Dr. Eneman and colleagues providea thorough and timely reviewof adjuvant endocrinetherapy for hormone-receptor–positiveearly breast cancer. This field is rapidlyshifting, with the accumulation of recentlypresented and published datafrom randomized trials in both pre- andpostmenopausal patients. As with mostnew clinical research data, findingsfrom these recent trials raise as manyquestions as they provide conclusions.A few of the issues discussed in thiswell-written review deserve comment.
Dr. Eneman and colleagues provide a thorough and timely review of adjuvant endocrine therapy for hormone-receptor-positive early breast cancer. This field is rapidly shifting, with the accumulation of recently presented and published data from randomized trials in both pre- and postmenopausal patients. As with most new clinical research data, findings from these recent trials raise as many questions as they provide conclusions. A few of the issues discussed in this well-written review deserve comment. Tamoxifen for 5 years remains a reasonable standard of care for both pre- and postmenopausal patients, with a 47% reduction in the annual rates of recurrence and a 26% reduction in the annual rates of death. The risk of contralateral breast cancer is also reduced by 47%. The risk of recurrence of breast cancer continues for many years after the completion of tamoxifen therapy. However, 10 years of tamoxifen is not superior to 5 years, and was actually inferior in terms of disease-free survival in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial. As of November 2004, no other adjuvant endocrine strategy has proven superior to tamoxifen in terms of overall survival, although the possibility of improved outcome has been strongly suggested by recent data. Adjuvant Endocrine Therapy for Premenopausal Patients
As indicated in this review, ovarian ablation with a luteinizing hormonereleasing hormone (LHRH) agonist alone for 2 to 3 years yields equivalent disease-free and overall survival rates, when compared to CMF chemotherapy (cyclophosphamide [Cytoxan, Neosar], methotrexate, fluorouracil [5-FU]) alone and is an option for lowrisk patients. The Austrian Breast and Colorectal Cancer Group Trial 5 compared ovarian ablation plus tamoxifen to CMF and demonstrated, for the hormonal treatment an improved diseasefree survival but not overall survival.[ 3] For many hormone receptor- positive premenopausal patients, however, there is enough risk of recurrence to advocate both chemotherapy and endocrine therapy in the adjuvant setting. There are no convincing data in this setting as to whether ovarian ablation adds to chemotherapy or, more importantly, adds benefit to chemotherapy followed by tamoxifen. The Intergroup trial INT0101 compared CAF (cyclophosphamide, doxorubicin [Adriamycin], 5-FU) for six cycles vs CAF plus the LHRH agonist goserelin (Zoladex) vs CAF plus goserelin and tamoxifen in patients who were premenopausal before the start of chemotherapy. Unfortunately, this study did not have a CAFplus- tamoxifen arm due to the lack of clear data supporting tamoxifen in premenopausal patients at the inception of the trial. The 5-year disease-free survival rates were 67% for CAF, 70% for CAF/goserelin, and 77% for CAF/ goserelin/tamoxifen. The study showed a statistically significant disease- free survival advantage for the addition of tamoxifen to CAF/ goserelin, but no clear advantage for the addition of goserelin to CAF. The 5-year overall survival rates were 77%, 78%, and 80%, respectively. An exploratory subset analysis suggested that patients less than 40 years old at trial entry may have benefited from the addition of goserelin to CAF. This is the group most likely to retain ovarian function after chemotherapy. Patients who retain or regain menstrual function after chemotherapy thus remain a challenging group to advise as to optimal endocrine therapy, as no trials are available to tell us whether ovarian function suppression adds to the benefits of tamoxifen. Based on the available adjuvant data- and given the survival advantage seen in the metastatic setting for ovarian suppression plus tamoxifen vs tamoxifen alone -it is imperative that these questions be answered. Every effort should be made to support the ongoing international Suppression of Ovarian Function Trial (SOFT). This trial randomizes patients who retain or regain ovarian function within 6 months of completion of adjuvant chemotherapy, or premenopausal women who don't receive chemotherapy, to either 5 years of tamoxifen alone, 5 years of tamoxifen and ovarian suppression, or 5 years of exemestane (Aromasin) plus ovarian suppression. Certainly, for some patients and physicians, the Tamoxifen and Exemestane Trial (TEXT) and Premenopausal Endocrine Responsive Chemotherapy Trial (PERCHE), as outlined in this review, may be considered as well. Adjuvant Endocrine Therapy for Postmenopausal Patients
The authors provide a fine review of recent trial data regarding the use of aromatase inhibitors for postmenopausal patients. Based on the study by Goss et al, it is appropriate to consider letrozole (Femara) after completion of 5 years of tamoxifen. Studies by Boccardo et al and Coombs et al are also persuasive regarding the use of either anastrozole or exemestane after 2 to 3 years of tamoxifen. A discussion based on risk (primarily bone density issues), cost, and benefit is important for every patient. It may be that the improvement in the incidence of second primary cancers is important enough to some women to make a change in therapy, even if they are at low risk of recurrence of their primary tumor. Another important question concerns whether data from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial are strong enough, when placed in context of the above data, to support anastrozole as initial therapy instead of tamoxifen or, more importantly, instead of tamoxifen followed by an aromatase inhibitor. This issue may be clarified with the upcoming results of the Breast International Group trial (BIG 1-98), which is investigating four strategies: tamoxifen for 5 years, letrozole for 5 years, tamoxifen for 2 years followed by letrozole for 3 years, or the reverse sequence. The optimal duration of aromatase inhibitor therapy is also yet to be determined. Should aromatase inhibitor therapy be given to complete a 5-year period of hormonal therapy (including tamoxifen treatment duration), as in the exemestane and anastrozole "switching" trials? Should it be given for 5 years as in the ATAC and letrozole trials? Or is a longer period beneficial? Hopefully, these questions will be answered by emerging data and subsequent clinical trials, such as the extension trial for patients completing 5 years of letrozole on the MA.17 trial. These patients will be randomized to receive another 5 years of letrozole or placebo. An intriguing analysis of the ATAC data, presented at the 2003 San Antonio Breast Cancer Symposium, deserves mention. This retrospective subset analysis looked at the results of the trial by hormone-receptor status. The hazard ratio for disease-free survival in the 5,704 estrogen-receptor (ER)- and progesterone-receptor (PR)-positive patients was 0.82, with a nonsignificant P value of .091. For the 1,370 ER-positive but PR-negative patients, the hazard ratio for disease-free survival was 0.48 in favor of anastrozole (P < .001). Although this was not a prospectively defined subset analysis, the robust numbers and magnitude of the effect suggested is difficult to ignore. It may be that patients who are PR-negative are more likely to be HER2-positive, and this subset of patients may also do better with an aromatase inhibitor compared to tamoxifen, as is discussed in the review. Patients With Amenorrhea After Chemotherapy or Therapeutic Oophorectomy
The utility of aromatase inhibitor therapy has not been well clarified in women who are premenopausal at the time of their breast cancer diagnosis. Although the definitions of "postmenopausal" in the aromatase inhibitor trials described above are varied, most of the participating women were postmenopausal at the time of their breast cancer diagnosis. Two specific situations arise whereby aromatase inhibitors might be considered in women who were premenopausal at the time of their breast cancer diagnosis. One situation relates to women with chemotherapy-induced cessation of menses. Caution is necessary here as some of these women may not be permanently postmenopausal, especially if they are less than 40 years old. If aromatase inhibitor therapy is initiated in a woman who has chemotherapy-induced menstrual cessation, confirmation of postmenopausal status by hormone levels should be considered at the time of aromatase inhibitor therapy initiation as well as several months thereafter. The other situation concerns women who are rendered postmenopausal by an oophorectomy. The value of aromatase inhibitor therapy is undergoing prospective clinical evaluation in the SOFT and TEXT trials, as described above. In both situations, aromatase inhibitor therapy is being compared to tamoxifen. Thus, tamoxifen therapy in this setting should be considered to be the standard of care. Conclusion
As new and maturing trial data become available, we hope that optimal adjuvant endocrine therapy can be determined for all women with breast cancer, along with detailed information regarding risk and benefit. Where this knowledge is not yet complete, all efforts should be made to support existing international adjuvant trials.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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