Breast Cancer Vol. 13 No. 2 April 2006

S y m p o s i u m 11 H o r m o n e therapy: from basic Who Benefitsfrom Hormone Therapy ?

s c i e n c e to clinical s c i e n c e

Masakazu Toi .1 and Yuichi lino .2

* ~Department of Clinical Trial and Research, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, *2Departmentof Emergency and Critical Care Medicine, Gunma University Faculty of Medicine, Japan. Not all hormone receptor (HR)-positive tumors respond to hormone therapy, although hormone therapy has brought significant benefits to breast cancer patients. In order to improve the efficacy of hormone therapy, a variety of new approaches are currently being tested in such as extended adjuvant therapy, selection of responders using array-based techniques and combination therapy with signal transducfion inhibitors. It is therefore necessary to distinguish between highly hormone responsive tumors and relatively less hormone sensitive tumors. Through reviewing recent outcomes of clinical trials, these issues are summarized and discussed in this review.

Breast Cancer 13:117-122, 2006.

Key words: Hormone therapy, Sensitivity, Adjuvant therapy

A gradation exists in response to hormone therapy (Fig 1). Although hormone therapy brings enormous benefits to breast cancer patients, not all hormone receptor (HR)-positive tumors respond to the treatment. In order to bring out the maximal power from hormone therapy, various novel approaches have been tested in clinical trials and the correlative researches. Recently it was postulated that extended adjuvant hormone therapy, consisting of 5 years aromatase inhibitor following 5 years tamoxifen, is better than 5 years tamoxifen alone, which was the gold-standard of treatment for HR-positive primary breast cancer patients, in reducing the risk of relapse 1). The combination of hormone therapy with other novel therapies such as anti-Her therapy is another example to explore for enhancing the effect of hormone therapy. Currently several new combination treatments are being tested pre-clinically or clinically. To identify patients with highly hormone-sensitive tumors, new microarray-based methodologies are being investigated. A recent report remarked that long-term survivors can be identified using a tumor gene signature from primary breast cancer patients treated by adjuvant anti-estrogen tamoxifen, which suggests that highly hormone sensitive tumors might be disfinReprint requests to Masakazu Toi, Department of Clinical Trial and Research, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, 3-18-22 Honkomagome, 8unkyo-ku, Tokyo, 113-8677, Japan.

guishable from less sensitive tumors 2). At the 2005 St. Gallen consensus meeting, the concept was proposed that HR-posifive tumors should be categorized into two subtypes consisting of hormone-responsive tumors and response-uncertain tumors 3). For hormone-responsive tumors, primarily hormone therapy alone should be considered, while for hormone response-uncertain tumors, other types of systemic therapies should be considered together with hormone therapy. This strategy could help to realize further individualized treatment for primary breast cancer patients and contribute to reduce or eliminate unnecessary treatments. This review summarizes and discusses these aspects through a reviewing the outcomes of recent clinical trials, particularly those involving aromatase inhibitor trials.

Prolonged Exposure to Antiestrogen and to Estrogen Depletion It is known that long-term prolonged exposure to hormone therapy changes the phenotype of hormone-dependent breast cancer cells. For example, hydroxytamoxifen was demonstrated to modify the chromatin structure and induce silencing of natural target genes 4). In addition, it was reported that oxidative stress plays a significant role in the conversion of tamoxifen-sensitive tumors to tamoxifen-resistant tumors, where the phosphorylated JNK and c-Jun levels and AP-1 activity were often 117

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Fig 1. Gradation of hormone therapy response and treatment indication:Gradation requires classificationinto several subgroups by translationalresearch.This is the initialprocess to exploreindividualizedtreatmentfor hormonereceptor-positive breast cancers.

increased s). Gene expression profile analysis documented that stress-induced molecules such as MLK-3 and SOD-1 are involved in apoptosis-related pathways and insulin-like growth factor (IGF) and the MAPK pathway are engaged in cell survival when hormone-responsive cells are treated by anti-estrogen 6~. In an experiment employing MCF-7 cells expressing active Akt-3, the tumor growth was inhibited by estradiol and enhanced by tamoxifen, suggesting that activation of the Akt pathway can drastically change the hormonedependent phenotype 7~. Similarly, growth of MCF7 cells engineered to express Her-2 and ER coactivator AIB1 was stimulated by tamoxifen 8~. The signaling molecules including Akt, Erk 1,2 and MAPK have been characterized to play an important role in the mechanism. Curiously, estrogen depletion inhibited the growth of these tumors and gefinifib, a Her tyrosine kinase inhibitor, restored the anti-tumor effects of tamoxifen, indicating two possible ways to overcome tamoxifen resistance, total estrogen blockade and inhibition of the pathways like Akt and MAPK 9~. Clinical studies confirmed that patients with Her-2 amplification, or Her-1 expression, or both are less responsive to tamoxifen and have a poor prognosis 1+. Several tamoxifen resistance-related gene signatures have been identified from these studies 11). Not only gefinitib but also other Her-family inhibitors such as trastuzumab and lapatinib have been shown experimentally to be effective in reversing tamoxifen sensitivity 12' 13>. Furthermore, signal 118

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inhibitors like the mammalian target of rapamycin (mTOR) were shown to restore tamoxifen sensitivity or provide a significant combination effects with tamoxifen in ER-posifive and tamoxifen-resistant breast cancer cells 14~.These data are important for considering switch-over treatment from tamoxifen to aromatase inhibitors, and combination hormone-therapy with anti-Her therapy such as trastuzumab. Long-term estradiol depletion seems to cause hormone sensitive breast cancer cells to adapt and develop hypersensitivity to estradiol '~). In these cells, it is reported that ER-a and signaling molecules such as MAPK and phosphoinositol 3 kinase (PI3-K) are frequently up-regnlated. It is also indicated that estradiol binds to cell membrane-associated ER-a and can elicit non-genomic actions like activation of the MAPK, Elk-1 and mTOR pathways. These findings help to understand the mechanism of resistance to aromatase inhibitors and the importance of extended adjuvant hormone therapy. A slight difference in intratumoral estradiol concentration may result in a large difference in cfinical outcome, because the cellular signaling pathways cause hypersensitivity.

Positive F e e d b a c k Loop As shown in Fig 2, estradiol production is controlled by an intracrine mechanism in the microenvironment of human breast cancer tissues. There is positive feedback loop between tumor cells and stromal cells. In the stroma, premature fibroblastic cells and adipose cells, educated by tumor cells, are thought to play a crucial function to activate the loop and maintain the activity 16). According to a hypothesis that long-term estrogen depletion causes hypersensitivity of signaling pathways such as Akt and MAPK, adjuvant aromatase inhibitor treatment may facilitate a shift of the loop from an intracrine mechanism-supported estradiol-dependent cell growth pattern to an autocrine mechanism supported growth factordependent cell growth pattern in hormone-sensitive breast cancer cells. The magnitude of hypersensitivity in the signaling pathways may significantly reflect the overall tumor phenotype. Tumors with hypersensitivity in the signaling pathways may be less hormone-sensitive, whereas tumors with less hypersensitivity may be highly hormonesensitive. These tumor properties should be investigated in future clinical trials.

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Fig 2. Positivefeedback loop in the hormone-dependentgrowth of breast cancer. Tumor stroma plays a crucial role in producingestradiolvia an intracrine mechanism.Cross-talkbetween membrane-associatedhormone receptors and growth factor receptors helps the cancer cells survive and avoid apoptosis. When the loop is blocked by anti-estrogen or estrogen depletion, it is hypothesized that the signaling pathways become hypersensitive, which may change the phenotype of the cells dramatically.Reversal of the hypersensitivitymight result in enhancing the effectof hormone therapy.

Her-2 and Combination Treatment with Anti-Her Therapy Enzymatic immunoassay studies showed that Her-2 protein concentrations in p r i m a r y breast t u m o r tissues are inversely associated with ER protein concentrations and with PgR protein concentrations, respectively 17). Therefore, it is possible to estimate that Her-2 positive and HR-positive tumors, d e t e r m i n e d by i m m u n o h i s t o c h e m i c a l assay, largely consist of tumors with relatively low HR protein concentrations. This issue needs to be clarified, because intratumoral HR expression level will be used more frequently for distinguishing between ' h o r m o n e responsive' and 'response uncertain' tumor phenotype in future clinical practice. On the other hand, trastuzumab has b e c o m e standard therapy for tumor overexpressing Her218,19). In most HR-positive cases, trastuzumab is

used in combination with hormone therapy. In this situation, it is important to know w h e t h e r trastuzumab helps to restore hormone sensitivity by suppressing Her-2 related signaling pathways. In a r e c e n t study, it was also d o c u m e n t e d that aromatase inhibitors can change the Her-2 phenotype of the tumor 2~ Both Her-2 protein expression and Her-2 gene-amplification were remarkably downregulated by treatment with aromatase inhibitors in neoadjuvant setting. The down-regulation of Her-2 expression correlated significantly with clinical t u m o r response. Therefore, monitoring of changes in tumor phenotype, as well as characterizing the phenotype of primary tumors, are essential to estimate the effects of combination hormone therapy with anti-Her therapy such as trastuzumab.

Aromatase Inhibitor Trials For adjuvant t r e a t m e n t of HR-positive post119

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menopausal primary breast cancer patients, it has been clarified that aromatase inhibitor is superior to tamoxifen in either starting or switching from tamoxifen. When anastrozole or letrozole were started immediately after local treatment, distant recurrence, local recurrence and contralateral breast cancer occurrence reduced significantly compared with tamoxifen alone 21'22). Concerning the switching-over strategy, the Intergroup Exemestane Study (IES) trial revealed that the switch to exemestane from tamoxifen at 2-3 years from local therapy is better than continuous 5 years tamoxifen TM. In the recent reports from the Austrian Breast & Colorectal Cancer Study Group (ABCSG)/Arimidex-Nolvadex (ARNO) study groups, it was also demonstrated that switching to anastrozole from tamoxifen was significantly superior to non-switch continuous tamoxifen treatment, indicating that the switch-over strategy from tamoxifen to aromatase inhibitor is widely acceptable in the treatment of postmenopausal HR-positive primary breast cancer patients TM. Since 10-year hormone therapy, consisting of 5 years of tamoxifen and 5 years of letrozole, was superior to 5 years of tamoxifen, all 5 mega-trials, including the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, Breast International Group (BIG)1-98 trial, IES group trial, ABCSG/ARNO trials and MA-17 trial, confirmed that aromatase inhibitors can exert excellent anti-tumor activities for primary breast cancer patients as a class effect. In fact, several guidelines have already recommended the use of aromatase inhibitors in adjuvant treatment for postmenopausal patients with a hormone-responsive tumor phenotype, although long-term adverse effects have not been fully clarified yet. Subgroup analyses in these clinical trials with aromatase inhibitors indicated that several differences in tumor characteristics relating to the response exist between the agents, and between the therapeutic schedules. These differences may be important in decision making on the use of aromatase inhibitors. According to the ATAC trial, anastrozole was more beneficial for node-negative patients and for estrogen receptor (ER)-positive and progesterone receptor (PgR)-negative patients than in node-positive patients or ER-positive and PgR-positive patients2% However, in the BIG198 trial, letrozole was more effective for node-positive patients than node-negative patients2% With respect to HR status, letrozole was equally effective for ER-positive and PgR positive patients and 120

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ER-positive and PgR-negative patients. Neither the ABCSG/ARNO study nor the IES study have shown any difference in subgroup analyses with respect to nodal status and PgR status so far. In the MA-17 trial, letrozole was better in node-positive than node-negative cases, but subgroup analysis on PgR status has not been reported.

Hormone Therapy Response Uncertain Phenotype Much attention is paid to clarification of the phenotype of hormone therapy response-uncertain tumors. PgR might be one candidate, however it seems difficult to explain such a complicated tumor phenotype by a single biomarker. It would be more reasonable to use multiple biomarkers or comprehensive biomarker sets for this purpose. According to the pioneering work of Paik et al. a 21-gene signature of the tumor helps to assess the risk of relapse and survival in HR-positive primary breast cancer patients treated by tamoxifen 2). Multiple categories of genes such as estrogen-related genes, Her-2 related genes, proliferation-related genes and invasion-related genes are included in this gene signature. Using microarray-based techniques, a variety of approaches and concepts are explored for the classification of tumor phenotype with to rergard the risk of disease relapse and therapy response 26'27).Furthermore, there is a new generation of clinical trials comparing chemo-hormone therapy and hormone therapy alone for HRpositive breast cancer patients with intermediate risk of recurrence. These clinical trials, in conjunction with translational research, promise to explain the gradation of hormone responsiveness not only by image concept but also by the real sequences consisting of multiple subgroups.

Conclusion and Perspectives Hormone responsiveness is the most important information group for breast cancer research and treatment. HR-posifive tumors are dominant in human breast cancer and hormone therapy often continues for more than 5 years. Therefore, we need to distinguish highly hormone-sensitive tumors from relatively less hormone-sensitive tumors and to know the changes of tumor phenotype caused by treatment, not only hormone therapy but also other types of therapies including chemotherapy and anti-Her therapy. Since some

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gene signatures have been demonstrated to predict the response to tamoxifen, we should study further about predictive biomarkers for total estrogen blockade. In order to overcome hormone therapy resistance, combinations with inhibitors of non-genomic signaling pathways, such as Her tyrosine kinase inhibitors, mTOR inhibitors and farnesyl transferase inhibitors seem promising. Several new combination therapies will be tested clinically in the near future. Of particular interest is to know the method for tailoring treatment for each individual.

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