Vol. 7, 4397s-4401s, December 2001 (Suppl.) Clinical Cancer Research 4397s Preliminary Data from Ongoing Adjuvant Aromatase Inhibitor Trials I Paul E. Goss z Introduction Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada The growth of hormone receptor-positive breast cancer can be altered clinically by several classes of agents that antagonize the effects of estrogen (1). The SERMs, 3 exemplified by tamox- Abstract ifen, constitute one such class of drugs. Pure antiestrogens such With recent results showing letrozole and anastrozole as fulvestrant (Faslodex) also exert a potent antiestrogenic effect to be superior to tamoxifen as initial therapy for advanced and show efficacy in tamoxifen-resistant cell lines in preclinical disease, the aromatase inhibitors are poised to establish their models. Thus, unlike tamoxifen, which exerts both an agonist place in the adjuvant therapy of postmenopausal receptor- and an antagonist effect, fulvestrant is a pure antagonist and acts positive breast cancer. A review of the rationale, design, and by down-regulating ER content (2). preliminary results of the ongoing adjuvant trials that in- Aromatase (estrogen synthetase) inhibitors antagonize the clude aromatase inhibitors will be presented, along with the action of estrogen by reducing its levels both in the circulation ongoing or planned substudies. Two strategies employing and in normal and malignant breast tissue (3). They were ini- aromatase inhibitors after tamoxifen are being evaluated. tially tested in postmenopausal women with breast cancer pro- gression after tamoxifen treatment. A superior outcome with The MA.17 international intergroup trial is randomizing these drugs compared to either megestrol acetate or aminoglu- postmenopausal patients who are disease-free after 5 years tethimide resulted in their becoming the established second-line of adjuvant tamoxifen to an additional 5 years of ietrozole or treatment for ER-positive metastatic breast cancer (4-13). More placebo. In a similar design, the National Surgical Adjuvant recently, three of the selective third-generation inhibitors, anas- Breast and Bowel Project (NSABP) B33 trial is randomizing trozole, letrozole, and exemestane, have been compared to ta- this patient population to 2 years of exemestane or placebo moxifen in the same setting (14-17). On the basis of both after the standard 5 years of adjuvant tamoxifen. The sec- improved efficacy and superior side effect profiles, anastrozole ond approach under study is the use of both aromatase and letrozole have now been approved for use as first-line inhibitor and tamoxifen in sequence within the first 5 post- treatment for women at first relapse of their disease. These data operative years. The International Cancer Collaboration are reviewed in detail elsewhere in this journal issue (18, 19). Group (ICCG) trial is comparing 2 years of exemestane Although useful in the treatment of advanced disease, the after 3 years of tamoxifen to a standard 5-year course of real benefits of tamoxifen have been seen in its ability to reduce tamoxifen. Similarly, the ARNO trial is comparing 5 years mortality by as much as one-third for up to 15 years after of tamoxifen versus 2 years of tamoxifen followed by 3 years primary surgery in women given 5 years of adjuvant treatment. 4 of anastrozole. In a four-arm study Breast International This makes tamoxifen one of the most successful anticancer Group/Femara-Tamoxifen (BIG/FEMTA) conducted by the therapeutics ever developed in terms of "number of years of life BIG, one arm contains letrozole given for 3 years after 2 saved." The recently demonstrated superiority of the aromatase years of tamoxifen. Several trials are investigating the role of inhibitors over tamoxifen in the advanced disease setting is, anastrozole, letrozole, or exemestane as a 5-year adjuvant therefore, a significant finding. Consequently, they are currently therapy to replace the standard 5 years of tamoxifen. Only being tested in the adjuvant setting in women with early-stage the Arimidex and Tamoxifen, Alone or in Combination breast cancer, and the results promise to alter the current treat- (ATAC) trial is testing a 5-year combination of tamoxifen ment paradigm of the disease. The trials that are ongoing and plus an aromatase inhibitor in this setting. Companion stud- their companion studies are briefly described. ies of effects on end-organs other than the breast are ongo- ing in a number of these trials. Aromatase inhibitors are Rationale and Design of Ongoing Adjuvant Trials poised to alter the treatment paradigm of breast cancer and Biological and Pharmacological Concepts: Disease "Re- hopefully improve outcome for a substantial number of sistance" Mechanisms. After initially responding to tamox- patients. ifen, metastatic breast cancer inevitably begins to progress de- 3 SERM, selective ER modulator; ER, estrogen receptor; BMD, bone 1 Presented at the First International Conference on Recent Advances mineral density; NSABP, National Surgical Adjuvant Breast and Bowel and Future Directions in Endocrine Therapy for Breast Cancer, June Project; NCIC, National Cancer Institute of Canada; CTG, Clinical 21-23, 2001, Cambridge, MA. Trials Group; ATAC, Arimidex and Tamoxifen, Alone or in Combina- z To whom requests for reprints should be addressed, at Princess Mar- tion (trial). garet Hospital, 610 University Avenue, Toronto, ON M5G 2M9, Can- 4 R. Peto, Oxford ECTG meta-analysis. Presented at Seventh Interna- ada. Phone: (416) 946-4501, extension 5103; Fax: (416) 946-2983; tional Conference on Adjuvant Therapy of Primary Breast Cancer, E-mail: [email protected]. February 21-24, 2001, St. Gallen, Switzerland. Unpublished data. Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2001 American Association for Cancer Research. 4398s Aromatase lnhibitors in Early Breast Cancer 1 ll~.vno~nn,i~ l~.Qfrno~n Fig. 1 Five examples of poten- tial mechanisms of stimulating 5.?E2 tumor cell growth: 1, exogenous estrogens; 2, ER mutation giving rise to estrogen hypersensitiv- ity; 3, tumor cell estrogen syn- thesis by tumor aromatase; 4, 4. Estrogen circulating extratumoral (pe- ripheral) estrogens; and 5, es- Biosynthes~ trogenic tamoxifen metabolites. Tamoxifen could block 1 and 4, and aromatase inhibitors could address 2, 3, and 4. The relative importance of these pathways as mechanisms of tumor resist- ance either to tamoxifen or to the aromatase inhibitors could determine whether tamoxifen m or the inhibitors should be given first or whether they II- ,, should be given in combination. spite ongoing therapy. On occasion, withdrawal of tamoxifen in may overcome the development of resistance by several of the this circumstance results in further clinical remission-a phe- mechanisms outlined above (Fig. 1). However, stimulation of a nomenon termed tamoxifen resistance or "dependence" (20, 21 ). "hypersensitive" receptor by exogenous estrogens or the agonist Further credence has been lent to this concept by the observation effects of tamoxifen and/or its metabolites would remain theo- in the NSABP B 14 trial and in a Scottish adjuvant trial (22, 23) retical mechanisms of resistance to this "total estrogen block- that patient outcome is worse if tamoxifen therapy is continued ade" strategy with combination therapy (Fig. 1). beyond 5 years of treatment. This has resulted in 5 years of Pharmacological Considerations. Pharmacological in- tamoxifen becoming the standard duration of treatment in the teraction between endocrine therapies may interfere with effi- adjuvant setting. cacy and disease outcome. Timing may be critical in switching Several theories have been offered as to the mechanism of from one treatment to another. For example, cells that have tamoxifen resistance. First, mutation of the ER has been dem- developed one or more of the resistance mechanisms outlined onstrated in MCF-7 cells, resulting in estrogen hypersensitivity above may be eradicated by subsequent therapy, provided the when passaged in estrogen-deprived media (20). This poten- switch is made promptly and the appropriate therapeutic doses tially results in tamoxifen exerting an estrogen agonistic effect. given. Potential problems exist with both of these requirements. It has been postulated that this may be enhanced by increasing First, drug interaction with tamoxifen results in a reduction in metabolism of tamoxifen to metabolites with weak estrogen the plasma levels of letrozole and anastrozole to 62.4% (26) and agonist action. In addition, hypersensitivity to residual estrogen 73% (27), respectively. It has been proposed that these small may result (Fig. 1). In vivo experiments have also shown that differences would unlikely be of importance, although they MCF-7 cells in nude mice initially regress in response to ta- might be in the presence of a hypersensitive receptor capable of moxifen but are later stimulated by its weak estrogen agonist being stimulated by very low picomolar concentrations of es- properties (24). Secondly, estrogen-deprived MCF-7 cells de- trogen. In addition, tamoxifen and its metabolites have very long velop up-regulation of aromatase, which may in turn result in half-lives and tissue binding (28), and by definition any switch increased autocrine stimulation by estrogen (20). In principle, from tamoxifen to an aromatase inhibitor would involve a tamoxifen might have the same effect. Thus, theoretically, ces- degree of combination therapy for a significant period. This sation of tamoxifen in a patient with