Journal of the National Cancer Institute Advance Access originally published online on December 11, 2007
JNCI Journal of the National Cancer Institute 2007 99(24):1825-1827; doi:10.1093/jnci/djm264
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© The Author 2007. Published by Oxford University Press.
EDITORIALS |
Extended Adjuvant Therapy for Breast Cancer—How Much Is Enough?
Affiliation of authors: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD
Correspondence to: Vered Stearns, MD, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Rm 145, Baltimore, MD 21231-1000 (e-mail: vstearn1{at}jhmi.edu).
Aromatase inhibitors are a class of drugs that inhibit the conversion of androgens to estrogen. They are generally regarded as the preferred first-line endocrine treatment for metastatic hormone receptor–positive breast cancer in postmenopausal women, in whom they produce outcomes that are equivalent or superior to those produced by tamoxifen (1). Tamoxifen, when given for 5 years to women with early-stage estrogen receptor–positive breast cancer, reduces the risk of recurrence by 41% and the risk of death by 33% and has long represented the standard of care for adjuvant endocrine therapy for both premenopausal and postmenopausal women (2). Given the superiority of aromatase inhibitors in the metastatic setting for postmenopausal women, three approaches to incorporate aromatase inhibitors into the adjuvant setting have been tested. One approach included the administration of an aromatase inhibitor for 5 years instead of 5 years of tamoxifen. A second approach tested switching tamoxifen to an aromatase inhibitor for a total of 5 years of adjuvant hormone therapy, and a third evaluated extended hormone therapy use by comparing aromatase inhibitors versus no additional therapy after 5 years of tamoxifen.
Two trials have reported results comparing 5 years of an aromatase inhibitor with 5 years of tamoxifen. Investigators for the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (3), which compared 5 years of tamoxifen with 5 years of anastrozole or the combination given concurrently, and for two arms of the ongoing Breast International Group 1-98 (BIG 1-98) trial (4), which compared 5 years of tamoxifen with 5 years of letrozole, have reported statistically significant improvements in disease-free survival favoring use of an aromatase inhibitor.
Four trials have reported results for switching adjuvant endocrine therapies: Austrian Breast and Colorectal Study Group (ABCSG) Trial 8 (5); the Arimidex/Nolvadex (ARNO) 95 trial (5); the Italian Tamoxifen Arimidex (ITA) trial (6), in which women who had completed 2–3 years of adjuvant tamoxifen were randomly assigned to receive anastrozole or to continue on tamoxifen; and the International Exemestane Study (7), in which women who had completed 2–3 years of adjuvant tamoxifen were randomly assigned to receive exemestane or to continue on tamoxifen for a total of 5 years. All four trials demonstrated statistically significant reductions of approximately 30%–40% in the relative risk of developing a new or recurrent breast cancer for the women who received an aromatase inhibitor but no statistically significant difference between treatment groups in overall survival (5–7). A subsequent meta-analysis that included data from the ABCSG Trial 8, ARNO 95, and ITA trials reported a statistically significant 29% improvement in overall survival favoring sequential therapy with tamoxifen followed by anastrozole (8).
Goss et al. (9) reported the first results in the extended adjuvant setting from the National Cancer Institute of Canada MA.17 trial. This was a randomized double-blind, placebo-controlled trial of 5187 postmenopausal women with early-stage hormone receptor–positive breast cancer who had completed 4.5–6 years of adjuvant tamoxifen; the trial was intended to compare 5 years of additional adjuvant therapy with letrozole versus placebo. The MA.17 trial was terminated early after a planned interim analysis at a median follow-up of 2.4 years revealed a statistically significant improvement in disease-free survival favoring the letrozole arm. A preplanned subset analysis of women with node-positive disease demonstrated a statistically significantly improved overall survival for the letrozole arm (10). Another trial in the extended adjuvant setting, National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-33, which compared 5 years of tamoxifen alone versus the same treatment followed by 5 years of exemestane, was closed to accrual early following publication of the MA.17 trial results. Nonetheless, in NSABP B-33, there was a non–statistically significant trend for improved disease-free survival favoring the extended treatment arm (11).
In this issue of the Journal, Jakesz et al. (12) report mature results of another extended adjuvant therapy trial, ABCSG Trial 6a, a randomized open-label trial that enrolled 856 postmenopausal women from ABCSG Trial 6. In ABCSG Trial 6, 2021 women with hormone receptor–positive stage I or II breast cancer were randomly assigned to 5 years of adjuvant tamoxifen with or without 2 years of concurrent aminoglutethimide. Disease-free and overall survival in ABCSG Trial 6 were not statistically significantly different between arms (13). In ABCSG Trial 6a, women who remained disease free at the end of ABCSG Trial 6 were randomly assigned to receive either 3 years of anastrozole or no further treatment. At a median follow-up of 62.3 months, compared with women who received no further treatment, women who received anastrozole had a statistically significant 38% reduction in the relative risk of new or recurrent breast cancer but no statistically significant difference in overall survival (12).
The ABCSG Trial 6a has some important limitations. The most notable is the lack of a double-blind, placebo-controlled design. Furthermore, all women who were free of recurrence at the end of ABCSG Trial 6 were randomly assigned before their consent for participation in ABCSG Trial 6a was obtained. The rates of informed consent varied among the women randomized to the two ABCSG Trial 6a arms, resulting in a considerable imbalance in the number of patients per arm. Finally, although the ABCSG Trial 6 failed to detect any statistically significant difference in outcome with the addition of 2 years of aminoglutethimide to 5 years of tamoxifen monotherapy [and the ATAC trial similarly detected no difference in efficacy between tamoxifen monotherapy and the concurrent administration of tamoxifen and an aromatase inhibitor (3)], it is possible that previous exposure of a sizeable percentage of the ABCSG Trial 6a participants to another aromatase inhibitor may have confounded the results.
Both ABCSG Trial 6a (12) and MA.17 (9) reported an approximately 40% reduction in the risk of new or recurrent breast cancer when an aromatase inhibitor was given for 3–5 years following 5 years of tamoxifen. Although a reduction in distant metastases accounted for approximately 60% of the reduced risk of events observed in each trial, neither trial detected a statistically significant difference in overall survival in the full study populations (9,10,12). In the case of the MA.17 trial, a high rate of patient crossover to the letrozole arm following the report of the interim results is likely to have obscured any potential difference in overall survival in the full study population (9). ABCSG Trial 6a, which enrolled considerably fewer patients than MA.17, was almost certainly underpowered to demonstrate a statistically significant difference in overall survival. Given the long natural history of hormone receptor–positive breast cancer and the competing comorbidities in the postmenopausal women who are eligible to receive aromatase inhibitors, either additional data from trials that are larger or limited to women at high risk of recurrence or a meta-analysis will likely be needed to ascertain the impact of extended courses of adjuvant endocrine therapy on overall survival.
The short-term safety profile of extended adjuvant therapy with an aromatase inhibitor following tamoxifen appears to be generally acceptable. In particular, bone fractures, which have been to date among the most worrisome adverse events associated with the aromatase inhibitors, were infrequently observed and occurred in similar percentages of patients in both treatment arms, perhaps reflecting the beneficial effect of tamoxifen on bone health (9,12). Nevertheless, with increasing clinical use of the aromatase inhibitors, it has become clear that clinical trials of aromatase inhibitors in the adjuvant setting may have underestimated the prevalence and severity of musculoskeletal symptoms that are associated with aromatase inhibitors (14). Indeed, recent observational studies have reported that nearly half of patients taking adjuvant aromatase inhibitors experienced symptoms of joint pain or stiffness, one-quarter of which were described as severe (15), and up to 13% of women discontinued their aromatase inhibitor within the first year of use because of musculoskeletal complaints (16). The impact of these aromatase inhibitor tolerability issues on patient adherence and quality of life requires further study.
The results of ABCSG Trial 6a provide further support for extending the total duration of adjuvant therapy with sequential tamoxifen and an aromatase inhibitor to 8 years; however, whether such a course of extended adjuvant therapy is superior to either aromatase inhibitor monotherapy or shorter courses of sequential therapy is presently unknown. The ongoing BIG 1-98 trial is a four-arm trial comparing 5 years of letrozole or tamoxifen monotherapy with sequential combined therapy with letrozole for 2 years followed by tamoxifen for 3 years or tamoxifen for 2 years followed by letrozole for 3 years (4). Ideally, a future trial would compare the winning arm of the BIG 1-98 trial with one or more arms of extended adjuvant endocrine therapy. In the meantime, accepted approaches to adjuvant endocrine therapy for postmenopausal women with early-stage hormone receptor–positive breast cancer include 5 years of an aromatase inhibitor, 5 years of tamoxifen, or a combination of tamoxifen and an aromatase inhibitor administered sequentially for a total treatment duration of 5 to as many as 10 years (17,18).
If more is indeed better when it comes to adjuvant endocrine therapy, how much is "enough"? Is there a duration of adjuvant endocrine therapy with sequential tamoxifen and an aromatase inhibitor beyond which efficacy, in addition to safety, is compromised, as may be the case with tamoxifen monotherapy (19), and, if so, what is it? The ongoing Secondary Adjuvant Longterm Study with Arimidex (SALSA) study should answer some of these questions.
Decisions regarding the most appropriate adjuvant regimen should take into account a patient's individual risk of, and her concerns regarding, a recurrence of breast cancer and serious adverse events such as fractures or thromboembolic events. Ongoing studies of tissue specimens obtained from women enrolled in the large randomized trials of aromatase inhibitors in the adjuvant setting may provide valuable information regarding tumor and host characteristics predictive of the efficacy and toxic effects of aromatase inhibitors. Results from both completed and ongoing studies should not only help to identify women who can safely forego adjuvant therapy as well as those who are best treated with short-term or long-term adjuvant hormone therapy but also provide a rationale for the selection of the most appropriate drug or drugs to incorporate.
NOTES
Vered Stearns has received investigator-initiated research funding from Pfizer, Inc., the maker of exemestane, and Novartis Pharmaceuticals, the maker of letrozole.
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