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Journal of Clinical Oncology, Vol 23, No 8 (March 10), 2005: pp. 1636-1643 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.11.027
Aromatase Inhibitors for Breast Cancer Prevention
From Cancer Research-UK, Centre of Epidemiology, Mathematics & Statistics, Wolfson Institute of Preventive Medicine, London, United Kingdom Address reprint requests to Jack Cuzick, PhD, Centre of Epidemiology, Mathematics & Statistics, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, United Kingdom; e-mail: jack.cuzick{at}cancer.org.uk.
Many lines of evidence point to sex hormones as the key factors in breast carcinogenesis. Classic risk factors include age at menarche, first child birth, and menopause. Estrogens, especially estradiol, appear to be the main factor. Hormone replacement therapy increases breast cancer risk,1-4 especially when the combined pills using estrogen and progesterone are used. Weight is a risk factor for postmenopausal breast cancer, where aromatization of androgens in adipose tissue is the major source of estrogen. The variability of serum oestrogen levels in postmenopausal women from the lowest to highest quintile (about a six-fold difference) is associated with a two-fold variation in breast cancer risk (Fig 1).5 Estrogen appears to be more closely linked with breast cancer than are the other steroid sex hormones, although they may also have an independent role.5 Lastly, four major trials using the estrogen agonist, tamoxifen, to block the activity of estrogen at the receptor6 have shown that about 50% of estrogen receptor (ER) -positive breast cancers (Fig 2A) can be prevented, although there appears to be little effect on ER-negative breast cancer (Fig 2B), leading to a 38% overall reduction in breast cancer.
Although the use of tamoxifen has been effective in reducing the incidence of breast cancer, both in the contralateral breast for women with early breast cancer, and for those at high risk who have not had the disease, it is not without side effects, especially thromboembolic events and gynecologic symptoms,6 and this limits its utility in a prevention setting. Recently, the third-generation aromatase inhibitors (AIs) have been introduced into the treatment of breast cancer, and their greater efficacy compared to tamoxifen, along with a more favorable side-effect profile, make them attractive agents for use in breast cancer prevention.
The first-generation AI aminoglutethimide became available in the late 1970s, but despite proven efficacy, its widespread use was limited by its overall toxicity and lack of selectivity for the aromatase enzyme necessitating concomitant corticosteroid supplementation. This was improved in the so-called second-generation AIs (formestane, fadrozole, vorozole), but they still lacked selectivity. Anastrozole, letrozole, and exemestane are third-generation AIs, and have greater specificity with fewer side effects.
AIs act via the inhibition of the cytochrome P450 enzyme aromatase, which catalyzes the conversion of androgens to estrogens. Their chemical structures are shown in Figure 3. Nonsteroidal AIs (anastrozole, letrozole, vorozole, fadrozole) bind reversibly to aromatase, whereas the steroidal AIs (formestane, exemestane) bind irreversibly, causing permanent inactivation of the complex, and are effective until new enzyme is synthesized.
Advanced Disease Several studies have shown that the AIs have benefits for metastatic cancers when compared with megestrol acetate in terms of tolerability. Efficacy results have been somewhat mixed, but are most promising for the third-generation compounds.7-12 In first-line treatment trials against tamoxifen, benefits have also been fairly marginal, but mortality benefits are seen with the newer compounds.13-20
Adjuvant Treatment and Contralateral Breast Cancer To date, four different adjuvant trials have reported on the use of three different AIs for postmenopausal women with breast cancer (Table 1).21-25 In these trials, adjuvant AIs have been found effective in three clinical settings. In the first setting, the AI was compared with tamoxifen as initial adjuvant hormonal therapy in patients with resected operable breast cancer. In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, 5 years of anastrozole significantly improved disease-free survival when compared with 5 years of tamoxifen.21,22,26 In the second setting, the AI was compared with tamoxifen in patients who had already received 2 to 3 years of adjuvant tamoxifen. In the Intergroup Exemestane Study (IES) trial and the Italian Tamoxifen versus Anastrozole (ITA) trial, 2 to 3 years of exemestane or anastrozole, respectively, improved disease-free survival compared with 2 to 3 years of tamoxifen in patients who had already completed 2 to 3 years of tamoxifen therapy.23,24 In the third setting, the AI was evaluated as extended adjuvant hormonal therapy following completion of 5 years of adjuvant tamoxifen. The National Cancer Institute of Canada (NCIC) MA.17 trial compared 5 years of letrozole with 5 years of placebo following completion of 5 years of adjuvant tamoxifen and demonstrated significant improvement in disease-free survival in favor of the group which received the AI.25 Based on the results from the above trials, AIs are currently being increasingly utilized in all three of these clinical settings.
In all of the above trials evaluating adjuvant AIs, a consistent reduction in the rates of contralateral breast cancer has been observed in the group receiving the AI (Fig 4). In the ATAC trial, the number of contralateral breast cancers was reduced from 59 in the tamoxifen arm to 35 on anastrozole, a 42% reduction (95% CI, 12% to 62%; P = .01). A larger reduction of 53% (95% CI, 27% to 71%; P = .001) was seen in the hormone receptor–positive patients.26 Tamoxifen is known to reduce the incidence of contralateral tumors by 46% in women with mostly ER-positive primary tumors, suggesting that the overall reduction of receptor-positive breast cancer associated with anastrozole may be around 70% to 80%. Information on the receptor status of the second cancers in this trial is not yet available, but one would expect the preventive effect to be restricted to ER-positive contralateral tumors, and to be greater for this group than for new breast tumors overall.
In the ITA trial, there were two cases of contralateral breast cancer in the tamoxifen group versus one in the tamoxifen/anastrozole group. The small number of patients included in that trial (n = 448), as well as the small number of events, precludes any meaningful comparison between the two groups. However, in the IES that employed a similar design to the ITA trial, women randomly assigned to 2 to 3 years of exemestane after 2 to 3 years of tamoxifen had a 56% reduction in contralateral breast cancer compared with those randomly assigned to continue tamoxifen for the remaining 2 to 3 years (nine v 20 cases; P = .04). A recent report of the combined ARNO95/ABCSG8 trial, which was of similar design to the ITA trial but involved 3,224 patients, showed a smaller 26% reduction in contralateral breast tumors (12 v 16; P = .4).27 Finally, in the MA.17 trial, women who were randomly assigned to 5 years of letrozole after 5 years of tamoxifen had a 46% reduction in new contralateral tumors compared with women randomly assigned to placebo (14 v 26 cases; P = < 0.01). Although the study designs of the above trials have been very different, all of the trials indicate that the impact of AIs on contralateral tumors has been greater than the impact on recurrences, which bodes well for prevention (Fig 4). When viewed cumulatively, the results are compatible with a 40% to 50% reduction in ER-positive contralateral breast cancer with the AI. Given that tamoxifen reduces ER-positive tumors by about 40% to 50%, a further 40% to 60% reduction by the AIs suggests that 70% to 80% of these tumors might be avoided by prophylactic treatment. However, no impact on ER-negative tumors is expected, and this remains a challenging area for breast cancer prevention. Possible agents for prevention of ER-negative tumors include cyclooxygenase-2 inhibitors, statins, low-dose tamoxifen, and vitamin D analogs, but none of these have randomized evidence for efficacy in humans, and their full evaluation presents major logistic challenges in terms of trial design. Undoubtedly, evidence from surrogate markers will be necessary to progress these compounds.
The profound estrogen depletion associated with AIs produces a new state of human existence, and this is bound to have other effects beyond those related to breast carcinogenesis. These effects can only be reliably studied in prevention trials where a placebo is employed. There are suggestions from adjuvant trials that AIs may also reduce endometrial cancer and cerebrovascular events to below baseline rates, but full evaluation is difficult because there is no untreated comparison group. Bone loss and increased fracture rates appear to be the most serious side effects, and methods for combating them will be essential if these drugs are to be used prophylactically. Because of the importance of side effects in the prevention setting, details of the available toxicity data from current adjuvant AI trials are summarized in the following sections.
ATAC Trial
There were two side effects that were clearly increased by anastrozole. One was the occurrence of musculoskeletal events—primarily arthralgias, which were increased by about one third, from 30% to 36%. Most of these were mild and did not lead to a discontinuation of treatment. They are probably best explained at being due to a "second menopause" induced by lower levels of estrogen, and appear to be similar to the aches and pains associated with the normal menopause. More important is the bone loss associated with estrogen deprivation. In a subset of 308 patients in the bone substudy, there was a median bone mineral loss over 2 years of 4.1% in the lumber spine and 3.9% in the hip on anastrozole compared with small increases on tamoxifen.28 With a median follow-up of 68 months, this has translated into an increase of fractures from 7.7% to 11.0%, or a 50% relative increase.
MA-17 Trial
No other side effects have emerged and treatment was well tolerated in this trial, with a treatment-related drop-out rate of 4.5% on letrozole and 3.6% on placebo (P = .11).
IES Trial
Early studies in animals29 suggested that the steroidal structure of exemestane might lead to bone preservation and even enhancement. Preliminary data from the IES trial do not support this possibility and suggest a picture similar to the other AIs. Again, further data are needed to be able to compare the effect on bone of exemestane with that of the other AIs.
International Breast Cancer Intervention-II Trial The International Breast Cancer Intervention (IBIS) -II prevention trial began in February 2003 and is comparing anastrozole to placebo in 6,000 postmenopausal women at increased risk of breast cancer. This study is still open to recruitment. Entry criteria are similar to IBIS-I, except that women with mammographic density covering at least 50% of the breast are also eligible. Mammographic density has emerged belatedly as an important risk factor for breast cancer, despite copious evidence being available for some time.30 In terms of population-attributable risk, it accounts for more breast cancers than does family history, and screening programs offer an excellent opportunity for identifying high-risk women. This could ultimately be a more important function than their role in early detection. Baseline measurements in IBIS-II include a dual-energy x-ray absorptiometry scan and spinal x-ray. Osteoporotic women will be required to take a bisphosphonate and have regular dual-energy x-ray absorptiometry scans if they wish to join the study, but women with a T score less than 4, or more than two fragility fractures, will be ineligible. In addition, 1,000 women will be recruited into the bone substudy, in which regular bone monitoring will take place (Fig 5). This study will comprise three strata. For women with T scores below –2.5 at either the hip or spine, or having a spinal fragility fracture, oral weekly risedronate will be required. For women with T scores in the range –1.5 to –2.5 (moderate to severe osteopenia), there will be an additional randomization to risedronate or placebo. Women with higher T scores will be monitored, and only offered residronate if they become osteoporotic.
A second complimentary study (IBIS II) will look at the role of anastrozole for postmenopausal women with locally excised hormone receptor–positive ductal carcinoma-in-situ (DCIS), which has clear margins. Based on the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 trial, this study has been restricted to receptor-positive DCIS and the comparator is tamoxifen. Again, treatment is for 5 years. A similar trial for DCIS is currently being carried out by the NSABP (B-35).
MAP.3
Data from the adjuvant trials provide a compelling rationale for exploring the use of AIs in the prevention setting. Their efficiency is greater than that of tamoxifen, especially for new contralateral tumors, suggesting that 70% to 80% of ER-positive breast cancers can be prevented with these drugs. No impact is expected for receptor-negative cancers, however, and this remains a challenging area for future trials. The AIs also are better tolerated than tamoxifen, without the gynecologic and thrombotic complications, but do lead to bone mineral loss and increased fracture rates in the absence of additional bone-sparing therapy. An important question will be the effectiveness of bisphosphonates in arresting and/or reversing bone loss associated with the almost complete depletion of estrogen associated with AIs. Recent data from the Continuing Outcomes of Raloxifene Evaluation study31 confirm earlier data from the Multiple Outcomes of Raloxifene Evaluation study that raloxifene is likely to be at least as effective as tamoxifen in preventing new tumors, but lacks the estrogen stimulus to the endometrium, thus avoiding excess cancers at that site. However, raloxifene still has thromboembolic complications and is not currently recommended for breast cancer prevention. Results of the direct comparison of raloxifene and tamoxifen in the Study of Tamoxifen and Raloxifene trial are awaited with great interest. If this trial is positive, the key issue will be a choice between raloxifene and an AI. The trial size needed to separate them is likely to be enormous (  50,000), and it is likely more indirect methods will be needed to choose between them.
The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant: Jack Cuzick, AstraZeneca, Pfizer, Lilly. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
Author's disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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BACKGROUND
PREVIOUS AND CURRENTLY AVAILABLE...
60 years, prior atypical ductal or lobular hyperplasia, or DCIS treated with mastectomy. The sample size calculations are based on an expected risk reduction of 65% with exemestane versus placebo. Exemestane will be given for 5 years, although celecoxib will be given for 3 years. 
