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The Potential for Aromatase Inhibition in Breast Cancer Prevention

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The Potential for Aromatase Inhibition in Breast Cancer Prevention Vol. 7, 4423s-4428s, December 2001 (Suppl.) Clinical Cancer Research 4423s The Potential for Aromatase Inhibition in Breast Cancer Prevention Per E. Le~nning, 2 Lars Erik Kragh, Introduction Bje~rn Erikstein, Anne Hagen, Terje Risberg, Breast cancer remains a major health threat to women, in Ellen Schlichting, and Jiirgen Geisler particular in western countries. It represents the most frequently diagnosed form of cancer in most of these countries and the Section of Oncology, Institute of Medicine, Haukeland University second leading cause of death from cancer. Although mammo- Hospital, N-5021, Bergen (P. E. L., J. G.); Department of Surgery, Central Hospital Stavanger (L. E. K.); Department of Oncology, The graphic screening (1) as well as implementation of adjuvant Norwegian Radium Hospital (B. E.); Department of Surgery, treatment strategies (2, 3) have been shown to reduce breast Trondheim University Hospital (A. H.); Department of Oncology, cancer mortality, many patients will subsequently develop me- Tromsci University Hospital (T. R.); and Department of Surgery, tastases for which no cure is currently available. Accordingly, Ullev~l University Hospital, Oslo (E. S.), Norway there is a need for alternative strategies to limit the number of breast cancer deaths. The problem of breast cancer prevention is complex. Abstract Whereas the role of estrogen effects in breast cancer develop- Although SERMs are currently being evaluated and ment has been well documented (see section "Aromatase Inhib- are approved for breast cancer prevention in several itors and Inactivators for Breast Cancer Prevention: Endocrine countries, aromatase inhibitors and inactivators may rep- Rationale"), the diverse biology of breast cancer questions the resent interesting options in this setting. The encouraging hypothesis of a uniform etiology. In a recent study (4) that results revealing these drugs to be superior to conven- analyzed breast tumor samples with microarrays, some estrogen tional therapy in metastatic breast cancer confirm their receptor-negative tumors were found to express genes associ- therapy efficacy and suggest that they may also have a ated with basal cells, which suggested a different origin and, role in adjuvant therapy and even for breast cancer pre- probably, etiology of development, compared with the larger vention. Secondly, whereas the bulk of "high-risk" breast group of receptor-positive tumors expressing luminal cell genes. cancer patients with confirmed founder mutations in the In addition to plasma estrogen levels, the concentration of BRCA1 or BRCA2 genes develop their cancers earlier in plasma IGF-I 3 has been correlated to breast cancer risk in life (during the premenopausal period), 75-80% of all premenopausal women (5). Although IGF-I is a potent mitogen breast cancers, in general, develop in postmenopausal to breast cancer cells in vitro (6) and most breast cancers express women. Thus, in considering prevention of breast cancer the IGF type I receptor, (7), its role in breast cancer therapy is in moderate-risk groups, strategies for prevention in post- poorly understood (8). In addition, the only therapeutic strategy menopausal women may play an important role. Also, apart from tamoxifen and estrogens (9) known to suppress among high-risk patients who have not developed breast plasma levels of IGF-I is the use of somatostatin analogues, which, thus far, have never been proven to have antitumor cancer by the time of the menopause, aromatase inhibi- effects in humans (10). Other potential approaches, such as the tion could be a feasible option. Considering the potential use of synthetic retinoids (11), will not be discussed in this hazards of long-term use of SERMs, switching to an article. aromatase inhibitor or inactivator in this setting may be Although conflicting results have been obtained with re- beneficial. Finally, the observation that postmenopausal gard to implementation of tamoxifen as a preventive strategy estrogen levels are related to subsequent risk of breast (12, 13), the encouraging results from the National Surgical cancer in the general population underlines the potential Adjuvant Breast and Bowel Project (NSABP) P-I study (14) for estrogen suppression as a preventive strategy. Results and with raloxifene in the Multiple Outcomes of Raloxifene from ongoing studies examining the toxicity of aromatase Evaluation (MORE) study of fracture prevention (15) both inhibitors and inactivators in postmenopausal women will showing a reduction in breast cancer risk, suggest that breast set the stage for future trials that explore them as pre- cancer may be partly prevented by endocrine manipulation. This ventive treatment options. viewpoint is further supported by studies showing tamoxifen to prevent subsequent tumor development in patients with ductal carcinoma in situ (16) as well as the overview data revealing tamoxifen to prevent the development of contralateral breast cancers (3). Presented at the First International Conference on Recent Advances Notably, for the high-risk patients with confirmed BRCA1 and Future Directions in Endocrine Therapy for Breast Cancer, June and BRCA2 mutations, there is a need for early interventions 21-23, 2001, Cambridge, MA. 2 To whom requests for reprints should be addressed, at Department of Oncology, Haukeland Hospital, University of Bergen, N-5021, Bergen, Norway. Phone: 47-55-97-50-00, extension 2027; Fax: 47-55-97-20-46; E-mail: [email protected]. 3 The abbreviation used is: IGF, insulin-like growth factor. Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2001 American Association for Cancer Research. 4424s Breast Cancer Prevention Steroidal Inactivators Androgen Substrate O O 0 0 CH2 OH Fig. 1 Structural formulas for the third-generation aromatase Exemestane Formestane Androstenedione inhibitors anastrozole and letro- zole and the third-generation aromatase inactivator exemes- Nonsteroidal Inhibitors tane together with the first- and second-generation compounds aminoglutethimide and formes- tane. N~N~ ~ NH2 ~~ N O"\y ~0 H C~mN Aminoglutethimido Letrozole Anastrozole (medical or surgical); probably for many of these patients, a aggressive strategies like ovarian oblation and prophylactic Anastrozole Letrozole mastectomy would be preferred options in the future (17). For those women who are not candidates for such invasive options, feasible endocrine prevention would probably involve SERMs, given the significant subjective side effects as well as morbidity associated with castration. This scenario may be different in postmenopausal women. First, the novel aromatase inhibitors and inactivators now available (Fig. 1) show little toxicity to the 2 years [ patient. Most importantly, although the drop in estrogen levels at the menopause is associated with accelerated bone loss as well as a detrimental effect on blood lipids and plasma homo- Tamoxifen 1 Aromatase Inhibitor [~ Placebo [~ cysteine (18-20), currently we do not know whether a drop from normal postmenopausal estrogen levels down to the very b Exemestane low levels seen in patients during treatment with aromatase inhibitors (21) is associated with any changes in these parame- ters. The few studies that have evaluated these issues were all conducted in patients suffering from metastatic breast cancer 5 years (22-24). However, patients with advanced malignancies often experience disturbances in metabolic as well as coagulation parameters (25-27) and may harbor bone metastases, making 2 years these parameters unreliable. Notably, cardiovascular disease is a main cause of death in older women as well as men, and Tamoxifen 1 Aromatase Inactivator [] Placebo [~ detrimental effects on such risk parameters may outweigh the Fig. 2 Design of current studies evaluating third-generation aromatase benefit of breast cancer prevention in moderate-risk groups. inhibitors (a) and inactivators (b) in the adjuvant setting. Aromatase Inhibitors and Inactivators: State of the Art static breast cancer (28-32), anastrozole as well as letrozole and After the beneficial results obtained with novel aromatase exemestane have all been compared with tamoxifen as first-line inhibitors and inactivators compared with regular second-line therapy in metastatic disease. For anastrozole, data from two therapy like megestrol acetate and aminoglutethimide in meta- large international trials have shown this drug to be at least as Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2001 American Association for Cancer Research. Clinical Cancer Research 4425s Randomization Table 1 Aromatase inhibition with different aromatase inhibitors/ inactivators administered to patients in different doses" Letters and figures in bold refer to results obtained with third- generation inhibitors/inactivators. Aromasin Placebo Percentage inhibition Drug Type %/%/% 2y 2y Rogletimide Inhibitor 51/64/74 BMD Formestane oral Inactivator 62/70/57 Bone Biomarkers Fadrozole Inhibitor 82/93 Lipid profile Formestane i.m. Inactivator 85/92 Follow-up AGb Inhibitor 91 Coagulation Formestane + AG Inactivator/Inhibitor 94 parameters ly Letrozole Inhibitor 98.4/98.9/99.1 Homocysteine Anastrozole Inhibitor 96.7/98.1/97.9 Exemestane Inactivator 97.9 Fig. 3 Outline of the OEXE 27 study evaluating the safety profile of exemestane in low-risk breast cancer patients. BMD, bone mineral "Results obtained from studies outlined in references 21, 46-48, density. and 52-56. b AG, aminoglutethimide. good as tamoxifen in this setting (33, 34). More convincing
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