【进展】皇帝原来没有穿衣服：芳香酶抑制剂的一线辅助治疗 JCO2009
这个帖子发布于 16 年零 128 天前，其中的信息可能已发生改变或有所发展。
这篇自己还没有看完，不过题目很有趣，似乎很合乎eeflying先生的口味。eeflying先生最近在营养论坛就特伦苏、方舟子问题投入了很多精力，引起了很大的争议。特此献上此文，聊表心意。姑且就算黄鼠狼给诸位拜年啦。
LOG
05-03-2009 为了让大家更好的理解这篇评论，我特地下载了作者所评论的那两个研究 ATAC实验的100月随访结果和BIG 1-98的50月随访结果（原文在楼下）。文章挺长的，不过应该还是值得学习学习的。 即看评论又看原文更能长见识。
07-03-2009 感谢TwT战友仔细读了这篇评论并写了读后感，基本上吧作者的本意都概括出来了，我这里就借用一下吧，帮助大家能更快的理解。
07-03-2009 补充资料，有关ATAC100和BIG 1-98实验中患者治疗顺应性，以及治疗毒副反应的统计。内容在相关帖子里。
____ ATAC100月随访结果
____ BIG 1-98实验50月随访结果
10-03-2009 内分泌治疗与子宫内膜癌关系：Big 1-98 ATAC SEER 数据分析
____ 单击此处直接查看
11-03-2007 大版主开通新话题：AI治疗与激素水平检测
____单击此处直接查看
TwT战友写道：
看了之后给我感觉就是：upfront使用AI国外很普遍，但是开始质疑他的地位了。“If you do not look, you do not find.”
基于ATAC和BIG198等试验，AI被ASCO推荐用于绝经后受体阳性乳腺癌术后的辅助治疗，包括序贯和初始应用两种方式；同时提出乳腺癌治疗的目的是延长生命或者改善患者生存质量，作者认为从TAM这个便宜的药物要换用昂贵的AI的，其前提条件能够达到延长生命或者改善患者生存质量，那么 upfront使用AI能够达到这些目标吗？
ATAC和BIG 198试验显示初始使用AI能够较TAM提高DFS，但是不能提高总的生存率！！！究其原因有三：DFS的定义包括局部复发和对侧乳腺癌；TAM治疗复发后有较长的生存期以及非乳腺癌原因死亡。作者列出ATAC 33m， 68m和100m随访结果，提示AI治疗组在长期随访中有较多的患者死于非乳腺癌原因，从而提出AI的长期毒副作用是否高于TAM这个问题？BTW：这个问题在药厂会议上基本上不会被提到！！！ 例外作者也列举了一些例子来说明在乳腺癌辅助治疗中，DFS并不是OS的确切的预测指标。
upfront 使用AI不提高总生存率，那么他会改善患者的生活质量吗？作者也从三方面回答这个问题：第一，AI延迟复发可以改善患者生活质量，但是用FACT-B生活质量问卷调查显示AI和TAM治疗组，其生活质量并没有差别；第二，文献报道AI治疗组治疗过程中的毒副反应较低，较少患者由于治疗的毒副反应而退组；但是作者提出，发生骨折的事件数，AI组340例，远远高于 TAM组的277例，但是这个有没有列入严重毒副反应？ 第三： Ana组因为肌肉关节症状而提前退组的只有13例，稍高于TAM组的6例；但是在临床中是真实的吗？ATAC临床试验用的是医生评判毒副反应，而不是 BIG198的患者问卷调查形式，所以毒副反应报告的频率有很大的出入，BIG198 AI有20%的肌肉关节症状，另外在临床中，TAM和AI由于各种原因（毒副反应有可能占较大比重），其依从性也较差，大约会有20~50%的患者没有完成5年的辅助治疗。
最后作者提出那AI还有没有用呢？作者列出了三种情况下AI可以使用，第一：有应用TAM禁忌症的患者，如有血栓史患者；第二：使用TAM序贯AI治疗这种方式（IES显示有生存率获益）；第三就是CYP2D6基因的多态性与TAM代谢的关系，验证这种关系会帮助我们选择部分TAM反应差的患者使用AI。
结论：只对有使用TAM的禁忌症的患者，推荐初始应用AI治疗。
Up-Front Use of Aromatase Inhibitors As Adjuvant Therapy for Breast Cancer: The Emperor Has No Clothes
Journal of Clinical Oncology, Vol 27, No 6 (February 20), 2009: pp. 840-842
In 2004, an American Society of Clinical Oncology (ASCO) technology assessment on adjuvant use of aromatase inhibitors (AIs) was updated to indicate that optimal adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer should include an AI, either as up-front therapy or as sequential therapy after tamoxifen.1 This recommendation was on the basis of improved disease-free survival (DFS) observed with AIs, given that no trial at that time had demonstrated improvement in overall survival. This recommendation and the publicity relating to trials such as the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial have had substantial impact worldwide on the endocrine treatment of early breast cancer.2 On the basis of the recent published update of the ATAC trial with a median 8 or more years of follow-up, and the report at the San Antonio Breast Cancer Meeting in December 2007, advertisements proclaim that the long-term data demonstrate continuing effectiveness for anastrozole over tamoxifen through treatment completion and beyond (for example, see the advertisement in the March 10, 2008 issue of this journal; Vol 26, No. 8).
The goals of therapy for any stage or type of cancer are to improve the duration and/or quality of survival. If we are to switch from an inexpensive and well-established treatment such as tamoxifen to a more expensive and newer alternative (an AI), then the onus of the companies and investigators supporting that switch must be to prove that the new treatment is more effective in one or both of those key end points.
The ATAC study is a large and well-designed trial that compares up-front therapy using anastrozole with that using tamoxifen for 5 years in postmenopausal women with hormone-sensitive early breast cancer. Results of the trial continue to show a significant improvement in DFS in favor of anastrozole (hazard ratio [HR] = 0.85), but they do not show improved overall survival (HR = 1.0).4 A related study, Breast International Group 1-98 (BIG 1-98), which is comparing up-front letrozole therapy with up-front tamoxifen therapy for 5 years, also shows improved DFS in favor of letrozole (HR = 0.82), but differences in overall survival are not significant after a relatively short median follow-up of 51 months (HR = 0.91).5
There are several reasons why improvement in DFS may not translate into improved overall survival for women participating in trials of adjuvant therapy for breast cancer. First, the definition of DFS varies among trials evaluating AIs,6 but these studies included local recurrence and new primary breast cancer (including preinvasive disease in the ATAC but not the BIG 1-98 trial), which have a minimal effect on overall survival. Second, an initial delay to relapse for women receiving up-front anastrozole might be balanced by longer survival after relapse for those who receive tamoxifen. Third, an improvement in cancer-specific survival might be counterbalanced by an increase in deaths as a result of other causes; indeed, there is a trend for such an effect in the ATAC trial, given that the 8-year results show a nonsignificant reduction in deaths after recurrence for the anastrozole arm counterbalanced by an increase in deaths without recurrence. Time-trends in the three publications reporting outcomes from the ATAC trial at median follow-up of 33, 68, and 100 months4,7,8 show an increasing excess in noncancer deaths for women receiving anastrozole as compared with tamoxifen, whereas the deficit in deaths after cancer recurrence for women receiving anastrozole has remained constant in the last two reports (Table 1); this raises concerns about the long-term serious toxicity of anastrozole.
There is strong evidence that DFS is a good surrogate for overall survival in trials of adjuvant therapy for colorectal cancer,9 but support for surrogacy of DFS in adjuvant trials for breast cancer is less solid.10 In some trials, an early large improvement in DFS has translated into a smaller later improvement in overall survival; however, smaller differences in DFS at short follow-up, as observed in trials comparing different endocrine therapies, may not be associated with subsequent differences in overall survival.
If overall survival is similar after adjuvant treatment with an AI or tamoxifen, up-front use of an AI might be preferred if it is better tolerated than tamoxifen and leads to better quality of life. Some would argue that quality of life will be better if there is a delay of recurrence of breast cancer, but that depends on the toxicity of treatment. The ATAC investigators have published specific analyses of quality of life and of adverse effects of treatment.11,12 They evaluated quality of life using the Functional Assessment of Cancer Treatment–Breast (FACT-B) and its endocrine subscale, and reported no overall differences between the arms of the study.11 The abstract of their article describing adverse effects indicates that treatment-related adverse effects occurred significantly less often with anastrozole than with tamoxifen, as did treatment-related serious adverse events and adverse events leading to withdrawal.12 However, these statements seem inconsistent with data provided in the article. For example, there were 340 fractures reported in patients receiving anastrozole (as compared with 237 for those receiving tamoxifen (P < .0001), yet the overall incidence of treatment-related serious adverse effects was reported as only 146 for anastrozole versus 277 for tamoxifen (P < .0001). Moreover, the only mention of arthralgias is a statement that few patients withdrew because of them (13 v six patients). This is not the experience of physicians managing patients outside of a clinical trial, where arthralgias and/or bone pain have been reported by 45% to 60% of patients, and despite use of anti-inflammatory medication, led to cessation of therapy in approximately 20% of women.13–15 In the ATAC trial (as opposed to BIG 1-98), there was no checklist of questions regarding toxicity, but there was instead a nonspecific request for physicians to report adverse events. By contrast, in the BIG 1-98 study there was such a checklist, and 20% and 13.5% of women reported arthralgias while receiving letrozole and tamoxifen, respectively (P < .01).5 As aptly stated by Coates et al16 in a comment on the most recent ATAC publication,4 "If you do not look, you do not find."
Noncompliance with treatment may occur without withdrawal from a study, and there is evidence that adherence to endocrine therapy in women with breast cancer is quite poor. In a study of women receiving adjuvant treatment, nonadherence to tamoxifen (defined as taking the drug on fewer than 80% of days for which it was prescribed) increased from 17% in the first year to 50% in the fourth year,17 and in another study, nonadherence (defined as 180 consecutive days without taking tamoxifen) increased from 22% in the first year to 35% after 3.5 years.18 In a study of 12,000 women who initiated anastrozole, similar or even worse trends for adherence to the drug were observed;19 the annual rate of nonadherence (defined as taking anastrozole on fewer than 80% of days for which it was prescribed) increased from 22% to 31% in the first year to 32% to 50% in the third year in data sets from three health programs. Emerging data indicate that the occurrence of hot flashes in women receiving adjuvant tamoxifen may be correlated with a reduced risk of breast cancer,20,21 and a similar analysis from the ATAC trial suggested that women who had hot flashes had significantly lower recurrence rates (regardless of treatment).22 Nonadherence to the drugs might be an explanation for lack of hot flashes in some women, leading to a higher chance of recurrence.
Although there is no evidence for superiority of AIs over tamoxifen when used as initial treatment, they remain useful drugs for the adjuvant therapy of breast cancer. They provide an alternative for women at high risk of toxicity from tamoxifen, such as those with a history of thromboembolic disease. Some trials have investigated switching to an AI after initial tamoxifen, and a meta-analysis of the trials suggests an advantage in overall survival from the time of switching compared with continued tamoxifen;23,24 this strategy allows shorter exposure to the specific toxicities of tamoxifen and AIs. The MA.17 trial demonstrated that extended treatment with letrozole beyond 5 years of tamoxifen decreased the rate of relapse,25 but it is not known if this strategy of prolonged treatment improves survival when compared with earlier switching.
It has been suggested that evaluation of CYP2D6 genotype might be used to select patients who are poor metabolizers of tamoxifen and unlikely to respond to it.26 Whereas genetic polymorphism of CYP2D6 has been shown to influence the metabolism of tamoxifen,27,28 results from retrospective clinical studies evaluating the effect of these polymorphisms on outcome of breast cancer in women who receive adjuvant tamoxifen are conflicting.29
In summary, recent evidence from clinical trials does not support the routine initial use of up-front AIs as adjuvant therapy. Recommendations for their use have been made on the basis of improvement in DFS despite evidence that it is an imperfect surrogate for overall survival, including evidence from serial reports of the ATAC trial (Table 1) and with no evidence of better tolerance or quality of life. Furthermore, several studies suggesting cost-benefit of up-front anastrozole compared with tamoxifen30–32 based their conclusions on the expectation that DFS would translate into improved survival, and at 8 or more years of follow-up, that has not occurred. If AIs do not improve survival when compared with tamoxifen, their added cost per life-year gained is infinite, and they are cost-ineffective. Despite the lack of supportive evidence, it is surprising how dramatically patterns of clinical practice have changed to endorse the up-front use of AIs.2 Future results from the BIG 1-98 clinical trial may or may not demonstrate benefit in overall survival for the up-front use of letrozole in comparison to tamoxifen alone or to the switching strategy, but on the basis of current data, up-front use of an AI can be recommended only in women who have contraindications to the use of tamoxifen.
LOG
05-03-2009 为了让大家更好的理解这篇评论，我特地下载了作者所评论的那两个研究 ATAC实验的100月随访结果和BIG 1-98的50月随访结果（原文在楼下）。文章挺长的，不过应该还是值得学习学习的。 即看评论又看原文更能长见识。
07-03-2009 感谢TwT战友仔细读了这篇评论并写了读后感，基本上吧作者的本意都概括出来了，我这里就借用一下吧，帮助大家能更快的理解。
07-03-2009 补充资料，有关ATAC100和BIG 1-98实验中患者治疗顺应性，以及治疗毒副反应的统计。内容在相关帖子里。
____ ATAC100月随访结果
____ BIG 1-98实验50月随访结果
10-03-2009 内分泌治疗与子宫内膜癌关系：Big 1-98 ATAC SEER 数据分析
____ 单击此处直接查看
11-03-2007 大版主开通新话题：AI治疗与激素水平检测
____单击此处直接查看
TwT战友写道：
看了之后给我感觉就是：upfront使用AI国外很普遍，但是开始质疑他的地位了。“If you do not look, you do not find.”
基于ATAC和BIG198等试验，AI被ASCO推荐用于绝经后受体阳性乳腺癌术后的辅助治疗，包括序贯和初始应用两种方式；同时提出乳腺癌治疗的目的是延长生命或者改善患者生存质量，作者认为从TAM这个便宜的药物要换用昂贵的AI的，其前提条件能够达到延长生命或者改善患者生存质量，那么 upfront使用AI能够达到这些目标吗？
ATAC和BIG 198试验显示初始使用AI能够较TAM提高DFS，但是不能提高总的生存率！！！究其原因有三：DFS的定义包括局部复发和对侧乳腺癌；TAM治疗复发后有较长的生存期以及非乳腺癌原因死亡。作者列出ATAC 33m， 68m和100m随访结果，提示AI治疗组在长期随访中有较多的患者死于非乳腺癌原因，从而提出AI的长期毒副作用是否高于TAM这个问题？BTW：这个问题在药厂会议上基本上不会被提到！！！ 例外作者也列举了一些例子来说明在乳腺癌辅助治疗中，DFS并不是OS的确切的预测指标。
upfront 使用AI不提高总生存率，那么他会改善患者的生活质量吗？作者也从三方面回答这个问题：第一，AI延迟复发可以改善患者生活质量，但是用FACT-B生活质量问卷调查显示AI和TAM治疗组，其生活质量并没有差别；第二，文献报道AI治疗组治疗过程中的毒副反应较低，较少患者由于治疗的毒副反应而退组；但是作者提出，发生骨折的事件数，AI组340例，远远高于 TAM组的277例，但是这个有没有列入严重毒副反应？ 第三： Ana组因为肌肉关节症状而提前退组的只有13例，稍高于TAM组的6例；但是在临床中是真实的吗？ATAC临床试验用的是医生评判毒副反应，而不是 BIG198的患者问卷调查形式，所以毒副反应报告的频率有很大的出入，BIG198 AI有20%的肌肉关节症状，另外在临床中，TAM和AI由于各种原因（毒副反应有可能占较大比重），其依从性也较差，大约会有20~50%的患者没有完成5年的辅助治疗。
最后作者提出那AI还有没有用呢？作者列出了三种情况下AI可以使用，第一：有应用TAM禁忌症的患者，如有血栓史患者；第二：使用TAM序贯AI治疗这种方式（IES显示有生存率获益）；第三就是CYP2D6基因的多态性与TAM代谢的关系，验证这种关系会帮助我们选择部分TAM反应差的患者使用AI。
结论：只对有使用TAM的禁忌症的患者，推荐初始应用AI治疗。
Up-Front Use of Aromatase Inhibitors As Adjuvant Therapy for Breast Cancer: The Emperor Has No Clothes
Journal of Clinical Oncology, Vol 27, No 6 (February 20), 2009: pp. 840-842
In 2004, an American Society of Clinical Oncology (ASCO) technology assessment on adjuvant use of aromatase inhibitors (AIs) was updated to indicate that optimal adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer should include an AI, either as up-front therapy or as sequential therapy after tamoxifen.1 This recommendation was on the basis of improved disease-free survival (DFS) observed with AIs, given that no trial at that time had demonstrated improvement in overall survival. This recommendation and the publicity relating to trials such as the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial have had substantial impact worldwide on the endocrine treatment of early breast cancer.2 On the basis of the recent published update of the ATAC trial with a median 8 or more years of follow-up, and the report at the San Antonio Breast Cancer Meeting in December 2007, advertisements proclaim that the long-term data demonstrate continuing effectiveness for anastrozole over tamoxifen through treatment completion and beyond (for example, see the advertisement in the March 10, 2008 issue of this journal; Vol 26, No. 8).
The goals of therapy for any stage or type of cancer are to improve the duration and/or quality of survival. If we are to switch from an inexpensive and well-established treatment such as tamoxifen to a more expensive and newer alternative (an AI), then the onus of the companies and investigators supporting that switch must be to prove that the new treatment is more effective in one or both of those key end points.
The ATAC study is a large and well-designed trial that compares up-front therapy using anastrozole with that using tamoxifen for 5 years in postmenopausal women with hormone-sensitive early breast cancer. Results of the trial continue to show a significant improvement in DFS in favor of anastrozole (hazard ratio [HR] = 0.85), but they do not show improved overall survival (HR = 1.0).4 A related study, Breast International Group 1-98 (BIG 1-98), which is comparing up-front letrozole therapy with up-front tamoxifen therapy for 5 years, also shows improved DFS in favor of letrozole (HR = 0.82), but differences in overall survival are not significant after a relatively short median follow-up of 51 months (HR = 0.91).5
There are several reasons why improvement in DFS may not translate into improved overall survival for women participating in trials of adjuvant therapy for breast cancer. First, the definition of DFS varies among trials evaluating AIs,6 but these studies included local recurrence and new primary breast cancer (including preinvasive disease in the ATAC but not the BIG 1-98 trial), which have a minimal effect on overall survival. Second, an initial delay to relapse for women receiving up-front anastrozole might be balanced by longer survival after relapse for those who receive tamoxifen. Third, an improvement in cancer-specific survival might be counterbalanced by an increase in deaths as a result of other causes; indeed, there is a trend for such an effect in the ATAC trial, given that the 8-year results show a nonsignificant reduction in deaths after recurrence for the anastrozole arm counterbalanced by an increase in deaths without recurrence. Time-trends in the three publications reporting outcomes from the ATAC trial at median follow-up of 33, 68, and 100 months4,7,8 show an increasing excess in noncancer deaths for women receiving anastrozole as compared with tamoxifen, whereas the deficit in deaths after cancer recurrence for women receiving anastrozole has remained constant in the last two reports (Table 1); this raises concerns about the long-term serious toxicity of anastrozole.
There is strong evidence that DFS is a good surrogate for overall survival in trials of adjuvant therapy for colorectal cancer,9 but support for surrogacy of DFS in adjuvant trials for breast cancer is less solid.10 In some trials, an early large improvement in DFS has translated into a smaller later improvement in overall survival; however, smaller differences in DFS at short follow-up, as observed in trials comparing different endocrine therapies, may not be associated with subsequent differences in overall survival.
If overall survival is similar after adjuvant treatment with an AI or tamoxifen, up-front use of an AI might be preferred if it is better tolerated than tamoxifen and leads to better quality of life. Some would argue that quality of life will be better if there is a delay of recurrence of breast cancer, but that depends on the toxicity of treatment. The ATAC investigators have published specific analyses of quality of life and of adverse effects of treatment.11,12 They evaluated quality of life using the Functional Assessment of Cancer Treatment–Breast (FACT-B) and its endocrine subscale, and reported no overall differences between the arms of the study.11 The abstract of their article describing adverse effects indicates that treatment-related adverse effects occurred significantly less often with anastrozole than with tamoxifen, as did treatment-related serious adverse events and adverse events leading to withdrawal.12 However, these statements seem inconsistent with data provided in the article. For example, there were 340 fractures reported in patients receiving anastrozole (as compared with 237 for those receiving tamoxifen (P < .0001), yet the overall incidence of treatment-related serious adverse effects was reported as only 146 for anastrozole versus 277 for tamoxifen (P < .0001). Moreover, the only mention of arthralgias is a statement that few patients withdrew because of them (13 v six patients). This is not the experience of physicians managing patients outside of a clinical trial, where arthralgias and/or bone pain have been reported by 45% to 60% of patients, and despite use of anti-inflammatory medication, led to cessation of therapy in approximately 20% of women.13–15 In the ATAC trial (as opposed to BIG 1-98), there was no checklist of questions regarding toxicity, but there was instead a nonspecific request for physicians to report adverse events. By contrast, in the BIG 1-98 study there was such a checklist, and 20% and 13.5% of women reported arthralgias while receiving letrozole and tamoxifen, respectively (P < .01).5 As aptly stated by Coates et al16 in a comment on the most recent ATAC publication,4 "If you do not look, you do not find."
Noncompliance with treatment may occur without withdrawal from a study, and there is evidence that adherence to endocrine therapy in women with breast cancer is quite poor. In a study of women receiving adjuvant treatment, nonadherence to tamoxifen (defined as taking the drug on fewer than 80% of days for which it was prescribed) increased from 17% in the first year to 50% in the fourth year,17 and in another study, nonadherence (defined as 180 consecutive days without taking tamoxifen) increased from 22% in the first year to 35% after 3.5 years.18 In a study of 12,000 women who initiated anastrozole, similar or even worse trends for adherence to the drug were observed;19 the annual rate of nonadherence (defined as taking anastrozole on fewer than 80% of days for which it was prescribed) increased from 22% to 31% in the first year to 32% to 50% in the third year in data sets from three health programs. Emerging data indicate that the occurrence of hot flashes in women receiving adjuvant tamoxifen may be correlated with a reduced risk of breast cancer,20,21 and a similar analysis from the ATAC trial suggested that women who had hot flashes had significantly lower recurrence rates (regardless of treatment).22 Nonadherence to the drugs might be an explanation for lack of hot flashes in some women, leading to a higher chance of recurrence.
Although there is no evidence for superiority of AIs over tamoxifen when used as initial treatment, they remain useful drugs for the adjuvant therapy of breast cancer. They provide an alternative for women at high risk of toxicity from tamoxifen, such as those with a history of thromboembolic disease. Some trials have investigated switching to an AI after initial tamoxifen, and a meta-analysis of the trials suggests an advantage in overall survival from the time of switching compared with continued tamoxifen;23,24 this strategy allows shorter exposure to the specific toxicities of tamoxifen and AIs. The MA.17 trial demonstrated that extended treatment with letrozole beyond 5 years of tamoxifen decreased the rate of relapse,25 but it is not known if this strategy of prolonged treatment improves survival when compared with earlier switching.
It has been suggested that evaluation of CYP2D6 genotype might be used to select patients who are poor metabolizers of tamoxifen and unlikely to respond to it.26 Whereas genetic polymorphism of CYP2D6 has been shown to influence the metabolism of tamoxifen,27,28 results from retrospective clinical studies evaluating the effect of these polymorphisms on outcome of breast cancer in women who receive adjuvant tamoxifen are conflicting.29
In summary, recent evidence from clinical trials does not support the routine initial use of up-front AIs as adjuvant therapy. Recommendations for their use have been made on the basis of improvement in DFS despite evidence that it is an imperfect surrogate for overall survival, including evidence from serial reports of the ATAC trial (Table 1) and with no evidence of better tolerance or quality of life. Furthermore, several studies suggesting cost-benefit of up-front anastrozole compared with tamoxifen30–32 based their conclusions on the expectation that DFS would translate into improved survival, and at 8 or more years of follow-up, that has not occurred. If AIs do not improve survival when compared with tamoxifen, their added cost per life-year gained is infinite, and they are cost-ineffective. Despite the lack of supportive evidence, it is surprising how dramatically patterns of clinical practice have changed to endorse the up-front use of AIs.2 Future results from the BIG 1-98 clinical trial may or may not demonstrate benefit in overall survival for the up-front use of letrozole in comparison to tamoxifen alone or to the switching strategy, but on the basis of current data, up-front use of an AI can be recommended only in women who have contraindications to the use of tamoxifen.
