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Adjuvant Endocrine Therapy in Postmenopausal Breast Cancer¹

Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905

	ABSTRACT

Top ABSTRACT Introduction Tamoxifen in the Adjuvant... AIs in the Adjuvant... Interpretation of the ATAC... Major Ongoing Adjuvant Trials... Conclusions Open Discussion REFERENCES

 
Adjuvant endocrine therapy with tamoxifen has a clearly established benefit in postmenopausal women with resected early breast cancer that expresses the estrogen receptor and/or progesterone receptor. Whereas there is a vast and long experience with tamoxifen, the major focus of clinical trials over the past 6 years has involved the study of the third-generation aromatase inhibitors. Recently published data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, which involved only postmenopausal women and is the largest adjuvant trial ever conducted, has demonstrated superior efficacy for anastrozole over tamoxifen alone or in combination with anastrozole. These data have engendered a great deal of discussion as to whether they provide a sufficient basis for changing the standard of practice in terms of choice of agent. Currently, a case can be made that further maturation of the ATAC trial is necessary and that tamoxifen should remain the standard of endocrine adjuvant therapy for most women, with anastrozole being used in those with a contraindication or intolerance to tamoxifen. However, close attention must be paid to new information as it develops not only related to efficacy but also to other end organ effects.

	Introduction

Top ABSTRACT Introduction Tamoxifen in the Adjuvant... AIs in the Adjuvant... Interpretation of the ATAC... Major Ongoing Adjuvant Trials... Conclusions Open Discussion REFERENCES

 
Two position statements have recently been published addressing endocrine therapy of postmenopausal women with resected early-stage invasive breast cancer. In November 2000, the NIH convened a Consensus Conference on Adjuvant Therapy of Breast Cancer (1) and concluded that adjuvant hormonal therapy should be recommended to women irrespective of age, menopausal status, axillary nodal status, and tumor size so long as the tumor was hormone receptor (i.e., ER³ or PgR) positive. The possible exception to this recommendation in postmenopausal women was one in which the tumor was small, i.e., less than 10 mm, and there was a history of venous thromboembolism. It was specifically noted that at that time, convincing data were available for the efficacy of tamoxifen, and there were no data to support the use of raloxifene or AIs. The second major position statement came from the Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer held in February 2001 in St. Gallen, Switzerland (2) . Considering endocrine-responsive tumors, defined as those with expression of ER and/or PgR, tamoxifen was judged to be indicated in all women regardless of menopausal status or presence or absence of nodal metastasis, with the qualification that tamoxifen versus no therapy was a consideration in those women in the minimal/low-risk category. This category was defined as those women who were at least 35 years of age and whose tumor was ER and/or PgR positive with negative axillary nodes, an invasive tumor size of 2 cm or less, and a histological and/or nuclear grade of 1. It was recognized that data were emerging with respect to the use of AIs in the adjuvant setting, but at that time, their use was not indicated outside of a clinical trial. It was also concluded that, given the available data, the use of SERMs other than tamoxifen was not justified.

Tamoxifen was considered the endocrine agent of choice when this topic was reviewed 1 year ago at this conference (3) . Since that time, substantial data have appeared that make the reassessment of adjuvant endocrine therapy not only possible but mandatory. This review will examine the impact on the management paradigm in postmenopausal women of new data relating to the use of AIs that have come from the ATAC trial and the status of other clinical trials addressing the use of AIs in the postmenopausal adjuvant setting.

	Tamoxifen in the Adjuvant Setting

Top ABSTRACT Introduction Tamoxifen in the Adjuvant... AIs in the Adjuvant... Interpretation of the ATAC... Major Ongoing Adjuvant Trials... Conclusions Open Discussion REFERENCES

 
Tamoxifen has been the endocrine agent of choice for adjuvant hormonal therapy for breast cancer in postmenopausal women since United States Food and Drug Administration approval in 1986 for those with resected node-positive disease and in 1990 for those with resected node-negative disease (3) . Numerous trials have examined duration of tamoxifen therapy; considering trials of 1, 2, and 5 years of tamoxifen, the Oxford Overview found a highly significant trend toward greater benefit with the longer duration of therapy (4) . The National Surgical Adjuvant Breast and Bowel Project B14 trial evaluated 5 versus 10 years of tamoxifen in women with ER-positive node-negative breast cancer and found an advantage that achieved significance in DFS (P = 0.03) and approached significance in overall survival (P = 0.07) for those who received tamoxifen for 5 years (5) . Although two trials are currently addressing the duration issue, ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTom (adjuvant Tamoxifen Treatment, offer more?), 5 years of tamoxifen is presently established as the recommended duration of adjuvant therapy.

Oxford Overview data (4) have revealed important information relating to the use of tamoxifen in the postmenopausal adjuvant setting. In particular, the value of the ER as a predictive factor has been demonstrated, in that its absence in a patient’s tumor indicates the lack of potential benefit from the use of tamoxifen. There was no evidence of benefit in about 8,000 women with low or no ER in their primary tumor. Excluding patients whose tumors lacked the ER, 5 years of tamoxifen produced highly significant reductions in recurrence and death over about 10 years of follow-up in women at least 50 years of age. Considering the age groups of 50–59, 60–69, and 70+ years, the proportional risk reductions for recurrence were 37% (SD = 6%), 54% (SD = 5%), and 54% (SD = 13%), respectively. For death, these corresponding reductions in risk were 11% (SD = 8%), 33% (SD = 6%), and 34% (SD = 13%), respectively. The reductions were similar irrespective of the presence or absence of chemotherapy. This substantial level of benefit remains with an additional 5 years of follow-up in the 2000 Overview, which is as yet unpublished.⁴ It is important to note that the levels of benefit with tamoxifen are greater than those with chemotherapy in women 50 years of age or greater. Considering women aged 50–69, the proportional risk reduction for recurrence with chemotherapy was only 20% (SD = 3%), and the reduction in risk of death was 11% (SD = 3%) (6) . It is clear that the potential benefit from adjuvant tamoxifen exceeds that for chemotherapy in the postmenopausal patient.

Chemotherapy is commonly used with tamoxifen. Recent data have addressed the question of concomitant versus sequential chemotherapy and tamoxifen. Albain et al. (7) addressed this question in 1116 postmenopausal women with hormone receptor-positive and node-positive breast cancer and found there was an absolute 5% improvement in 8-year DFS (from 62% to 67%), with a one-sided P of 0.045 after adjustment for stratification factors, for patients in whom the tamoxifen was administered sequentially rather than concurrently. Delaying tamoxifen until completion of chemotherapy, which in this case was cyclophosphamide, Adriamycin, and 5-fluoruracil, resulted in an estimated 18% improvement in DFS. These data provide a reasonable basis for choosing the sequential approach when using chemotherapy and hormonal therapy as adjuvant treatment in postmenopausal women.

Numerous SERMs other than tamoxifen have been evaluated in breast cancer in the metastatic setting (8) , but to date, none have shown an advantage over tamoxifen. Preliminary data from a randomized trial of tamoxifen and toremifene, each given for 3 years, in the adjuvant setting in postmenopausal women with positive nodes have been published (9) . This report, which involved the first 899 patients of the 1480 patients entered, demonstrated no significant differences in time to recurrence, overall survival, and tolerability between the two agents. Thus, at present, there is no basis to consider a newer-generation SERM as preferable to tamoxifen in the adjuvant setting.

The foregoing demonstrate the vast amount of experience and evidence relating to the use of tamoxifen in the adjuvant setting. Tamoxifen has set a high standard against which new endocrine agents must be tested in postmenopausal women.

	AIs in the Adjuvant Setting

Top ABSTRACT Introduction Tamoxifen in the Adjuvant... AIs in the Adjuvant... Interpretation of the ATAC... Major Ongoing Adjuvant Trials... Conclusions Open Discussion REFERENCES

 
Trials Involving AG.
Before the ATAC trial reports (see below), very few data were available evaluating AIs in the adjuvant setting in early breast cancer. Jones et al. (10) reported a randomized double-blind placebo-controlled trial evaluating AG (250 mg 4 times a day) plus hydrocortisone (20 mg daily) for 2 years involving 336 assessable postmenopausal patients with resected node-positive breast cancer, 43% of whom did not have receptor data available. In a log-rank analysis, there was no benefit for the administration of AG in terms of event-free survival (P = 0.41) or overall survival (P = 0.98). Inspection of the event-free survival curves reveals an early separation in favor of AG in the first several years, and a log-rank test reveals a P of 0.005 up to approximately 4 years, but the curves subsequently come together. Examination of the log ratio of hazard rates for event-free survival significantly favor AG during the first 2 years, nonsignificantly favor AG from years 2–4, and then favor the placebo group after year 4. This raises the question of duration of therapy that may be necessary with an AI and whether there is a "carry-over" effect with this class of agents as seen with tamoxifen, in which benefit persists once the agent is stopped.

Boccardo et al. (11) presented early results of a trial in which patients who had received about 3 years of tamoxifen were then randomized to either an additional 2 years of tamoxifen or AG. In 380 patients randomized from 1992 to 1998, there was no difference (P = 0.8) in event-free survival, but overall survival was significantly better (P = 0.005) for the tamoxifen followed by AG arm. The tamoxifen plus AG arm had more patients relapsing with local disease and fewer relapsing with visceral disease than the tamoxifen-alone arm.

Trials Involving Third-Generation AIs.
The third-generation AIs, anastrozole, exemestane, and letrozole, currently represent the major hope for improving the effectiveness of adjuvant hormonal therapy in postmenopausal women, and their study represents a major global research effort. At present, clinical trials are evaluating the use of AIs in sequence with tamoxifen, instead of tamoxifen, and in combination with tamoxifen (12 , 13) .

The first major report of a trial evaluating the third-generation AIs was presented at the San Antonio Breast Cancer Symposium in December 2001 (14) and was published recently (15) . The ATAC trial involved 9366 postmenopausal women randomized with tamoxifen alone, anastrozole alone, or the combination. The study was double-blind, and treatment length is planned for 5 years, but the median follow-up for this dataset was 33.3 months. The primary end point is DFS, which is defined as the time to local or distant recurrence, new primary breast cancer, or death. Anastrozole was superior to tamoxifen with a hazard ratio of 0.83 (95% CI, 0.71–0.96; P = 0.013). The relative reduction in event rate was 17%, with an absolute reduction of 2% at 3 years. The combination arm was nearly identical to the tamoxifen arm. The finding of a lack of benefit of combining an AI with tamoxifen seen in the ATAC trial is consistent with clinical studies using AG in the metastatic setting (16) and third-generation AIs in preclinical studies (17) . Because ATAC is the only trial addressing the issue of combining an AI and tamoxifen in the adjuvant setting, no additional information is anticipated on this issue.

Considering the receptor-positive population in the ATAC trial, the DFS was again superior for anastrozole with the hazard ratio (anastrozole versus tamoxifen) reaching 0.78 (95.2% CI, 0.65–0.93; P = 0.005). Analyses of time to recurrence were performed comparing anastrozole and tamoxifen in various subgroups, and a beneficial effect of anastrozole over tamoxifen was not seen in the hormone receptor-negative patients, as might be expected, and in the approximately 20% of patients who had received prior chemotherapy. The authors concluded that further follow-up is necessary before any conclusion regarding the relative efficacy of anastrozole and tamoxifen in patients who receive adjuvant chemotherapy.

Considering new contralateral breast primaries, there was a 58% reduction for anastrozole relative to tamoxifen (odds ratio, 0.42; 95% CI, 0.22–0.79; P = 0.007). Of particular note is that the contralateral breast cancers reduced by anastrozole were invasive cancers (9 invasive cancers on the anastrozole arm and 30 invasive cancers on the tamoxifen arm), whereas the numbers of noninvasive cancers were similar (5 and 3 noninvasive cancers, respectively).

The toxicity profiles of anastrozole and tamoxifen differed. Anastrozole, relative to tamoxifen alone, was associated with a significantly lower incidence of endometrial cancer, vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flushes, whereas tamoxifen was associated with significantly fewer episodes of musculoskeletal disorders and fractures. No significant differences were seen between anastrozole and tamoxifen in terms of cataracts, ischemic cardiovascular disease, fatigue/tiredness, mood disturbances, nausea, and vomiting. The study withdrawal rates due to drug-related events were 5.1% for anastrozole and 7.2% for tamoxifen. Prof. Michael Baum, principal investigator for the main ATAC trial, noted in a presentation of these results in May 2002 at the ASCO annual meeting that survival information should be available in about 18 months.

	Interpretation of the ATAC Results

Top ABSTRACT Introduction Tamoxifen in the Adjuvant... AIs in the Adjuvant... Interpretation of the ATAC... Major Ongoing Adjuvant Trials... Conclusions Open Discussion REFERENCES

 
The results of the ATAC trial have engendered substantial discussion regarding whether these findings should change clinical practice such that anastrozole replaces tamoxifen as the endocrine treatment of choice in postmenopausal women. Acknowledging the importance of these findings and the potentially enormous implications, the leadership of ASCO impaneled an AIs Expert Panel in January 2002, and the panel’s recommendations have been published (18) . Based on the available data, the panel concluded that the results of the ATAC trial were very promising but not sufficient to change the standard of practice given the extensive and long-term data for tamoxifen. The panel did conclude that it was reasonable to use an AI in women with a relative or absolute contraindication to tamoxifen. Thus, an AI would be a reasonable consideration in a woman with a history of a thrombotic event or cerebrovascular disease because the incidence of these events was lower for women treated with anastrozole in the ATAC trial. There are women who are intolerant of tamoxifen for whom an AI should be considered. If an AI is to be used, the ASCO panel considered anastrozole to be the preferred agent because it is the only one for which data are available in the adjuvant setting. The panel clearly recommended that physicians discuss the available information with their patients and that they will need to come to their own conclusions.

On September 5, 2002, the United States Food and Drug Administration granted accelerated approval to anastrozole (Arimidex; AstraZeneca) for adjuvant therapy in postmenopausal women with hormone receptor-positive early breast cancer. In this author’s view, this approval was expected and appropriate, and although it does not change the validity of the ASCO panel’s position, it does increase the adjuvant endocrine options for postmenopausal women.

There are many issues that remain to be resolved with the AIs. In particular, the optimal duration of therapy needs to be determined. Further information is needed in the patient who develops chemotherapy-related amenorrhea, particularly in light of data indicating that premenopausal serum estradiol levels may persist in this setting (19) . Additional important issues concern the effects of long-term AI therapy on bone, lipids, urogenital function, vasomotor symptoms, cognition, and other quality of life parameters.

Data are emerging with respect to some of the important endpoints noted above. A quality of life subprotocol was conducted over a 24-month period involving 1105 of the patients entered on the ATAC trial (20) . Overall, the quality of life as determined by the Total Outcome Index from the FACT-B questionnaire plus an endocrine subscale questionnaire was similar for anastrozole and tamoxifen alone as well as the combination, and all three groups showed some improvement over the 24-month period of the study. No statistically significant difference was identified between tamoxifen and anastrozole in the total endocrine symptoms score. However, some advantage was identified for anastrozole in terms of vaginal discharge and sweating and for tamoxifen in terms of vaginal dryness and sexually related symptoms. Of importance in this study was the finding that there was substantial under-reporting by patients to physicians of certain symptoms, particularly sexual-related symptoms, compared with those identified in the questionnaires.

An endometrial subprotocol from the ATAC trial was performed in 279 patients and consisted of transvaginal ultrasound and hysteroscopy at 12 and 24 months (21) . This study revealed that tamoxifen (alone or in combination with anastrozole) was associated with a greater increase in endometrial thickness and higher incidence of endometrial abnormalities than anastrozole alone. A bone subprotocol is also being conducted as a part of the ATAC trial, and results should be forthcoming in the latter part of 2002.

	Major Ongoing Adjuvant Trials in Postmenopausal Women Involving AIs

Top ABSTRACT Introduction Tamoxifen in the Adjuvant... AIs in the Adjuvant... Interpretation of the ATAC... Major Ongoing Adjuvant Trials... Conclusions Open Discussion REFERENCES

 
In addition to ATAC, there are ongoing clinical trials that address the value of all three third-generation AIs in the adjuvant setting (Fig. 1) . Most of the trials involve a comparison of 5 years of tamoxifen with 5 years of an AI or 5 years of a sequence of tamoxifen and an AI. Two trials are evaluating an AI, using a placebo control, after 5 years of tamoxifen.

View larger version (41K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Designs of adjuvant therapy trials involving third-generation aromatase inhibitors.

Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial.
The study is evaluating exemestane for 5 years versus tamoxifen for 5 years. This consists of multiple substudies that will be combined in a meta-analysis. The study opened in 2001. Accrual is ongoing.

International Cancer Collaboration Group (ICCG) Study 96.
The study is evaluating tamoxifen for 2–3 years followed by exemestane for 2–3 years (for a total of 5 years) versus tamoxifen for 5 years. The study opened 1998. Accrual is complete.

German Adjuvant Breast Cancer Group (GABG) Study IV-C/ARNO Trial.
The study involves a randomization to tamoxifen for 3 years, or anastrozole for 3 years following 2 years of tamoxifen. The study opened in 1996. Accrual is ongoing.

Austrian Breast Cancer Study Group, Study 8.
The study involves a randomization to tamoxifen for 3 years or anastrozole for 3 years following 2 years of tamoxifen. The study opened in 1996. Accrual is ongoing.

(J)MA.17.
The study involves a randomization to letrozole for 5 years versus placebo for 5 years following 5 years of tamoxifen. The study opened in 1998, and the accrual goal was achieved in May 2002. The study has been extended to complete accrual on bone subprotocol.

National Surgical Adjuvant Breast and Bowel Project B33.
The study involves a randomization to exemestane for 3 years versus placebo for 3 years following 5 years of tamoxifen. The study opened in 2001. Accrual is ongoing.

As can be seen, there are multiple trials that are addressing the value of AIs in postmenopausal women with breast cancer. Unfortunately, it appears that it will be at least 2004 before data will be forthcoming on any trial other than ATAC.

	Conclusions

Top ABSTRACT Introduction Tamoxifen in the Adjuvant... AIs in the Adjuvant... Interpretation of the ATAC... Major Ongoing Adjuvant Trials... Conclusions Open Discussion REFERENCES

 
It is considered highly likely that, ultimately, the third-generation AIs will replace tamoxifen in the adjuvant setting in postmenopausal patients. Although premenopausal women are not the subject of this review, it is important to emphasize that the third-generation AIs have not been adequately studied in this subset of patients and that the discussions relate only to postmenopausal women. Given the large number of randomized trials conducted with the AIs in the adjuvant setting, this will be a subject followed closely in the future, but it appears that the field will be dominated by the ATAC study data at least for the next several years. It is anticipated that there will be ongoing discussions of the implications of current and developing data as they relate to practice and directions for research. In particular, there will be an increased consideration of women’s health issues and the impact of therapy on them in addition to risk of developing breast cancer recurrence.

	Open Discussion

Top ABSTRACT Introduction Tamoxifen in the Adjuvant... AIs in the Adjuvant... Interpretation of the ATAC... Major Ongoing Adjuvant Trials... Conclusions Open Discussion REFERENCES

 
Dr. Stephen Johnston: Do you think the ASCO guidelines that are coming out soon are going to change clinical practice?

Dr. James Ingle: I think the guidelines will be valuable if people read them. I’ve seen premenopausal women put on AIs.

Dr. Steven Come: In regard to the ASCO taskforce’s guidelines, the recommendation it made is the responsible recommendation. The data are early. We should be cautious. But since AIs have always been as good or better than tamoxifen in every other setting or model, I wondered how readily the taskforce came to consensus on this issue.

Dr. Eric Winer: We came to consensus very quickly. I don’t think that any of us would say that it’s unethical to give a woman an AI in the adjuvant setting. I think the finding that really pushed us was the fact that the absolute difference in terms of distant recurrence is 0.8%. The difference is very small. There’s no difference in overall survival. We do know that a 5-year course of tamoxifen is required to see the full benefits, and the situation may or may not be the same with an AI. I think the panel was quite concerned about the possibility of late toxicities and felt that we should have a little more data before there was widespread use.

Dr. Kathleen Pritchard: AIs are being used long term in women who are fairly well, some of whom are going to be at quite low risk of suffering a recurrence, and I think bone health and other quality of life issues are going to be the determining factors. In this initial flush of enthusiasm, you see a result—it’s better—then I think you have to see all of the data. The other thing that’s worrying me is this issue of previous chemotherapy. In this setting, how many of our patients, yours and mine, are on adjuvant chemotherapy as well?

Dr. Aman Buzdar: There are differences in the types of chemotherapy administered to these patients between the three arms of the ATAC study. Here we are talking 1% or 2% differences, and we know from the overview of the chemotherapy data that it’s not like giving somebody tamoxifen, where either it works or it doesn’t work. There are differences in the efficacy of the chemotherapy. So I think at this point we can’t say that there are interactions with chemotherapy. It may be variations in the chemotherapy that we need to adjust for, and we need more events to see what happens.

Dr. Kent Osborne: While the data with tamoxifen suggest it may not be so hot to give it with CAF (cyclophosphamide, Adriamycin, and 5-fluoruracil), we don’t know that for the AIs. There are certain apoptosis genes that would be down-regulated with an AI that are up-regulated with tamoxifen, so you could make a hypothesis that the combination could be worse or it could be better. You can’t assume that simultaneous treatment is going to be bad as it seems to be with tamoxifen.

Dr. Mitch Dowsett: I have a couple of points about the ATAC study. We tend to focus now on the agonist effects of tamoxifen. I think we will forevermore. That was clearly an important experiment in terms of the combination arm, which seems to have answered that issue once and for all. What was remarkable was when you go through the various different end points, and there were many end points in terms of adverse events predefined and nonpredefined, there was not one end point that was statistically significantly different between the tamoxifen and the combination arm.

Dr. Osborne: They were identical. It was like there were two arms of tamoxifen. Some people didn’t want to have that combination arm because they predicted this was what was going to happen. It is probably a good thing that it was done because it absolutely nails down the fact that tamoxifen is an agonist at a low level in some patients.

Dr. Dowsett: Do you think it’s too much to actually say that tamoxifen may be worth about 3 pmol/liter estradiol? That’s essentially the level we get with AG, AG plus tamoxifen is equivalent to AG, which is equivalent to tamoxifen. You’re at that threshold level. It’s going to vary a great deal between patients because of differences in levels of AIB1 and other ER coregulators. But overall, that seems to be the level. Then I think you can begin to hypothesize that you might get more effect with tamoxifen plus Zoladex than Zoladex alone, because you’re still working in an estrogen environment at 25 pmol/liter.

Dr. Buzdar: There is a study I happened to review for a journal in which a fairly large number of patients were given AG with or without tamoxifen, and in that study the results are exactly the same as what you see in the ATAC study; the combination arm had no benefit over tamoxifen. It’s a much larger study with fairly long follow-up.

Dr. Osborne: Are there any data on whether other normal tissues have aromatase and rely on it for physiological processes?

Dr. Buzdar: There was a whole issue of the Journal of Steroid Biochemistry and Molecular Biology that was dedicated to looking at the aromatase activity in different sites.

Dr. Winer: On the ASCO panel, the four patient advocates were even more insistent than the doctors about maintaining tamoxifen as the standard at the moment. The guidelines may help reassure some patients and prevent them from demanding AIs from doctors who otherwise would be on the fence. I tell patients that I think it’s pretty likely that AIs will have a role in the adjuvant setting in the not-distant future, but my hunch and the ATAC data are not enough, in my mind, to lead to a change in practice. We just need a little more time and some additional follow-up data.

Dr. Osborne: There are some potential serious differences in toxicity that we just don’t know about in AIs. We’re thinking about long-term toxicity with an endocrine therapy compared to a chemotherapy. That’s what worries me. With AI as adjuvant therapy, there’s no estrogen in the brain for 5 years.

	FOOTNOTES

 
¹ Presented at the Second International Conference on Recent Advances and Future Directions in Endocrine Manipulation of Breast Cancer, June 28–29, 2002, Cambridge, MA.

² To whom correspondence should be addressed, at Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: (507) 284-2511; Fax: (507) 284-1803; E-mail: ingle.james{at}mayo.edu

³ The abbreviations used are: ER, estrogen receptor; PgR, progesterone receptor; AI, aromatase inhibitor; ATAC, Arimidex, Tamoxifen, Alone or in Combination; SERM, selective estrogen receptor modulator; AG, aminoglutethimide; DFS, disease-free survival; CI, confidence interval; ASCO, American Society of Clinical Oncology.

⁴ Early Breast Cancer Trialists’ Collaborative Group, 2000 Oxford Overview, unpublished observations.

	REFERENCES

Top ABSTRACT Introduction Tamoxifen in the Adjuvant... AIs in the Adjuvant... Interpretation of the ATAC... Major Ongoing Adjuvant Trials... Conclusions Open Discussion REFERENCES

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ingle, J. N. Search for Related Content PubMed PubMed Citation Articles by Ingle, J. N.