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The renaissance of_endocrine_therapy_in_breast.9

  1. 1. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CURRENT OPINION The renaissance of endocrine therapy in breast cancer Nicole Williamsa and Lyndsay N. Harrisa,b Purpose of review Endocrine therapy for breast cancer has been the cornerstone of treatment for over a century since the discovery of the regressive effect of oophorectomy on ‘cancer of the mamma’ in 1896 by Beatson. Studies in the prevention and treatment of both early and metastatic breast cancer will be reviewed with a focus on recent large randomized clinical trials that may be practice changing. Recent findings Data from pivotal clinical trials that looked at the duration of adjuvant tamoxifen therapy in premenopausal women will be discussed. In addition, several recent clinical trials that address the optimal sequence of endocrine therapy and advances in the treatment of endocrine-resistant metastatic disease will be reviewed. New findings from molecular studies that demonstrate targets in the endocrine axis and the role of aromatase inhibitors in the prevention setting will be highlighted. Summary Overall, these clinical trials show the benefit of aromatase inhibitors in the prevention setting, longer duration of tamoxifen in the adjuvant setting for premenopausal women, and new biologic agents with hormonal therapies. Keywords androgen receptors, aromatase inhibitors, endocrine therapy, mTOR inhibitors, tamoxifen INTRODUCTION Hormone-receptor-positive breast cancer is the most common breast cancer subtype in developed countries, regardless of the age or stage at presen- tation. Approximately 60% of breast cancers diag- nosed in premenopausal women and 75–80% of breast cancers found in postmenopausal women are hormone receptor positive. Recent guidelines from the College of American Pathologist re-defined hormone-receptor-positive breast cancer as express- ing estrogen receptor or progesterone receptor at at least 1% by immunohistochemistry [1]. Although not agreed upon by all of the academic community, these guidelines recognize the fact that even at very low levels of estrogen receptor expression, benefit is observed from antiestrogen therapy. Endocrine therapy for breast cancer has been the cornerstone of treatment for over a century since the discovery of the regressive effect of oophorectomy on ‘cancer of the mamma’ by Beatson in 1896 [2]. Despite its central role in treatment, and although it is indeed the first ‘targeted therapy’, few advances have been made until very recently. Decades of research on endocrine resistance and discovery of new genomic targets have led to new hormonal targets, combinations of hormonal therapy with biologic agents, and with duel hormonal therapies. This is indeed a ‘hormonal renaissance’ for breast cancer, and not a moment too soon as much prog- ress has been made in other breast cancer subtypes. This review will address the recent studies in the prevention and treatment of hormone-receptor- positive breast cancer and their impact on clinical practice. a Seidman Cancer Center, University Hospitals of Case Western Cleve- land and b Division of Hematology/Oncology, Department of Medicine, Case Western Reserve School of Medicine, Cleveland, Ohio, USA Correspondence to Lyndsay N. Harris, MD, Lakeside 1127, 11100 Euclid Avenue, Cleveland, OH 44106, USA. Tel: +1 216 286 4414; e-mail: Curr Opin Obstet Gynecol 2014, 26:41–47 DOI:10.1097/GCO.0000000000000039 1040-872X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins REVIEW
  2. 2. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. ENDOCRINE TREAMENT OF METASTATIC BREAST CANCER Endocrine therapy is considered the first-line treat- ment for women with estrogen receptor and pro- gesterone receptor positive breast cancer for both premenopausal and postmenopausal women, pro- vided the pace or burden of disease does not indicate the need for chemotherapy. There are differences in the treatment of premenopausal and postmeno- pausal patients, as the endocrine environment in the menopausal state leads to variability in drug activity. The following paragraphs describe the standard and new approaches for each type of patient. Endocrine therapy in metastatic postmenopausal women Aromatase inhibitors such as anastrozole, letrozole, and exemestane are considered the first-line endo- crine treatment for postmenopausal women because of their proven superiority over tamoxifen [3–5]. Fulvestrant is an analog of estradiol that down- regulates the estrogen receptor by disrupting the estrogen receptor dimerization and accelerating degradation of the unstable fulvestrant–estrogen receptor complex. It is typically used after aromatase inhibitor therapy, although newer studies suggest an earlier line may be reasonable [6,7]. Several studies have evaluated the timing of single and combination therapies in the first and second line setting which are reviewed in Table 1. It should be noted that in many of these trials, the patients who experience the most benefit had not received prior endocrine therapy or had de novo metastatic disease. On the basis of the results of these studies, the optimal order of exposure to hor- monal agents in the advanced setting still needs to be determined as well as the true benefit of combi- nation endocrine therapy in the first-line metastatic setting. Endocrine therapy in premenopausal women For premenopausal women with estrogen receptor and progesterone receptor positive metastatic breast cancer, a luteinizing hormone releasing hormone (LHRH) agonist plus tamoxifen remains the stand- ard of care based on trials showing a survival advantage for the combination [14]. This practice has not changed significantly in the recent years. Patients then are typically treated as postmeno- pausal upon progression. It should be noted there is no evidence that using an aromatase inhibitor with a LHRH agonist is superior to tamoxifen with a LHRH agonist and should be reserved for pro- gression of disease. Novel targeted therapies for metastatic breast cancer Unfortunately, not all patients will have a response to first-line endocrine therapy (de novo resistance) and patients who respond will eventually progress (acquired resistance). In the last 2 decades, there have been major efforts to better understand the various biological mechanisms responsible for the development of endocrine resistance with the aim of identifying new therapeutic strategies. Preclinical data show a benefit in blocking the mammalian target of rapamycin (mTOR) pathway in endo- crine-resistant tumors because the mTOR complex has the ability to directly active the estrogen recep- tor. Bolero-2 (Breast Cancer Trials of Oral Everoli- mus) was a randomized phase 3 trial comparing everolimus and exemestane vs. exemestane and placebo in 724 patients with hormone-receptor- positive advanced breast cancer that had a recur- rence or progression while receiving therapy with a nonsteroidal aromatase inhibitor in the adjuvant or advanced disease setting [15 && ]. Everolimus com- bined with an aromatase inhibitor improved pro- gression-free survival (PFS) in patients previously treated with nonsteroidal aromatase inhibitors (10.6 vs. 4.1 months; 95% confidence interval 0.35–0.54; P < 0.001). The results of this study was also supported by, Tamoxifen plus Everlimus, a KEY POINTS Two large randomized trials (ATLAS and aTTom) have shown that 10 years of adjuvant tamoxifen therapy is superior to 5 years in premenopausal women. The combination of inhibition of the mTOR pathway with everolimus and estrogen receptor blockage results in improved progression-free survival after progression on a nonsteroidal aromatase inhibitor. The FIRST trial showed improved progression-free survival with the first-line fulvestrant in postmenopausal hormone-receptor-positive women with metastatic breast cancer when compared with a nonsteroidal aromatase inhibitor. Combination endocrine therapy with fulvestrant and exemestane in the first-line setting in postmenopausal women with hormone-receptor-positive metastatic breast cancer was superior to single-agent therapy in women with no prior endocrine therapy. The MAP-3 trial demonstrated that exemestane reduced the incidence of invasive breast cancers with 3 years of follow-up reported. Breast cancer 42 Volume 26 Number 1 February 2014
  3. 3. Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited. phase 2 randomized study involving 111 postme- nopausal women with estrogen-receptor-positive advanced breast cancer previously treated with an aromatase inhibitor [16 ]. The combination of ever- olimus and tamoxifen was associated with improved PFS (8.6 vs. 4.5 months, P ¼ 0.002) and with signifi- cantly improved overall survival (OS). These studies suggests that everolimus plays a role in the treat- ment of patients with endocrine-resistant disease. New endocrine targets for therapy Two novel endocrine targets currently being studied in the clinical trial setting are the androgen receptor and the LHRH receptor. The androgen receptor (AR) is expressed in 70–90% of all breast cancers [17]. During the first half of the 20th century, postme- nopausal women were treated with androgen therapy. However, in the 1970s, the use of androgen therapy stopped with the development of tamox- ifen. Emerging data suggest that the androgen receptor may play a role in breast cancer pathogen- esis and may serve as a potential therapeutic target, especially in more difficult-to-treat triple-negative breast cancers [18]. A recent study conducted in AR- positive, estrogen-receptor-negative metastatic breast cancer patients treated with bicalutamide (an oral antiandrogen therapy) showed a clinical benefit of 21%, making this an interesting potential therapeutic target especially for patients with endo- crine-resistant disease or triple-negative breast can- cer [19]. The LHRH also known as gonadotropin-releas- ing hormone (GnRH) was identified in the early 1970s. LHRH binds to its specific receptor, known today as type 1 LHRH receptor. Approximately 40– 50% of breast cancer expresses the LHRH receptor, suggesting that it may be a useful therapeutic target. AEZS-108 is a LHRH agonist–cytotoxic hybrid drug with doxorubicin. In preclinical studies, AEZS-108 was found to inhibit breast cancer in mouse models with minimal side-effects. Currently, there is a Table 1. First and second line endocrine therapies for metastatic postmenopausal hormone receptor positive breast cancer Robertson, 2012 (FIRST) [8 ] Mehta, 2012 (SWOG S0226) [9 ] Bergh, 2012 (FACT) [10 ] Chia, 2008 (EFECT) [11] First line First line First line Second line Ana Ful Ana Ana þ Ful Anas Ana þ Ful Exe Ful n 103 102 345 349 258 256 342 351 CBR 67% 72.5% 70% 73% 55% 55.10% 31.50% 32.20% PFS (months) 13.1 23.4à 13.5 15à 10.2 10.8à 3.7 3.7à OS (months) NR NR 41.3 47.7 38.2 37.8 NR NR Significanceà HR 0.66; 95% CI 0.47–0.92; P ¼ 0.01 HR 0.80; 95% CI 0.68–0.94; P ¼ 0.007 HR 0.99; 95% CI 0.81–1.20; P ¼ 0.91 HR 0.93; 95% CI 0.819–1.133; P ¼ 0.65 Johnston, 2013 (SoFEA) [12 ] Di Leo, 2010 (CONFIRM) [13] Howell, 2002 [6] Second line Second line Second line Ana þ Ful Ful Exe Ful 500 mg Ful 250 mg Ana Ful n 243 231 249 362 374 229 222 CBR 34% 32% 27% 45.60% 39.60% 45% 44.60% PFS (months) 4.4à 4.8 3.4 6.5à 5.5 5.1 5.5à OS (months) 20.2 19.4 21.6 25.1 22.8 NR NR Significanceà (primary endpoint) HR 1; 95% CI 0.83–1.21; P ¼ 0.98 HR 0.80; 95% CI 0.68–0.94; P ¼ 0.006 HR 0.98; 95% CI 0.80–1.21; P ¼ 0.84 à primary endpoint; Ana, anastrozole; CBR, clinical benefit rate; CI, confidence interval; Exe, exemestane; Ful, fulvestrant; HR, hazard ratio; NR, not reported; OS, overall survival; PFS, progression-free survival; FIRST, Fulvestrant First-line study Comparing Endocrine Treatment; SWOG SO226, Combination Anastrozole and Fulvestrant in Metastatic Breast Caner; FACT, Fulvestrant and Anastrozole Combination Therapy; EFECT, The Evaluation of Faslodex versus Examestane; SoFEA, Study of faslodex with or without concomitant arimidex vs exemestane following progression on non-steroidal aromatase inhibitors; CONFIRM, Comparison of Faslodex in Recurrent or Metastatic Breast Cancer. The updated FIRST trial shows a PFS benefit with first-line fulvestrant. A high proportion of patients enrolled in this trial were treatment naı¨ve (71.6% in the fulvestrant arm and 77.7% in the anastrozole arm). The SWOG S0226 trial examined the role of combination therapy with anastrozole and fulvestrant vs. anastrozole alone, and found an improved PFS and OS which in contrast to the results of the FACT trial showed no improvement in PFS and OS with combination anastrozole and fulvestrant. It should be noted that there was a large proportion of patients with de novo metastatic disease (38.9%) in the SWOG S0228 trial and a higher proportion of patients in the FACT trial had prior exposure to tamoxifen (67 vs. 40%). Several studies including Howell et al. showed that fulvestrant had similar PFS compared with anastrozole after prior endocrine therapy. The CONFIRM trial showed that 500 mg dose was superior to the 250 mg dose. Also, the EFECT trial showed similar benefits with exemestane or fulvestrant in the second-line setting therapy. The SoFEA trial showed that combination therapy offered no additional benefit in the second-line setting when compared to single agent therapy. Endocrine therapy in breast cancer Williams and Harris 1040-872X ß 2014 Wolters Kluwer Health | Lippincott Williams Wilkins 43
  4. 4. Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited. phase II clinical trial examining the benefit of AEZS-108 in chemotherapy-resistant triple-negative breast cancer that expresses the LHRH receptor [20 ]. ENDOCRINE THERAPY FOR EARLY-STAGE BREAST CANCER Endocrine therapy in the adjuvant setting can con- sist of treatment with tamoxifen, ovarian suppres- sion, or aromatase inhibitors. Again, variability in menopausal hormone environment leads to differ- ent indicated treatment. Tamoxifen The benefits of adjuvant tamoxifen therapy have been repeatedly demonstrated. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) published a recent collaborative meta-analysis of individual patient data from 20 trials with a median follow-up of 13 years and showed that 5 years of adjuvant tamoxifen therapy reduced the 15-year risk of breast cancer recurrence and death [21]. Tamoxifen continues to be the standard of care for adjuvant hormonal therapy in premenopausal women as aromatase inhibitors are not active in this population. The duration of endocrine therapy remains an important clinical question. The Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial assessed the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years [22 ]. This trial accrued 12 894 women with early breast cancer who had completed 5 years of treatment with adju- vant tamoxifen therapy and they were randomly assigned to continue tamoxifen to 10 years or stop at 5 years. After a median follow-up of 7.6 years, they found that continuing tamoxifen reduced the risk of breast cancer recurrence (P ¼ 0.002), reduced breast cancer mortality (P ¼ 0.01) and reduced overall mortality (P ¼ 0.01). Ten years of tamoxifen therapy produced a further reduction in recurrence and mortality, particularly after year 10. Longer therapy was associated with an increased risk for pulmonary embolism, and endometrial cancer, although this risk was lower in premenopausal women. No increase in the incidence of stroke was seen with 10 vs. 5 years and a decrease in the incidence of ischemic heart disease was noted. The UK adjuvant aTTom (Adjuvant Tamoxifen treatment-to offer more) trial randomly allocated 7000 women, most with unknown estrogen receptor status, to continue tamoxifen to 10 years or stop at 5 years [23 ]. This study confirmed the reduction in recur- rence and death seen with extended endocrine therapy. On the basis of the results of the above studies, a new standard of care for premenopausal women with estrogen-receptor-positive tumors is now 10 years of adjuvant tamoxifen therapy. Ovarian suppression or ablation Estrogen receptor expression is a powerful positive predictive factor for antiestrogen therapy. However, estrogen receptor expression may also be a negative predictive factor for benefit from chemotherapy. The EBCTCG examined the effects of ovarian ablation on recurrence and death and showed that in women less than 50 years of age, ablation of functioning ovaries significantly improved the long-term survival in the absence of chemotherapy [24]. This led to a number of studies that have eval- uated ovarian suppression vs. chemotherapy and combination chemotherapy and ovarian suppres- sion therapy in estrogen-receptor-positive premeno- pausal women which are illustrated in Table 2. The IBCSG (International Breast Cancer Study Group) II-93, IBCSG VIII, and Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) studies show that a subset of premenopausal women have benefit from adjuvant ovarian suppression without systemic chemotherapy. In addition, younger women who do not experience chemother- apy-induced amenorrhea may benefit from ovarian suppression with goserelin plus tamoxifen as illus- trated by the INT (Intergroup) 0101 and IBCSG VIII studies. A recent Cochrane review examined the role of LHRH agonists as ovarian suppression treatment for early breast cancer in premenopausal women and included 14 randomized trials that involved over 13 000 premenopausal women [32]. They concluded that LHRH agonists show clinical benefit in the adjuvant setting for premenopausal women; how- ever, definitive comparisons against third-gener- ation chemotherapy regimens and tamoxifen are required before their place in the adjuvant setting can be properly defined. Also, the American Society of Clinical Oncology (ASCO) review panel stated that ovarian suppression is not recommended either as addition to systemic therapy or as an alternative to systemic therapy and reiterated that the difficulty with the available data is that ovarian function suppression has not been compared with many systemic treatment options (anthracycline-based and taxane-based chemotherapy, aromatase inhibi- tors) in use today [33]. They stated that ovarian suppression should be considered only for women who will not receive systemic treatment (e.g., those patients who cannot tolerate or refuse systemic Breast cancer 44 Volume 26 Number 1 February 2014
  5. 5. Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited. therapy). However, if treatment with cyclophospha- mide, methotrexate, and fluorouracil (CMF) is being considered, there is available evidence to suggest that ovarian suppression is a reasonable alternative. More definitive information will be forthcom- ing when the results of two ongoing studies are available. One such trial is the Suppression of Ovar- ian Function Trial (SOFT) that will assess the role of ovarian suppression in combination with an aroma- tase inhibitor (exemestane) compared with ovarian suppression plus tamoxifen or tamoxifen alone as adjuvant therapy [34]. The Tamoxifen and EXemes- tane Trial (TEXT) trial will assess the benefit of an LHRH agonist with the additional of either tamox- ifen or exemestane for 5 years from the start of adjuvant therapy [35]. In the TEXT trial, adjuvant systemic chemotherapy was optional and lymph node status was found to be the predominant deter- minant of chemotherapy use [36]. The results of both of these trials are anticipated in 2014 and may greatly impact our current treatment approaches. Aromatase inhibitors Premenopausal women who undergo ovarian func- tion suppression may be treated with aromatase inhibitors. The ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group Trial-12) random- ized early-stage premenopausal women receiving goserelin to either anastrozole or tamoxifen with or without zoledronic acid [27]. At a median follow- up of 62 months, there was no difference seen in disease-free survival between patients receiving anastrozole or tamoxifen, but those on anastrozole alone had an inferior OS. Many premenopausal women with early breast cancer develop amenorrhea after chemotherapy, Table 2. Role of adjuvant ovarian function suppression/ovarian ablation in premenopausal women Study Population Intervention Endpoints Significant outcomes Thurlimann, 2009 IBCSG 11-93 [25] Node-positive HR þ premenopausal women AC Â 4, OFS T vs. OFS T DFS, OS No difference in DFS and OS between two groups. This trial had lower risk node-positive patient and small sample size IBCSG VIII, 2003 [26] Node-negative pre/ premenopausal women CMF vs. Z vs. CMF ! Z DFS In HR-positive node-negative patients, CMF alone and Z alone had similar results. An advantage to CMF ! was seen in women 40 Ghant, 2011 ABCSG-12 [27] Stage I or II HR þ premenopausal Z þ Ana; Z þ T DFS, OS No difference in DFS between patients receiving Ana and T overall, but those on Ana alone had inferior OS Davidson, 2005 INT 0101 [28] Node-positive HR þ premenopausal women CAF Â 6 vs. CAF ! Z vs. CAF ! Z þ T DFS, OS, TTR CAF-ZT improved TTR and DFS but not OS but the addition of Z did not significantly improve outcome to CAF alone. Women 40 did appear to benefit from Z Ejlertsen, 2006 [29] Node positive or tumors 5 cm HR þ premenopausal women OA vs. CMF Â 6 DFS, OS OA had similar effect to CMF on disease-free survival and OS Jonat, 2002 ZEBRA study [30] Node-positive premenopausal women Z vs. CMF Â 6 DFS, OS In HR-positive patients, Z had similar outcomes in DFS and OS Jakesz, 2002 ABCSG5 [31] Stage I or II HR þ premenopausal Z þ T vs. CMF X6 RFS, OS Z þ T had significantly improved RFS and trend toward OS compared with CMF IBCSG, International Breast Cancer Study Group; ABCSG, Austrian Breast and Colorectal Cancer Study Group; Int, Intergroup; ZEBRA, Zoladex Early Breast Cancer Research Association; HR, hormone receptor; Ana, anastrozole; AC, adriamycin, cyclophosphamide; CAF, cyclophosphamide, doxorubicin, and fluorouracil; CMF, cyclophosphamide, methotrexate, and fluorouracil; DFS, disease-free survival; OFS, ovarian function suppression; OA, ovarian ablation; OS, overall survival; RFS, relapse-free survival; T, tamoxifen; TTR, time to recurrence; Z, goserelin; Zol, zoledronic acid. The ZEBRA, IBCSG VIII, IBCSG 11-93, and Ejlertsen studies compare ovarian suppression vs. systemic chemotherapy and show that there are no differences between disease-free survival and OS between the two arms. ABSCGF showed that complete ovarian suppression was better than systemic chemotherapy in relapse-free survival. In INT 0101 and IBCSG VIII, systemic chemotherapy followed by ovarian suppression was found to be most beneficial in younger women (40 years of age). ABCSG-12 showed no difference between tamoxifen or anastrozole combined with goserelin in disease-free survival. Endocrine therapy in breast cancer Williams and Harris 1040-872X ß 2014 Wolters Kluwer Health | Lippincott Williams Wilkins 45
  6. 6. Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited. and in the majority of those older than age 40, this is permanent. Some oncologists have started extending the use of aromatase inhibitors to women older than age 40 with chemotherapy- induced ovarian failure. Aromatase inhibitors must be used with caution in premenopausal women who have had chemotherapy-induced amenorrhea because they can be associated with return of ovarian function and pregnancy. On the basis of the results of the available data, we would recommend continued use of tamoxifen in the adjuvant setting in premenopausal women. How- ever, if a premenopausal woman develops amenor- rhea after chemotherapy and her hormone levels are reflective of a postmenopausal setting, an aromatase inhibitor could be used with close monitoring. The results of the SOFT and the TEXT trial will provide further recommendations for the role of aromatase inhibitors in premenopausal women. In postmenopausal women, 5 years of adjuvant aromatase inhibitors when compared with tamox- ifen significantly lowered the recurrence rates; however, no clear survival benefit has been demon- strated until recently. The Breast International Group (BIG) 1-98 trial was updated with a median follow-up of 8.1 years and a survival benefit was noted with letrozole monotherapy [37 ]. The optimal duration of adjuvant endocrine therapy for postmenopausal women is currently unknown. The MA17 trial examined the effect of adding an aromatase inhibitor after 5 years of tamoxifen therapy in postmenopausal women and benefit has been seen with the addition of an aroma- tase inhibitor [38]. The results of the ATLAS trial, discussed earlier, showed a benefit to extended endocrine therapy using tamoxifen, suggesting that this strategy may be useful; however, no trial has evaluated 10 years of aromatase inhibitor therapy. There are several ongoing studies comparing extended vs. 5 years of aromatase inhibitor therapy and results are anxiously awaited! On the basis of the available data, standard of care is monotherapy with an aromatase inhibitor for 5 years or sequential therapy with tamoxifen for 2–5 years followed by an aromatase inhibitor for 5 years. However, if a woman is at high risk for relapse, it may be beneficial to extend aromatase inhibitor therapy beyond the 5-year mark. ROLE OF ENDOCRINE THERAPY IN PRIMARY PREVENTION OF BREAST CANCER Tamoxifen and raloxifene are currently approved for risk reduction in women at least 35 years of age at greater than 1.2-fold increased risk of breast cancer [39]. In MAP-3 (Mammary Prevention.3 trial), exemestane was given to postmenopausal women at risk for developing invasive breast cancer, and after 3 years of follow-up, exemestane was found to significantly reduce invasive breast cancer with no serious toxic side-effects [40]. Results of the Inter- national Breast Cancer Intervention Study 2 trial (IBIS-2) evaluating anastrozole in the prevention setting will be available in 2013. CONCLUSION Endocrine therapy continues to be the mainstay of treatment for hormone-receptor-positive breast can- cer at all stages and ages. Results of the recent clinical trials demonstrate the benefit of 10 vs. 5 years of tamoxifen in the adjuvant setting for pre- menopausal women and have examined the benefit of combination endocrine therapy in the first-line and second-line setting. In addition, targeted therapy has been developed and validated as a useful approach to overcoming resistance to endocrine therapy. These studies will lead to practice change for hormone-receptor-positive breast cancer. They also pose new clinical questions and will guide future research in order to determine the optimal duration of adjuvant endocrine therapy, the most beneficial sequence of endocrine therapy in the metastatic setting and how to continue to overcome endocrine resistance. Acknowledgements None. Conflicts of interest L.N.H. and N.W. have no conflicts of interest to report. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Hammond ME, Hayes D, Dowett M, et al. ASCO–CAP guideline recommen- dations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010; 28:2784–2795. 2. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma. Suggestions for a new method of treatment with illustrative cases. Lancet 1896; 148:162–165. 3. Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomized trial. Lancet 2002; 359:3131–3139. 4. Thurlimman B, Keshavian A, Coates AS, et al., Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353:2747–2757. 5. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010; 28:509–518. Breast cancer 46 Volume 26 Number 1 February 2014
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Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast cancer prevention in postmenopausal women. N Engl J Med 2011; 364:2381– 2391. Endocrine therapy in breast cancer Williams and Harris 1040-872X ß 2014 Wolters Kluwer Health | Lippincott Williams Wilkins 47