arms, tamoxifen or letrozole for 5 years, and two sequencing arms involving tamoxifen for 2 years followed by letrozole for 3 years or letrozole for 2 years followed by tamoxifen for 3 years. Thurlimann et al. (23) presented the results of the primary core analysis, comparing tamoxifen with letrozole, at the 2005 ASCO meeting with a median follow-up of 25.8 months. This analysis involved patients entered on the two monotherapy arms plus events and follow-up for the patients on the corresponding sequencing arm for the first 2 years. A total of 8,010 patients were available for the direct comparison of tamoxifen and letrozole. Hormone receptor positivity was a requirement for study entry. Patient characteristics included 41% of patients with positive nodes and 25% with prior adjuvant chemotherapy. Disease-free survival was the primary end point: an event was defined as any invasive breast cancer recurrence, invasive contralateral breast cancer, second non–breast cancer, or death without a prior event. Disease-free survival was significantly better for patients treated with letrozole (HR, 0.81; 95% CI, 0.70-0.93; P = 0.003) with advantages seen for letrozole when other end point definitions were considered, e.g., systemic disease-free survival, time to recurrence, and time to distant recurrence. As expected, toxicity patterns were different for tamoxifen and letrozole. Letrozole was associated with significantly more bone fractures (5.7% versus 4.0% of patients) and grades 3 to 5 cardiovascular events (2.1% versus 1.1% of patients), but significantly fewer grades 3 to 5 thromboembolic events (0.8% versus 2.1% of patients) and endometrial events (e.g., endometrial biopsies in 2.3% versus 9.1% of patients). The full publication of the results of this analysis is awaited with interest.

Progesterone status as a predictive factor for choice of initial endocrine therapy. A retrospective and exploratory analysis of time to recurrence according to estrogen receptor and progesterone receptor status was done by Dowsett (24) in 7,993 patients representing 86% of the patients entered on the ATAC trial. A remarkable difference in the HR for disease recurrence (anastrozole/tamoxifen) was identified between the progesterone receptor–positive and progesterone receptor–negative women who were known to be estrogen receptor–positive. The HR was 0.82 (P = 0.091) in the former group and 0.48 (P < 0.001) in the latter.

Recent results from the other large trial comparing an aromatase inhibitor to tamoxifen as initial adjuvant endocrine therapy, BIG 1-98, did not identify this differential effect. Thurlimann et al. (23) reported at the 2005 ASCO meeting that in 6,686 women randomized to either letrozole or tamoxifen, the HRs (letrozole/tamoxifen) for disease-free survival were similar in estrogen receptor–positive patients whether their progesterone receptor status was positive (HR, 0.84) or negative (HR, 0.83).

Both the ATAC and BIG 1-98 analyses were based on local determinations of the estrogen receptor and progesterone receptor status. Further analyses, including central review and central determination, if possible, would be of value. As in numerous instances for studies considered in this report, full publication with peer review is necessary.

Patient management implications of trials of initial endocrine adjuvant therapy. The ATAC trial (19) brought about a major change in the adjuvant endocrine therapy of postmenopausal women with hormone receptor–positive early breast cancer. The findings that anastrozole was associated with improved efficacy and a lower incidence of thromboembolic events, ischemic cerebrovascular events, endometrial cancer, and vaginal bleeding formed the basis for considering this agent to be preferred over tamoxifen as initial adjuvant endocrine therapy (25). The increased risk of bone fractures with anastrozole, a common theme with aromatase inhibitors, was acknowledged but considered to be an issue that could be ameliorated with close attention to bone density and appropriate treatment thereof. The findings from the BIG 1-98 provide consistent supportive data for the value of the third-generation aromatase inhibitors as initial endocrine therapy. The differential effects for progesterone receptor–positive and progesterone receptor–negative cohorts seen in the analysis of the ATAC patients (24) are of note. However, despite the smaller difference between anastrozole and tamoxifen in the estrogen receptor– and progesterone receptor–positive patients in ATAC, there is no indication that tamoxifen is superior and the toxicity differences remain in favor of the aromatase inhibitor.

The question has been raised as to whether the optimal strategy is to use an aromatase inhibitor as initial, and thus as monotherapy, or to use an aromatase inhibitor after some period of tamoxifen treatment. The impetus for considering the latter approach is that the differential advantage of the aromatase inhibitors is greater after initial tamoxifen and seems to be greater after 5 years compared with 2 years of tamoxifen treatment considering the findings of the largest trials (5, 14). The ASCO technology assessment panel (26) on aromatase inhibitors has concluded that optimal adjuvant treatment for postmenopausal women includes an aromatase inhibitor either as initial therapy or after treatment with tamoxifen but has not taken a position on a preferred strategy. Given the large amount of clinical trial data, models have been developed in order to identify an optimal strategy. Two modeling efforts were presented at the 2005 ASCO meeting (27, 28) that considered different cohorts of patients based on progesterone receptor status from ATAC (24) and different end points of interest, i.e., 10-year disease-free survival (27) and time lost to recurrence (28) without agreement on the optimal strategy. Modeling will be considered in greater detail in an accompanying article in this issue. In this author's opinion, modeling is a work in progress with the potential to provide valuable insights, but additional work must be done before it can be used to develop management recommendations for the individual patient.

	Conclusions

Top Abstract Aromatase Inhibitors as Extended... Switching to Aromatase... Initial Adjuvant Endocrine... Conclusions Open Discussion References

 
The recent past has seen the release of substantially more data firmly establishing the aromatase inhibitors, anastrozole, exemestane, and letrozole, as effective agents to decrease the risk of breast cancer recurrence in postmenopausal women with hormone receptor–positive early breast cancer. Multiple questions remain, including whether sequencing of tamoxifen and an aromatase inhibitor is superior to monotherapy with an aromatase inhibitor, the optimal duration of aromatase inhibitor treatment, the long-term adverse effects, the predictive value of molecular markers such as progesterone receptor, and whether there is a "best" aromatase inhibitor. These questions are being addressed by ongoing clinical research. It is clear that the aromatase inhibitors have become established as being of value for many postmenopausal women with early breast cancer.

	Open Discussion

Top Abstract Aromatase Inhibitors as Extended... Switching to Aromatase... Initial Adjuvant Endocrine... Conclusions Open Discussion References

 
Dr. Ingle: In looking at the receptor status subgroups for disease-free survival, the ATAC data were based on tumor recurrence, whereas the BIG 1-98 data are based on disease-free survival, which has many events in that category. Whether that makes a difference or not, I don't know.

Dr. Eric Winer: This disease-free survival definition in BIG 1-98 is contralateral, ipsilateral, and distant recurrence, as well as deaths from other causes.

Dr. Aman Buzdar: The data are similar to Dr. Dowsett's analysis by subgroup in ATAC [Breast Cancer Res Treat 2003; 82(suppl 1): S7].

Dr. Mitch Dowsett: Pretty similar, yes. We did another analysis in which we cut out the contralateral breast cancer events on the concept that the contralateral breast cancers are less likely to be influenced by the phenotype. In fact, the relationships are stronger still.

Dr. Ingle: You censored all those other causes of death, and they obviously did not censor other events because they included everything in this disease-free survival definition.

Dr. Dowsett: They've got rather more PR negatives than we have: 25% versus our 20%.

Dr. Ingle: For BIG 1-98, there were more deaths overall in the tamoxifen group, but there were more deaths without a prior cancer event with letrozole, although neither difference was statistically significant [Thulimann B, presented at ASCO 2005]. The number of cardiac deaths was twice as high with letrozole but was only a fraction of a percent (0.32% versus 0.15%). But is this a signal we have to keep an eye on? We are all concerned with the long-term toxicity of these very potent aromatase inhibitors.

Dr. Myles Brown: You can't presume that all AIs are equal, particularly with these rare adverse effects. Exemestane has more androgenic effects.

Dr. Ingle: That is really a good point: there are the differences in potency and in metabolites. With letrozole, when the data were presented at St. Gallen in January [Primary Therapy in Early Breast Cancer, St. Gallen, Switzerland, 2005], I think everybody was concerned with this issue. But the numbers are very, very small.

Dr. Stephen Johnston: The other consideration is the cardioprotective effects of tamoxifen. If you look at MA.17, letrozole versus placebo post-tamoxifen, you don't see this difference. The other finding that can be misinterpreted is the cholesterol data in BIG 1-98. If you look at the baseline cholesterol data, there is no change in cholesterol on an AI, while on tamoxifen there is. So, in actual fact, the difference is due to losing the protective effect of tamoxifen, rather than the AIs enhancing cardiac and cholesterol problems over and above a placebo.

Dr. Buzdar: But we don't have the data unless we prospectively look at this in one subgroup, which is what I proposed to the American College of Surgeons Oncology Group. They are going to do a neoadjuvant therapy with the three aromatase inhibitors, head on. I suggested they look at the lipid profile at baseline and at 4 months to see what happens. I think that will provide the cleanest data.

Dr. Ingle: Whether all AIs are created equal is as yet an unanswered question. That is where MA.27 (comparing anastrozole with exemestane) is going to be very important. Ideally, it should be a three-arm study, but there are some realities in life that make certain things impossible.

Dr. Kathleen Pritchard: Once we get out to 10 years posttherapy we don't have survival data from any of these trials. What is the design of the NSABP study?

Dr. Ingle: As I understand their proposed design, any woman who has had 5 years of endocrine therapy with any AI and up to 2 years of tamoxifen will then be randomized to letrozole or placebo for 5 years.

Dr. Brown: I know that it is a brief window between the previous endocrine therapy and the randomization. I am concerned with all the patients who completed their adjuvant therapy sometime in the past, any time in the past. Is anybody addressing the management of those women? For example, a woman who completed 5 years of tamoxifen 5 years ago.

Dr. Ingle: We addressed that question in the fall of 2003 when MA.17 came out. It was decided that patients who had been randomized to placebo could be offered letrozole. That was out to 4 or 5 years. Then, the consensus was that 5 years since completion of tamoxifen was the limit for which we had any experience.

Dr. Brown: There is a 2% hazard ratio over the next 5 years. It makes no sense to me a priori not to offer women the AI at any time after the tamoxifen. It seems to me that the benefit they get is the same in terms of risk reduction at any point on that curve.

Dr. Buzdar: However, there are no data to support that. The only data we have concern tamoxifen. There was one study carried out in Europe in women with estrogen receptor–positive nonmetastatic disease who received tamoxifen at variable time points following local therapy. In that subgroup, despite long delays in initiation of therapy, there was a benefit of endocrine therapy compared to no treatment [Ann Oncol 2000;11:515–9].

Dr. Winer: Clinical practice is that physicians are offering AIs in that window of 5 to 10 years post-tamoxifen. Many patients take them and many don't.

Dr. Ingle: Now that we have the 15-year survival data for tamoxifen from the Overview [Lancet 2005;365:1687–717], we can try to quantify the risks and benefits. Currently, we tend not to raise the issue of starting an AI with patients once they are more than 5 years beyond their tamoxifen therapy.

	Footnotes

 
Presented at the Fifth International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer, June 13-14, 2005, Cambridge, Massachusetts

Received 9/28/05; revised 10/14/05; accepted 10/26/05.

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Top Abstract Aromatase Inhibitors as Extended... Switching to Aromatase... Initial Adjuvant Endocrine... Conclusions Open Discussion References

 

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