This is a random-ized, open labeled trial designed to compare the efficacy and tolerability of toremifene 120 mg to exemestane in postmenopausal women with hormone receptor positive mBC with disease progression after prior nsAI treatment. The use of aromatase inhibitors in the neoadjuvant (preoperative) setting has not been widely investigated. Esteban JM, Warsi Z, Haniu M, et al: Detection of intratumoral aromatase in breast carcinomas. It will accrue 3,500 patients. Breast cancer is the second most common cancer in women after skin cancer. Patients will receive CB-103 capsules orally (QD) in combination with NSAI therapy (letrozole or anastrozole, continuing prior therapy) also orally once daily, and based on a 28-day treatment cycle. Dixon JM, Love CD, Renshaw L, et al: Lessons from the use of aromatase inhibitors in the neoadjuvant setting. [40-43] Although the validity of these findings is debated in the literature, they suggest a role for estrogen in the growth of viable metastases from tumor cells disseminated at the time of surgery. 6. Verzenio is a prescription medicine used to treat a type of breast cancer. Hum Pathol 25:530-535, 1994. D. Tripathy: Grants, personal fees: Novartis; Personal fees: Pfizer. Ingle JN, Green SJ, Ahmann DL, et al: Randomized trial of tamoxifen alone or combined with aminoglutethimide and hydrocortisone in women with metastatic breast cancer. Vorobiof DA, Kleeberg UR, Perez-Carrion R, et al: A randomized, open, parallel-group trial to compare the endocrine effects of oral anastrozole (Arimidex) with intramuscular formestane in postmenopausal women with advanced breast cancer. The development of vorozole has been terminated, so it will not be discussed below. Lonning PE, Bajetta E, Murray R, et al: Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: A phase II trial. In the case of aromatase inhibitors, Dixon et al have reported on a series of hormone-receptor-positive patients treated with a 3-month course of letrozole, anastrozole, or tamoxifen. The median duration of response was 14 months, and the median time to progression was 15 weeks. At the MONARCH 3 interim analysis, abemaciclib plus a nonsteroidal aromatase inhibitor (AI) significantly improved progression-free survival (PFS) and objective response rate (ORR) with a tolerable safety profile as initial treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). The first symptom of breast cancer that most women notice is a lump or an area of thickened tissue in their breast. 17. Studies in nude mice, on the other hand, would predict that there is unlikely to be any clinical benefit from combining tamoxifen with either anastrozole or letrozole. An objective response was seen in 7% of patients, and stabilization of disease for at least 6 months occurred in another 17%. 28. The most common (≥5% in either arm) Grade 3 and 4 adverse events are shown in the table. Jatoi I: Timing of surgery for primary breast cancer with regard to the menstrual phase and prognosis. In vivo aromatase activity is assessed by radioimmunoassay of urinary estrogens following administration of radiolabeled androstenedione. 67. Preliminary data from these investigations have established the aromatase inhibitors as the therapy of choice for estrogen-receptor-positive metastatic breast cancer in menopausal patients. Official Title: A Phase III Randomized, Double-blind, Placebo-controlled Study of LEE011 or Placebo in Combination With Tamoxifen and Goserelin or a Non-steroidal Aromatase Inhibitor (NSAI) and Goserelin for the Treatment of Premenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer Ann Oncol 10:377-384, 1999. Oncology 12:36-40, 1998. Combinations of the new aromatase inhibitors with LHRH agonists are therefore now being prospectively studied. Bergh J, Bonneterre J, Illiger HJ: Vorozole versus aminoglutethimide in the treatment of postmenopausal breast cancer relapsing after tamoxifen (abstract 543). Dowsett M, Tobias JS, Howell A, et al: The effect of anastrozole on the pharmacokinetics of tamoxifen in post-menopausal women with early breast cancer. Eur J Cancer 36:1283-1287, 2000. As neither anastrozole nor letrozole influences tamoxifen pharmacokinetics,[54,55] the issue of combined therapy has been revisited in the previously mentioned ATAC trial. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomized trials. The German Adjuvant Breast Cancer Group (GABG) and the Austrian Breast Cancer Study Group (ABCSG) are both comparing 5 years of tamoxifen with 2 years of tamoxifen followed by 3 years of anastrozole in patients with node-positive or node-negative, low- to moderate-grade tumors. 24. Read our disclaimer for details. J Enzyme Inhib 4:315-325, 1991. J Clin Endocrinol Metab 80:2658-2660, 1995. 18 January 2021 Personal story Cancer doesn’t just invade your body, it … Clin Cancer Res 5:1642-1649, 1999. [56] Likewise, there is no rationale for combining letrozole with tamoxifen, as coadministration of these agents results in a significant (38%) reduction of plasma letrozole levels. Other early aromatase inhibitors, such as fadrozole (CGS 16949A) and the parenterally administered formestane (4-OHA), demonstrated antitumor activity and fewer adverse effects than aminoglutethimide, but they have now been supplanted by the third-generation inhibitors described below.[22]. 10. 23. 39. J. Alam: Employee: Novartis. Endocrine therapy options include anastrozole, letrozole, exemestane, fulvestrant and tamoxifen.5, 6The choice of first-line endocrine therapy for advanced breast cancer depends on which treatment was used in the (neo) adjuvant setting, the duration of that treatment as well as the time elapsed from the end of the (neo) adjuvant treatment. The safety profile was manageable, irrespective of race, and was consistent with that observed in the full population. All funding for this site is provided directly by ESMO. Letrozole vs Megestrol Acetate or Aminoglutethimide: Letrozole has been compared with both megestrol acetate[30] and aminoglutethimide[26] in randomized trials. Bulun SE, Price TM, Aitken J, et al: A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. 4. She explains how she’s always been a positive and active person and appreciates life. Oncology 11:21-23, 1997. 54. The premise here is that 5 years is the optimal duration of tamoxifen therapy, but that late relapse occurs because dormant cells have retained estrogen dependence and subsequently reactivate following tamoxifen withdrawal. Exemestane: Exemestane was compared with tamoxifen in a randomized phase II study. The combination of everolimus (EVE) and exemestane (EXE) is approved for the treatment of patients with metastatic hormone receptor‐positive breast cancer (mHRBC) who progress on nonsteroidal aromatase inhibitor (NSAI) therapy. Steroids 50:537-548, 1987. [62,63] Long-acting LHRH agonists, such as goserelin (Zoladex) or buserelin (Suprefact), may be used to inhibit ovarian cycling, thereby suppressing ovarian estrogen production to postmenopausal levels. Endocrinology 137:3061-3068, 1996. Protocol B-33 of the National Surgical Adjuvant Breast and Bowel Project (NSABP) is randomizing patients who are disease-free after 5 years of tamoxifen to 2 years of either exemestane or placebo. In a combined analysis, 40% of patients had unknown estrogen-receptor status, 60% were estrogen-receptor-positive and/or progesterone-receptor-positive, and 9% had received adjuvant hormonal therapy. The third generation of aromatase inhibitors-comprising anastrozole, letrozole, and exemestane-is now the standard of care for postmenopausal patients with estrogen-receptor-positive metastatic breast cancer. Premenopausal pts (≤1 line of prior chemotherapy; no prior ET for ABC) received RIB or PBO + NSAI (letrozole or anastrozole)/TAM + GOS. Natalie was diagnosed with secondary (metastatic) breast cancer in 2017 and received news it had spread to her brain a year later. Cancer Epidemiol Biomarkers Prev 7:65-78, 1998. 71. Proc Am Soc Clin Oncol 19:147a, 2000. 25. British investigators have made a preliminary report of their study of premenopausal women who received anastrozole with goserelin for locally advanced or metastatic breast cancer. Significantly prolonged progression-free survival (PFS) and improved response rates were demonstrated in the phase III, MONARCH 3 trial of abemaciclib in combination with the non-steroidal aromatase inhibitors (NSAI), anastrozole or letrozole, in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer (ABC). Sasano H, Ozaki M: Aromatase expression and its localization in human breast cancer. 30. Importantly, the superiority of anastrozole was more evident in patients who had not received prior hormonal therapy (ie, tamoxifen) than in those who had, so the advantage cannot be dismissed as being the result of preexisting tamoxifen resistance. N. El Saghir: Honorarium for lectures and advisory boards: Novartis, Pfizer, Lilly. Lipton A, Santen RJ, Santner SJ, et al: Prognostic value of breast cancer aromatase. AZD4547 & Anastrozole or Letrozole (NSAIs) in ER+ Breast Cancer Patients Who Have Progressed on NSAIs (RADICAL) (RADICAL) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. No clear correlation between the level of tumor aroma-tase activity and the biological behavior of the tumor has yet been demonstrated. The study randomized 381 patients; the median age was 66 years, and 70% of patients had positive axillary nodes. J Steroid Biochem Mol Biol 37:1055-1059, 1990. [53] This may partially explain the clinical findings. Proc Am Soc Clin Oncol 18:67a, 1999. [16,18,19] Notably, two small studies have suggested a correlation between tumor aromatase activity and response to aromatase inhibition therapy with aminoglutethimide (Cytadren).[20,21]. Am J Pathol 140:337-343, 1992. Circulating estrogen levels in postmenopausal women are approximately 20% of those of premenopausal women, and they achieve a steady-state concentration in the absence of cyclical ovarian function. 36. J Steroid Biochem Mol Biol 61:293-298, 1997. Cancer Res 42:3409-3414, 1982. Aromatase inhibitors are a class of drugs used in the treatment of breast cancer in postmenopausal women and gynecomastia in men. ESMO is a Swiss-registered not-for-profit organisation. Aminoglutethimide inhibits the production of other adrenal steroids, including cortisol, and therefore must be taken with hydrocortisone. 64. 62. What does NSAI stand for in Medical? Editorial assistance was provided by Kate Gaffey, PhD of ArticulateScience Ltd. S-A. Anastrozole vs Megestrol Acetate: Anastrozole was compared with megestrol acetate in two large randomized trials, the results of which were pooled for publication. 70. As first-line therapy, letrozole was shown to be superior to tamoxifen in terms of response rate (30% vs 20%, P = .001), clinical benefit (49% vs 38%, P = .001), time to progression (41 vs 26 weeks, P = .0001), and time to treatment failure (40 vs 25 weeks, P = .0001). Miller W, Forrest A: Oestradiol synthesis from C19 steroids by human breast cancer. Background: The combination of everolimus (EVE) and exemestane (EXE) is approved for the treatment of metastatic hormone receptor-positive breast cancer (mHRBC) patients who progress on non-steroidal aromatase inhibitor (NSAI) therapy.However, none of the subjects enrolled in the trial that led to this approval (BOLERO-2) had previously received CDK4/6 inhibitors (CDK4/6is), which have … All patients had received nSAI for metastatic disease prior to exemestane therapy. 7. The first trial was double-blind and randomly assigned 363 patients to receive either megestrol acetate or letrozole at a daily dose of either 0.5 or 2.5 mg. Eight of nine evaluable patients were progression-free after 6 months of treatment. Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results of a phase III study of the International Letrozole Breast Cancer Group. Consistent PFS benefit for RIB + NSAI vs PBO + NSAI was observed in Asian and non-Asian pts (Table). 53. NST stands for No Special Type. J Clin Oncol 4:958-964, 1986. Lonning PE: Aromatase inhibition for breast cancer treatment. Preclinical models suggest that it may be possible to obtain chemopreventive effects without total suppression of aromatase and circulating estrogen levels. Most invasive breast cancers have no special features and are classed as No Special Type. Many of the epidemiologic factors associated with an increased risk of breast cancer (eg, early menarche, late menopause, increased age at first full-term pregnancy) point to the importance of estrogen exposure, regardless of whether the tumor expresses hormone receptors. Specifically, some investigators have found that women who undergo surgery during the proliferative phase of the menstrual cycle, a time when circulating estrogens are at their highest levels, are at greater risk of metastases. Sasano H, Nagura H, Harada N, et al: Immunolocalization of aromatase and other steroidogenic enzymes in human breast disorders. Cancer Res 45:2900-2906, 1985. In the hormone-receptor-positive subgroup (n = 611), however, there was a statistically significant advantage to the aromatase inhibitor (10.7 vs 6.4 months, P = .022). [14,15] Studies of tumor aromatase levels and known prognostic factors, such as tumor cell proliferative activity or lymph node involvement, have yielded conflicting results. Kaufmann M, Bajetta E, Dirix LY, et al: Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: Results of a phase III randomized double-blind trial. Rutqvist LE: Zoladex and tamoxifen as adjuvant therapy in premenopausal breast cancer: A randomised trial by the Cancer Research Campaign Breast Cancer Trials Group, the Stockholm Breast Cancer Group, the Southeast Sweden Breast Cancer Group and the Gruppo Interdisciplinare Valutazione Interventi in Oncologia (abstract 251). Geisler J, King N, Anker G, et al: In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly. [28] This study demonstrated that letrozole is a more potent aromatase inhibitor than anastrozole (aromatization suppression rates were > 99.1% vs 97%, P = .003, with confirmatory estrogen suppression data). Invasive breast cancer means that the cancer cells have grown through the lining of the ducts into the surrounding breast tissue. Toxicity, particularly rash, was less common in the letrozole treatment arms. Oncology (Basel) 44:345-9, 1987. Male breast cancer comprises approximately 1% of all breast cancer cases. The study will accrue 2,200 patients. Lancet 348:1189-1196, 1996. The study has completed accrual, and is now in follow-up. The ATAC (Arimidex, Tamoxifen Alone and Combination) trial, coordinated by the British Cancer Research Campaign and AstraZeneca, has accrued a total of 9,100 node-positive and node-negative patients to receive anastrozole or tamoxifen, or anastrozole plus tamoxifen, each for 5 years. Santen RJ, Yue W, Naftolin F, et al: The potential of aromatase inhibitors in breast cancer prevention. Lancet 2:104-107, 1896. Endocr Relat Cancer 6:227-230, 1999. [57], Aromatase Inhibitors Plus LHRH Agonists in Premenopausal Women. Brodie A, Lu Q, Liu Y, et al: Preclinical studies using the intratumoral aromatase model for postmenopausal breast cancer. 63. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used. Assikis VJ, Jordan VC: Risks and benefits of tamoxifen therapy. Numerous large randomized studies are being conducted to address the value of these agents in the adjuvant setting. [58-60] The role of aromatase inhibitors in premenopausal women is now being revisited, however, for a number of reasons. Dowsett M, Donaldson K, Tsuboi M, et al: Effects of the aromatase inhibitor anastrozole on serum oestrogens in Japanese and Caucasian women. RIB benefit was observed irrespective of endocrine therapy (ET) partner (NSAI or TAM). Geisler J, Johannessen DC, Anker G, et al: Treatment with formestane alone and in combination with aminoglutethimide in heavily pretreated breast cancer patients: Clinical and endocrine effects. [14,16,17], Studies examining the relationship between aromatase expression and estrogen- and progesterone-receptor positivity have also been inconsistent. J Clin Oncol 16:453-461, 1998. 3. Cancer Chemother Pharmacol 46:35-39, 2000. 43. A total of 1,300 patients will be accrued to the German trial GABG IV-C (also known as ARNO), and 1,200 patients will be accrued to ABCSG Study 8. The only registered steroidal inhibitor of the current generation is exemestane (Aromasin). Eur J Cancer 18:333-337, 1982. It effectively antagonizes estrogen in the tumor, reducing relapse by 47% and death by 26%, regardless of menopausal status,[4] and has positive effects on bone mineral density and lipid profiles. The survival benefit in this study was interpreted cautiously, as it was evident only in patients who received the lower, 1 mg dose. Early Breast Cancer Trialists’ Collaborative Group: Ovarian ablation in early breast cancer: an overview of the randomized trials. Cancer Res 50:5851-5857, 1990. Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide (Cytadren), the progestins, and tamoxifen, Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the hormonal therapy of choice in estrogen-receptor-positive, postmenopausal, metastatic breast cancer. Breast Cancer Res Treat 52:217-225, 1998. Lipton A, Santner SJ, Santen RJ, et al: Aromatase activity in primary and metastatic human breast cancer. NST is sometimes called NOS (not otherwise specified). Goss PE, Gwyn KM: Current perspectives on aromatase inhibitors in breast cancer. Goldhirsch A, Gelber RD, Castiglione M, et al: Menstrual cycle and timing of breast surgery in premenopausal node-positive breast cancer: Results of the International Breast Cancer Study Group (IBCSG) Trial VI. J Clin Oncol 12:2460-2470, 1994. [25] When radioimmunoassays are used to assess estrogen suppression, they generally correlate with the degree of aromatization suppression observed (see Table 2). 10.1093/annonc/mdy428, Ribociclib (RIB) + non-steroidal aromatase inhibitor (NSAI) + goserelin in premenopausal Asian women with hormone-receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC): Results from the randomized Phase III MONALEESA-7 study, Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach, MMR deficiency(d) in an unselected cohort of endometrial cancer (EC) patients, the Royal Marsden experience, Proffered Paper session 1: Invited discussant, Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumours: Pooled analysis of STARTRK-2, STARTRK-1, and ALKA-372-001, Interpreting Oncological Study Publications, Cancer Diagnosis and Treatment Evaluation, Rehabilitation Issues During Cancer Treatment and Follow-Up, Cancer Treatment in Special Clinical Situations, Clinical Pharmacology of Anti-Cancer Agents, Curriculum in Translational Research in Breast Cancer, ESMO Members: Build Your Own ESMO Library, International Prognostic Index Tools for Lymphoma, Anti-Cancer Agents and Biological Therapy, Drug-Drug Interactions with Kinase Inhibitors, PARP inhibition and DNA Damage Response (DDR), Cancer Aetiology, Epidemiology and Prevention, Cancer in Special situations (pregnancy, young, elderly, hereditary...), Multikinase Inhibitor-Related Skin Toxicity, Precision Medicine and Validated Biomarkers, ESMO Recommendations in Precision Medicine, Translational Research: Biomarkers & Diagnostics, Patients with measurable disease at baseline, n, Most common (≥5% in either arm) Grade 3 AEs, %, Most common (≥5% in either arm) Grade 4 AE, %. Response rates and adverse events were comparable in the two treatment arms. Methods. 8. van Landeghem AA, Poortman J, Nabuurs M, et al: Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. 26. Although its use as second- or third-line endocrine therapy achieved response rates of 20% to 40%, the drug was associated with problematic effects. The toxicity profiles of the two agents were otherwise comparable. I. Diaz-Padilla, O. Kong, M. Miller: Employee, stock holder: Novartis. This is because the long-term effects on bone mineralization and cardiovascular function have not yet been adequately assessed. 50. 52. J Steroid Biochem Mol Biol 63:53-58, 1997. Adjuvant Aromatase Inhibition After 5 Years of Tamoxifen: Another study design addresses whether the introduction of an aromatase inhibitor following 5 years of tamoxifen treatment can further improve survival. [1] Although it has yet to be proven that estrogen is directly responsible for the initiation of breast tumors, it is clear from epidemiologic evidence,[2] from "prevention" studies using the antiestrogen tamoxifen (Nolvadex),[3] and from the clinical impact of hormonal manipulation[4,5] that estrogen is a significant factor in the maintenance and progression of established tumors. Forward D, Cheung KL, Jackson L, et al: Combined use of goserelin and anastrozole in premenopausal women with metastatic breast cancer, (abstract 582). 49. Claire Scott. Approximately 60% of estrogens in premenopausal women are synthesized in the aromatase-rich cytoplasm of the granulosa cells of the ovaries. [23] Plasma endogenous estrogens are usually measured with highly sensitive radioimmunoassays after separation with high-performance liquid chromatography.[24]. Lu Q, Nakmura J, Savinov A, et al: Expression of aromatase protein and messenger ribonucleic acid in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers. The irreversible nature of the binding between exemestane and aromatase may realize some advantage in this setting, particularly if the drug is administered at higher doses than those used in postmenopausal disease. 48. Cancer 74:1111-1124, 1994. This article will review the role of aromatase in the pathogenesis of breast cancer and the results of recent studies that have established the role of its inhibitors in estrogen-receptor-positive breast cancer. [6], Although circulating levels of estrogens are relatively low in postmenopausal women, aromatase expression is maintained in breast tissue after menopause. J Natl Cancer Inst 90:1371-1388, 1998. 55. There are few clinical data on aromatase inhibitors in premenopausal women, since early studies showed that these agents were unable to effectively inhibit estrogen synthesis in the presence of an intact premenopausal estrogen-follicle-stimulating hormone feedback loop. This strategy assumes that any deleterious effects of aromatase inhibition will be less evident if the period of aromatase inhibition is kept to a minimum. Verzenio (abemaciclib) is an inhibitor of CDK4 and CDK6, which are activated by binding to D-cyclins. 9. 56. As of Aug 20, 2017, among pts of Asian race, 48 pts in the RIB + NSAI arm vs 26 pts in the PBO + NSAI arm and 83 vs 67 pts of non-Asian race were still receiving treatment; the most common reason for discontinuation was disease progression (Asian: 27 vs 49; non-Asian 61 vs 76). Gershanovich M, Chaudri HA, Campos D, et al: Letrozole, a new oral aromatase inhibitor: Randomized trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. 15. 38. 32. Lilly MONARCH 3 Study Published in Journal of Clinical Oncology Demonstrates Benefit of Verzenio™ (abemaciclib) Plus NSAI in Advanced Breast Cancer PRESS RELEASE PR Newswire Oct. 6, … Thorsen T, Tangen M, Stoa K: Concentrations of endogenous estradiol as related to estradiol receptor sites in breast tumor cytosol. 3596 - Updated overall survival (OS) and quality of life (QoL) in premenopausal patients (pts) with advanced breast cancer (ABC) who received ribociclib (RIB) or placebo (PBO) plus goserelin and a nonsteroidal aromatase inhibitor (NSAI) in the MONALEESA-7 (ML-7) trial The remaining 40% of estrogens in premenopausal women are synthesized in the peripheral tissues, particularly in fat. All rights reserved. [33] In a study of 242 patients, 44% had received aminoglutethimide and 56%, another aromatase inhibitor. In the 1980s, four studies were published that compared tamoxifen alone with tamoxifen plus amino- glutethimide in metastatic disease. A phase II study also addressed the activity of exemestane after failure of a nonsteroidal aromatase inhibitor. A total of 1,700 patients are expected to be rerandomized. If you do not have an ESMO account, please create one for free. Proc Am Soc Clin Oncol 16:155a, 1997. It is possible that, at the time of surgery, the inhibition of estrogen with an aromatase inhibitor, alone or in combination with a luteinizing hormone-releasing hormone (LHRH) agonist, could improve the outcome for women undergoing breast cancer surgery. Four-Way Treatment Design: The Breast International Group (BIG) has combined these first two study designs into BIG 01-98 (or IBCSG 18-98), coordinated by the International Breast Cancer Study Group (IBCSG). The hormonal dependency of  breast cancer was first recognized more than a century ago. If one accepts the premise that relapse is partially due to the emergence of tamoxifen dependence, tamoxifen withdrawal and estrogen deprivation by aromatase inhibition may indeed provide a survival advantage.