Treatment of established breast cancer in post-menopausal women: Role of aromatase inhibitors

review S. Samphao1 J. M. Eremin2 M. El-Sheemy1,3,4 O. Eremin1,3,5 1

Research & Development Department, 2Department of Clinical Oncology, 3Lincoln Breast Unit, Lincoln County Hospital, Lincoln, 4 Faculty of Health, Life and Social Sciences Department, University of Lincoln, Lincoln, 5 Department of Surgery, Queen’s Medical Centre, Nottingham Correspondence to: S. Samphao, Research & Development Department, Lincoln County Hospital, Greetwell Road, Lincoln LN2 5QY, UK Tel: +44(0)1522 573872 Fax: +44(0)1522 573499 email: ssamphao@hotmail. com

TREATMENT OF ESTABLISHED BREAST CANCER IN POSTMENOPAUSAL WOMEN: ROLE OF AROMATASE INHIBITORS Endocrine therapy plays a crucial and historically important role in the treatment of women with hormoneresponsive breast cancer. Tamoxifen has been the standard endocrine treatment for advanced and earlystage breast cancer for almost three decades. However, patients receiving tamoxifen may either fail to respond or develop disease recurrence following completion of therapy. The aromatase inhibitors (AIs) have become the new and alternative modalities of endocrine treatment for post-menopausal women with oestrogen receptor-positive breast cancer, as a result of promising data from randomised trials in metastatic and locally advanced breast cancers. Recently, the results from several large, randomised, controlled adjuvant trials have provided further evidence that the use of AIs, either as initial treatment or sequentially after tamoxifen, improves disease-free survival and, in certain patients, overall survival. With relatively short-term follow-up, the use of AIs has been shown to be safe and welltolerated. Nevertheless, some detrimental adverse effects, particularly skeletal-related events or cardiovascular disease, remain important issues of concern and warrant continued monitoring and follow-up. The optimal use of AIs, the appropriate timing of treatment, and the superiority of individual agents are under investigation. Use of AIs in women with chemotherapy-induced amenorrhoea should be cautious due to the possibility of return of ovarian function. Cost-effectiveness and quality of life remain issues of interest since the high and ever increasing incidence of breast cancer has contributed to signicant healthcare costs and patients with breast cancer following appropriate treatment are living longer but not necessarily being cured of their diseases. keywords: breast cancer, aromatase inhibitor, post-menopause, oestrogen receptor Surgeon, 1 February 2009, pp. 42-55

INTRODUCTION Breast cancer is the commonest cancer to occur in women in the UK. More than 44,000 new cases of breast cancer were diagnosed in 2004.1-4 Although the incidence appears to be increasing, the mortality has been steadily declining, albeit that the longterm outcome is uncertain.5 An important factor in this improved clinical outcome has been the use of anti-hormonal therapy for women with oestrogen receptor (ER) expressing cancers.6 Oestrogen has been recognised as a significant factor in the development and progression of breast cancer.7,8 Following the report of the remarkable outcome of oophorectomy in women with advanced breast cancer by Beatson in 1896, deprivation of oestrogenic signalling has been the mainstay of endocrine management.9 The development of agents targeting and affecting oestrogenic signalling pathways has been well documented. The expression of the ER in breast cancer cells has been shown to be a significant predictive factor for response to endocrine manipulation; approximately 75% of breast cancers are ER positive.10 42

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Tamoxifen, a selective oestrogen receptor modulator, inhibits the growth of breast cancer through competitive antagonism of oestrogen binding to its receptor. Tamoxifen has partial oestrogen agonist effects that help prevent bone demineralisation in post-menopausal women and improves the lipid profile.11 Tamoxifen is approved for the systemic treatment of metastatic breast cancer (MBC) and has been the standard adjuvant therapy for earlystage ER-positive breast cancer for many years.12 A recent meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group has shown that five years of adjuvant tamoxifen in patients whose breast cancers expressed the ER reduced the annual breast cancer death rate by 31%.6 Treatment with tamoxifen beyond five years had no additional benefit, but increased the risk of endometrial cancer, and thromboembolic and cerebrovascular diseases.13,14 In addition, at least two-thirds of patients do not appear to benefit from tamoxifen.15 Therefore, an alternative hormonal therapy with a more favourable morbidity and efficacy may decrease the long-term disease recurrence and mortality. © 2009 Surgeon 7; 1: 42-55

Androstendione

<

>

Testosterone

Aromatase Inhibitors

Aromatase

Oestrone

>

<

Aromatase

<

>

Oestradiol

Fig 1. Schematic outline of mechanisms of action of aromatase inhibitors in peripheral tissues

METASTATIC BREAST CANCER Aromatase inhibitors (AIs) act by blocking the aromatase enzyme, a member of the cytochrome P450 (CYP) family, which is responsible for the conversion of adrenal androstendione to oestrogen in peripheral tissues (Figure 1) – the predominant source of oestrogen in post-menopausal women.16 Unlike tamoxifen, AIs lack oestrogenagonist activity, and pre-menopausal women with functioning ovaries do not benefit from AIs due to their inability to affect the ovarian production of oestrogen. AIs are classified by their chemical structure and mechanism of action into steroidal (type I) and non-steroidal (type II) inhibitors. Type I inhibitors bind aromatase irreversibly, whilst type II interact competitively with the haem group of the aromatase enzyme.17,18 AIs have been developed pharmacologically from the first-generation, non-selective aminoglutethemide. The AIs in current clinical use are third-generation agents, very potent, selective, and less toxic than the original drug. Third-generation AIs include the type II non-steroidal inhibitors, anastrozole and letrozole, and the type I steroidal inhibitor exemestane. The third-generation AIs can reduce serum oestrogen by more than 95%, although the degree of suppression varies with individual agents. A randomised, cross-over study of the effectiveness of anastrozole and letrozole in suppressing total-body aromatisation and plasma oestrogen levels has shown that letrozole is a more potent suppressor than anastrozole.19 Another small study has confirmed that letrozole is the most effective in suppressing oestrone and oestradiol followed by anastrozole and then exemestane.20 However, there are insufficient data to determine whether the small differences in oestrogen suppression between the different AIs affect clinical efficacy.21 Data from the phase III randomised direct comparisons between anastrozole and exemestane (MA.27 trial), and letrozole and anastrozole (Femara versus Anastrozole Clinical Evaluation [FACE] trial) are awaited with interest. This article discusses the role of AIs in post-menopausal women with breast cancer, and reviews the evidence for their efficacy and safety. © 2009 Surgeon 7; 1: 42-55

Second-line therapy AIs have been compared with megestrol acetate in the second-line treatment of MBC. The results from phase III studies showed the superiority of AIs with acceptable toxicity profiles (Table 1).22-27 An open-label multicentre randomised study compared letrozole with anastrozole in 713 post-menopausal patients with tamoxifen-resistant MBC; 52% of patients had unknown hormone receptor status.21 The study showed no difference in time to disease progression (TTP), time to treatment failure (TTF) and overall survival (OS). However, the objective response rate (ORR) was significantly higher in the letrozole group, compared with the anastrozole group (19% vs 12%, p=0.01). In a sub-group analysis of hormone receptor-positive patients, the ORR was comparable between the two groups. Possibly due to the limitations in study design and unknown hormone receptor status in the majority of patients, the superior efficacy of either AI could not be established. A number of studies have shown no cross-resistance between the AIs, particularly the benefits of exemestane therapy after failure of the non-steroidal AIs.28,29 A recent study has also shown the benefit of using a non-steroidal AI after failure of exemestane.30 First-line therapy Several phase III randomised multicentre trials have compared the use of AIs with tamoxifen in post-menopausal women with MBC (Table 2).31-38 Anastrozole has been compared with tamoxifen in two identically designed studies, one in North America and the other in Europe.31-33 No significant difference in ORR was demonstrated in either study, whilst a significantly longer TTP and clinical benefit (CB) were observed only in the first study, in which the majority of patients had hormone receptor-positive cancers. However, a pooled analysis of data from both trials did not show a difference in either TTP or CB.34 Letrozole has been evaluated in a large double-blind, double-dummy, randomised trial and has shown a superiority over tamoxifen in TTP, TTF, ORR and CB.35 The OS during the first two years was significantly better with letrozole.36 An open-label phase III

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Table 1. Phase III trials comparing aromatase inhibitors with megestrol acetate as secondline therapy for advanced breast cancer Study

AIs

No. of patients

TTP (months)

ORR (%)

CB (%)

OS (months)

Jonet et al. (1996)22

Anastrozole

378

N/A

N/A

34 vs 33

N/A

Buzdar et al. (1997)23

Anastrozole

386

5.6 vs 5.0

10 vs 6

37 vs 35

N/A

Buzdar et al. (1998)24

Anastrozole

764

4.8 vs 4.6

13 vs 12

42 vs 40

26.7 vs 22.5 (p < 0.03)

Dombernowsky et al. (1998)25

Letrozole

551

5.6 vs 5.5

24 vs 16 (p = 0.04)

35 vs 32

25.3 vs 21.5

Buzdar et al. (2001)26

Letrozole

602

3.0 vs 3.0 N/A

17 vs 13

29.0 vs 26.0

Kaufmann et al. (2000)27

Exemestane

769

4.7 vs 3.9 15 vs 12 (p = 0.04)

37 vs 35

NR vs 28.7 (p = 0.04)

Abbreviations: AIs, aromatase inhibitors; TTP, time to progression; ORR, objective response rate; CB, clinical benet; OS, overall survival; N/A, not applicable; NR, not reached

Table 2. Phase III trials comparing aromatase inhibitors with tamoxifen as rst-line therapy for advanced breast cancer Study

AIs

No. of patients

TTP (months)

ORR (%)

CB (%)

OS (months)

Nabholtz et al. (2000)31

Anastrozole

353

11.1 vs 5.6 (p = 0.005)

21 vs 17

59 vs 46 N/A (p = 0.01)

Bonneterre et al. (2000)33

Anastrozole

668

8.2 vs 8.3

33 vs 33

56 vs 55

N/A

Bonneterre et al. (2001)34

Anastrozole

1021

8.7 vs 7.0 29 vs 27

57 vs 52

N/A

Mouridsen et al. (2003)36

Letrozole

907

9.4 vs 6.0 (p < 0.0001)

32 vs 21 (p = 0.0002)

50 vs 38 (p = 0.0004)

34.0 vs 30.0

Paridaens et al. (2004)38

Exemestane

382

10.9 vs 6.7 (p = 0.04)

44 vs 29

72 vs 66

N/A

Abbreviations: AIs, aromatase inhibitors; TTP, time to progression; ORR, objective response rate; CB, clinical benet; OS, overall survival; N/A, not applicable

randomised study has shown a higher ORR and significantly longer TTP with exemestane, compared with tamoxifen.37,38 These studies have shown the benefit of AIs with acceptable toxicity profiles. AIs, therefore, have been approved for first-line endocrine therapy in postmenopausal women with MBC. A meta-analysis comparing several generations of AIs with standard hormonal treatment (tamoxifen or progestagens) in MBC has shown a survival benefit with third-generation AIs as first-, second- and subsequent-line therapies.39 Recently, a Cochrane systematic review of 30 published randomised trials, comparing the effects of any AI 44 |

with other endocrine therapies, no endocrine therapy, or a different AI in the treatment of MBC, has confirmed a survival benefit with an AI over other endocrine therapies, but overall benefits in TTP, CB, and ORR were less clear.40

EARLY BREAST CANCER Based on the efficacy of AIs in MBC, several phase III randomised studies comparing AIs with tamoxifen or placebo in the adjuvant treatment of early breast cancer in post-menopausal women have been carried out, with AIs prescribed as initial or sequential therapy after two to three years or five years of tamoxifen.

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Table 3. Phase III trials comparing aromatase inhibitors with tamoxifen or placebo as adjuvant therapy in post-menopausal women with early breast cancer (intention-to-treat analysis) Study

Design; No. of patients

Follow-up (months)

DFS; EFS (HR)

TTR (HR)

OS (HR)

ATAC44

Doubleblind; 9366

100

0.90; p = 0.025

0.81; p = 0.0004

1.00; p = 0.99

BIG 1-9849

Doubleblind; 8028

51

0.82; p = 0.007

0.78; p = 0.004

0.91; p = 0.35

IES54

Doubleblind; 4742

55.7

0.76; p < 0.001

0.63; p < 0.001

0.85; p = 0.08

ITA56

Open-label; 448

52

0.42; p = 0.0001

0.43; p = 0.001

0.52; p = 0.1

ABCSG 8/ARNO 9557

Open-label; 3224

28

0.60; p < 0.001

0.61; p = 0.007

97% vs 96%; p = 0.2

MA.1762

Doubleblind; 5187

30

0.58; p < 0.001

0.58; p < 0.001

0.82; p = 0.3

Abbreviations: ATAC, Anastrozole or Tamoxifen Alone or in Combination; BIG 1-98, Breast International Group; IES, Intergroup Exemestane Study; ITA, Italian Tamoxifen Anastrozole; ABCSG 8/ARNO 95, Austrian Breast Cancer Study Group Trial 8/Arimidex-Nolvadex 95; MA.17, National Cancer Institute of Canada Clinical Trial Group MA.17; DFS, disease-free survival; EFS, event-free survival; TTR, time to recurrence; OS, overall survival; HR, hazard ratio

Initial adjuvant therapy Two large randomised, controlled trials have compared AIs with tamoxifen as initial adjuvant therapy (Table 3). The Anastrozole or Tamoxifen Alone or in Combination (ATAC) trial compared five years of tamoxifen, anastrozole or the combination of both agents.41-44 The first analysis at a median follow-up of 33 months showed improved outcome with anastrozole over tamoxifen and combination arms. The combination arm was closed due to no advantage over tamoxifen alone. Further analysis at a median follow-up of 47 months and, more recently, 68 months confirmed a significant advantage of anastrozole over tamoxifen in disease-free survival (DFS), time to recurrence (TTR), distant recurrence and occurrence of contralateral breast cancer.42,43 Data at 100-month follow-up, recently published, has confirmed these results, especially in hormone receptor-positive patients.44 The study also has demonstrated the superiority of anastrozole over tamoxifen in this sub-group of patients for the carryover benefit after treatment completion in either DFS (absolute benefit of 2.5% at five years which increased to 4.1% at nine years) or TTR (absolute benefit of 2.8% at five years which increased to 4.8% at nine years). However, no difference in OS between the two groups was seen. A retrospective subgroup analysis showed a benefit of anastrozole in patients with ER-positive/progesterone receptor (PgR)negative tumours at a median follow-up of 68 months (hazard ratio [HR] 0.43; p<0.001).45 This benefit seems to be even greater at a median follow-up of 100 months (HR 0.42; p=0.001).44 However, this subgroup finding has not been confirmed in the subsequent TransATAC study, where the tissues were retrospectively collected and centrally assessed for ER, PgR, and human epidermal growth factor receptor (HER-2/neu) status.46 No significant benefit was seen in patients with tumour-involved regional lymph nodes and in those women who had received adjuvant chemotherapy.44,47 © 2009 Surgeon 7; 1: 42-55

The Breast International Group (BIG) 1-98 trial compared letrozole with tamoxifen in four treatment arms: five years of tamoxifen, five years of letrozole, two years of tamoxifen followed by three years of letrozole, and two years of letrozole followed by three years of tamoxifen.48,49 The published analysis included data from the monotherapy arms and the first two years of therapy from the sequential arms. At 25.8 months follow-up, the results of the primary core analysis showed that letrozole significantly improved DFS (HR 0.81; p = 0.003) and reduced distant metastases (HR 0.73; p=0.001). A recent analysis at 51 months follow-up revealed a significant advantage of letrozole over tamoxifen in DFS, TTR and distant metastases (Table 3).49 However, OS between the two groups did not differ significantly. In a subgroup analysis, a significant benefit in DFS in favour of letrozole was seen in high risk patients with tumour-involved axillary lymph nodes and in those patients who were treated with chemotherapy.48 However, this benefit was less pronounced in the subsequent study with a longer follow-up.49 Recent studies also have demonstrated the benefit of letrozole over tamoxifen in DFS for all patients with centrally-assessed ER-positive tumours, irrespective of PgR or HER-2/neu status.50,51 The comparison between tamoxifen and exemestane is currently being investigated in the Tamoxifen and Exemestane Adjuvant Multicentre (TEAM) trial. Eight thousand post-menopausal women with breast cancer (ER-positive) will be randomised to receive five years of tamoxifen or exemestane. Due to the results of the Intergroup Exemestane Study (IES), the protocol has been amended to five years of exemestane, compared with 2.5 years of tamoxifen followed by 2.5 years of exemestane.

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Sequential adjuvant therapy The IES is a double-blind randomised trial comparing five years of tamoxifen with the sequential use of two to three years of tamoxifen followed by exemestane for a total treatment of five years.52-54 At a median follow-up of 30.6 and 37.4 months, there was a significant improvement in DFS in favour of the sequential arm (HR 0.68; p<0.001 and HR 0.73; p<0.001, respectively).52,53 An updated assessment at 55.7 months follow-up demonstrated that switching to exemestane significantly improved DFS, TTR and distant metastases, and reduced incidence of contralateral breast cancer (Table 3).54 No OS difference, however, has been seen between the two groups. Nonetheless, there was a small benefit in OS for the sequential arm in the subgroup of patients with ER-positive/unknown cancers (adjusted HR 0.83; p=0.04). The small, open-label phase III Italian Tamoxifen Anastrozole (ITA) trial evaluated the efficacy of anastrozole after two to three years of tamoxifen until completion of five years.55,56 At a median follow-up of 36 months, DFS was significantly longer in the anastrozole group (HR 0.35; p=0.001). The study also showed a significant benefit in event-free survival (EFS) (HR 0.35; p= 0.0002) and local DFS (HR 0.15; p=0.003).55 Recently, updated results at 52 months follow-up have been confirmed (Table 3).56 A combined analysis of the Austrian Breast Cancer Study Group (ABCSG) Trial 8 and the Arimidex-Nolvadex (ARNO) 95 trial also demonstrated significantly better EFS and fewer distant metastases for two years of tamoxifen followed by three years of anastrozole, compared with five years of tamoxifen at a median follow-up of 28 months (Table 3).57 The mature data of the ABCSG Trial 8 (n= 3700), the only trial which randomised patients after surgery, showed a significant EFS in favour of the switching arm (HR 0.68; p=0.02) at a median follow-up of 30 months.58 The results from the ARNO 95 trial (n=979) showed significantly improved DFS (HR 0.66; p=0.049) with a small advantage in OS (HR 0.53; p=0.045) in the sequential arm at a median follow-up of 30.1 months.59 However, it is important to note that the number of deaths was very small (15 in the anastrozole arm vs 28 in the tamoxifen arm). A meta-analysis of ARNO 95, ABCSG 8 and ITA trials has recently been announced.60 At a median follow-up of 30 months, the results showed a significant improvement in DFS (HR 0.59; p<0.0001), EFS (HR 0.55; p<0.0001), distant DFS (HR 0.61; p=0.002) and OS (HR 0.71; p=0.04) in patients who switched to anastrozole, compared with those who remained on tamoxifen. These results suggested that clinical benefit in EFS seen in the individual trials translate into a benefit in OS when the trials data was combined. However, there are major concerns, regarding interpretation of outcomes where there are differences in patient characteristics (e.g. nodal involvement, preoperative chemotherapy, type of surgery) and time of randomisation. The combined study has shown that there was no difference in OS between both groups in the ABCSG trial 8 (HR 0.93; p=0.73), whilst a difference has been demonstrated in favour of anastrozole for both the ARNO 95 (HR 0.48; p = 0.03) and the ITA trials (HR 0.50; p=0.09).60 These findings suggest possible selection bias in the latter trials which excluded the patients who developed disease recurrences during the first two to three years on tamoxifen. Extended adjuvant therapy Based on the data showing no further clinical advantage of adjuvant 46

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tamoxifen beyond five years but the likely risk of disease recurrence persisting, the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) has conducted a double-blind randomised (MA.17) trial, comparing the efficacy of letrozole with placebo following five years of tamoxifen.61-64 The first interim analysis at a median follow-up of 2.4 years showed an estimated 4-year DFS benefit for letrozole, compared with placebo (HR 0.57; p = 0.00008).61 Updated findings after a median follow-up of 30 months confirmed a significantly longer DFS and lower incidence of distant metastases in the letrozole group (Table 3).62 The OS was significantly improved with letrozole in patients with lymph node-involved cancers (HR 0.61; p=0.04). This study was discontinued following the publication of the promising results. The study was unblinded in 2003, and 1655 women originally assigned to placebo crossed over to letrozole, whilst 613 elected to have no further treatment. At 54 months of follow-up, DFS was significantly improved in the patients who crossed over to letrozole, compared with those who had no further treatment (HR 0.31; p<0.001).63 These data support the efficacy of letrozole despite a prolonged period since completion of tamoxifen. The intention to treat analysis of all outcomes, before and after unblinding, based on the original randomisation was performed. A better 4-year DFS (HR 0.64; p<0.001), longer time to distant recurrence (HR 0.76; p=0.04) and lower incidence of contralateral breast cancer (HR 0.61; p=0.04) in patients originally randomised to letrozole, compared with placebo, have been demonstrated. The OS, on the other hand, did not differ significantly in any of the subgroups.64 These results highlight the beneficial effects of letrozole in extended adjuvant therapy. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 compared five years of exemestane with placebo after completion of five years of tamoxifen in post-menopausal women with hormone receptor-positive cancers.65 The study was unblinded in 2003 after the promising results of the MA.17 trial had been reported. At the time of unblinding, 1598 patients had been randomised. Upon unblinding, 560 of the 783 patients on exemestane continued exemestane; of the 779 patients on placebo, 344 switched to exemestane. With a median follow-up of 30 months, there was a borderline statistically significant improvement in DFS in favour of the exemestane arm (HR 0.68; p=0.07) and a significant improvement in relapse-free survival (HR 0.50; p=0.03) but no difference in OS (HR 1.2; p=0.63). As the majority of women with invasive breast cancer harbour the risk of recurrence, even after more than ten years following potentially curative surgery, the OS with AIs needs prolonged follow-up to establish more reliably this outcome.5 Clinical use of AIs as adjuvant therapy Based on the data from these large phase III adjuvant trials, the thirdgeneration AIs (anastrozole, letrozole, exemestane) have been approved worldwide for adjuvant endocrine therapy in post-menopausal women with hormone receptor-positive early breast cancer. However, there are several unanswered questions – the optimal duration of treatment, whether continuous or sequential therapy is best and in what patient groups, or which of the AIs is the clinically superior agent – that need to be addressed. A meta-analysis evaluating the efficacy and safety of AIs as adjuvant therapy for post-menopausal women with hormone receptor-positive breast cancer has recently been reported.66 The results showed a supe-

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riority of AIs, either as an initial or as a sequential therapy after two to five years of tamoxifen, over tamoxifen alone in DFS. For OS, however, there was a benefit only when an AI was used sequentially following two to three years of tamoxifen. Two studies have developed and used models to predict long-term (ten years) outcomes in the different uses of AIs. Using the Markov models, Punglia et al. (2005) suggested that sequential therapy with tamoxifen followed by an AI after 2.5 years yielded a significant improvement in DFS, compared with either drug alone or cross-over treatment after five years of tamoxifen.67 However, this model used heterogeneous end-points from different trials and assumed constant recurrence rates. By contrast, another study using a different model concluded that early treatment with an AI was superior to using it as a sequential agent after two to five years of tamoxifen.68 Data from the sequential therapy trials have demonstrated more favourable outcomes in DFS and OS, compared with the initial therapy trials. However, this direct comparison cannot be confirmed unequivocally since the sequential trials, except the ABCSG Trial 8, enrolled patients who were disease-free after two to three years of tamoxifen, while the initial therapy trials randomised patients immediately after surgery. The sequential trials, therefore, excluded those patients who developed recurrences in the first few years on tamoxifen. While the optimal treatment strategy for the use of AIs is being debated, true clinical outcomes can only be determined from large prospective, randomised, controlled trials and long-term patient follow-up. The results from the ongoing BIG 1-98 trial, directly comparing initial AIs with sequential therapy will provide important and, hopefully, more definitive information. The BIG 1-98 trial has recently published a retrospective review of data evaluating predictors of early breast cancer relapse.69 At a median follow-up of two years, breast cancer relapse was higher in the tamoxifen group, compared with the letrozole group. Significant predictive factors for early relapse included large tumour size, high tumour grade, vascular invasion, tumour involved lymph nodes, and absence of expression of hormone receptors and HER-2/neu overexpression/amplification. The result has shown that letrozole significantly reduced the risk of early relapse, compared with tamoxifen. It was qualitatively more effective than tamoxifen within some subgroups (e.g. patients with four or more positive nodes, tumours >2cm, or with vascular invasion). Data regarding prognostic value of hormone receptor status remain uncertain. However, this study confirmed the results from the subgroup analysis of TTR in the ATAC trial which showed equivalent prognosis between patients with ER-positive/ PgR-positive, compared with those with ER-positive/PgR-negative tumours.45 Thus, the benefit of letrozole or anastrozole in preventing early relapse has been shown in both hormonal subgroups. The use of AIs as initial therapy, therefore, may be the most beneficial for high risk patients. All studies of AIs carried out to date were planned for a total of five years of adjuvant therapy. It is generally accepted that a five-year course of AIs is well tolerated with acceptable toxicity profiles. There is no evidence to date to support the use of AIs beyond five years. The MA.17R study, an extension of the MA.17 trial, is randomly assigning patients to a further five years of either letrozole or placebo. This study, hopefully, will provide answers as to the optimal duration of AIs in adjuvant therapy. As noted in the previous section, the MA.27 and FACE trials, © 2009 Surgeon 7; 1: 42-55

which are directly comparing the efficacy and safety of each individual AI in an adjuvant setting, will also provide important clinical information. Guideline recommendations The American Society of Clinical Oncology (ASCO) Technology Assessment in 2005 recommended that the optimal adjuvant hormonal therapy for post-menopausal women with hormone receptor-positive breast cancer should include an AI either as initial therapy or after treatment with tamoxifen.70 AIs are appropriate as initial treatment for women with contraindications to tamoxifen, and patients who are intolerant of AIs should receive tamoxifen. The ASCO also suggested that the HER-2/neu status should not be considered when making choices about adjuvant hormonal therapy. Recently, the 2007 St. Gallen Consensus Panel suggested that five years of tamoxifen was still a viable option for certain patient categories.71 The majority of the panel preferred a switching from tamoxifen to an AI after two to three years of tamoxifen, whilst a minority supported an initial use of an AI. They also supported the addition of an AI after completion of tamoxifen for five years only for patients with nodal tumour disease. Furthermore, the panel suggested that AIs should be given initially in patients at high risk (e.g. tumour involved lymph nodes) or with HER-2/neu expressing tumours. In the UK, all third-generation AIs were approved by the National Institute for Health and Clinical Excellence (NICE) for adjuvant endocrine therapy in post-menopausal women with hormone receptor-positive early breast cancer.72 Due to limited evidence on efficacy of the different AIs in different risk groups of patients, NICE was not able to issue guidance on the use of AIs for individual subgroups, although the initial therapy with AIs might be preferable to tamoxifen in patients who are at high risk of early recurrence (e.g. tumour involved lymph nodes). Local treatment guidelines may help inform the clinician in selecting the optimal therapy for patients. In 2005 the Mid Trent Cancer Network, for example, recommended that five years of tamoxifen remains an appropriate option for patients at low risk of recurrence, as assessed by the Nottingham Prognostic Index.73 For all other patients, adjuvant endocrine therapy should include an AI.

LARGE OR LOCALLY ADVANCED BREAST CANCER Neoadjuvant therapy Neoadjuvant chemotherapy plays an important role in the treatment of large or locally advanced breast cancers with the objective of downstaging the disease locally and increasing the rate of breast conserving surgery (BCS). However, the most commonly used chemotherapy regimens are accompanied by a high morbidity. Endocrine therapy, therefore, is an attractive alternative, particularly in elderly postmenopausal women with hormone receptor-positive breast cancer. Randomised studies comparing tamoxifen, used as neoadjuvant therapy prior to surgery, followed by adjuvant tamoxifen, have demonstrated an initial reduction in tumour size without impact on OS; however, the long-term local disease control is poor.74-77 As a result of documented superiority of AIs over tamoxifen in metastatic and adjuvant therapy, several randomised studies have investigated the efficacy of the AIs as neoadjuvant therapy. In the Immediate Pre-operative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) trial, 330 post-menopausal women with

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hormone receptor-positive operable breast cancer were randomised in a double-blinded fashion to three months of pre-operative treatment with anastrozole, tamoxifen, or both.78 The ORR did not significantly differ between the anastrozole and the tamoxifen groups (Table 4). In patients who were assessed as requiring mastectomy at baseline (n = 124), 44% received BCS after anastrozole, compared with 31% of those given tamoxifen (p = 0.2); this difference became significant for patients who were deemed candidates for BCS by their surgeons. The ORR for patients with HER-2/neu expressing tumours (n = 34) was higher with anastrozole than with tamoxifen (58% vs 22%; p = 0.2). The Preoperative Arimidex Compared with Tamoxifen (PROACT) trial, a phase III randomised, double-blind study evaluated the efficacy of three months of treatment with anastrozole versus tamoxifen as neoadjuvant therapy in 451 post-menopausal women with hormone receptor-positive breast cancer.79 Additional pre-operative chemotherapy was optional and was determined before randomisation. The results revealed that the ORR was higher with anastrozole than with tamoxifen (Table 4). In the subset of patients receiving hormonal therapy only (n = 314), a higher percentage of those treated with anastrozole underwent BCS, compared with those treated with tamoxifen (43% vs 31%; p = 0.04). A phase III, double blind, randomised multicentre study (P024) was conducted to compare the efficacy of letrozole with tamoxifen in 337 post-menopausal women with hormone receptor-positive primary untreated breast cancer. After four months of treatment, the ORR was significantly higher in the letrozole group, compared with the tamoxifen group (Table 4).80 Patients receiving letrozole also had a higher incidence of BCS. Further subgroup analysis demonstrated a marked difference in the clinical response rate between letrozole and tamoxifen (88% vs 21%; p<0.001) in tumours that expressed the ER and either HER-1/neu or HER-2/neu.81

The correlation between response to treatment and ER and PgR expression levels has been assessed further by the introduction of the Allred score (using an intensity score [range, 1-3] with a frequency score [range, 0-5]).81,82 The results using this scoring system have shown that letrozole response rates were superior, compared with tamoxifen response rates in every ER Allred category from 3 to 8. A small trial randomly assigned 151 post-menopausal women with hormone receptor-positive breast cancer to receive either tamoxifen or exemestane as neoadjuvant therapy. The study showed higher ORR and BCS with exemestane therapy compared with the usage of tamoxifen (Table 4).83 One study has directly compared neoadjuvant endocrine therapy with chemotherapy in 121 post-menopausal women with hormone receptor-positive breast cancer. The findings from this study have recently been presented.84 Patients were randomly assigned to receive either three months of anastrozole or four cycles of doxorubicin and paclitaxel. No differences in ORR (90% vs 76%; p>0.05) and BCS (37% vs 21%; p=0.05) were documented between the anastrozole and chemotherapy groups. Based on the results from these randomised trials, letrozole appears to demonstrate a greater efficacy, compared with tamoxifen, in the neoadjuvant setting. However, the difference between various AIs is under evaluation in the current American College of Surgeons Oncology Group-Z1031 trial which directly compares anastrozole, letrozole and exemestane in the neoadjuvant setting. Renshaw et al. (2004) suggested that a longer duration of neoadjuvant AIs (six months) may produce a greater response.85 The optimal duration of treatment, thus, needs to be established. The precise level of ER expression, required to define groups of patients who are likely to have a good response to endocrine therapy, remains unclear, to date. Generally, at least 10% of the nuclei in the

Table 4. Phase III trials comparing aromatase inhibitors with tamoxifen as neoadjuvant therapy in post-menopausal women with breast cancer Study

AIs

No. of patients

Duration (months)

ORR (%)

BCS (%)

IMPACT78

Anastrozole

330

3

37 vs 36 (p = 0.9)

46 vs 22 (p = 0.03)

PROACT79

Anastrozole

451

3

40 vs 35 (p = 0.3)

43 vs 31 (p = 0.04)

P02480

Letrozole

337

4

55 vs 36 (p < 0.001)

45 vs 35 (p = 0.02)

Russian Trial83

Exemestane

151

3

76 vs 40 (p = 0.05)

37 vs 20 (p = 0.05)

Abbreviations: IMPACT, Immediate Preoperative Arimidex, Tamoxifen, or Combined with Tamoxifen; PROACT, Pre-Operative Arimidex Compared to Tamoxifen; AIs, aromatase inhibitors; ORR, objective response rate; BCS, breast conserving surgery

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invasive component of the tumours staining positive for hormonal receptors are considered to represent ER and/or PgR-positive cancers (corresponding to an Allred score of five or more). The observations from P024 neoadjuvant hormonal study have shown a benefit of letrozole over tamoxifen in a subgroup of patients who had ERpositive tumours with Allred scores of three to five (corresponding to 1-10% positive cells).80 However, the results from the TransATAC adjuvant study, using ER Allred score cutoff levels of more than two, have demonstrated that quantitative expression of ER and PgR did not identify patients who benefited from anastrozole, compare with tamoxifen.46 These results suggest that patients with low ER expression (Allred score of three to five) may derive benefit from endocrine therapy in either neoadjuvant or adjuvant settings. Nevertheless, a clear cut level for ER expression requires further investigation.

ROLE OF AROMATASE INHIBITORS IN PRE-MENOPAUSAL WOMEN Ovarian function suppression (OFS), either by oophorectomy or medical castration with a luteinising hormone-releasing hormone (LHRH) agonist, has been shown in randomised trials and confirmed by a recent meta-analysis to provide survival benefit in prememopausal women with hormone receptor-positive breast cancer. This occurred whether OFS was used alone or combined with tamoxifen or chemotherapy.86 In pre-menopausal women, the combination of a LHRH agonist and an AI has been shown to be effective in the treatment of MBC.87,88 Several large, ongoing randomised trials are addressing the value of AIs in pre-menopausal women. The Suppression of Ovarian Function Trial (SOFT) has randomly assigned 3000 pre-menopausal women to receive either five years of tamoxifen, OFS with tamoxifen or OFS with exemestane. The Tamoxifen and Exemestane Trial (TEXT) has compared 1845 pre-menopausal women who received either five years of triptorelin with tamoxifen or triptorelin with exemestane. The ABCSG Trial 12 has randomly assigned 2000 pre-menopausal women to receive three years of either tamoxifen or anastrozole, in combination with goserelin. The use of AIs should be cautious in patients with chemotherapyinduced amenorrhoea, as ovarian function may return. Biochemical assessment of ovarian function should be carried out. The results from a recent study showed a return of ovarian function (renewed menses, pregnancy, and pre-menopausal hormonal status) in 27% of premenopausal women with chemotherapy-induced amenorrhoea after starting an AI.89 Thus, serial monitoring of serum hormonal profiles should be considered during treatment with the AIs in such patients.

ADVERSE EVENTS OF AROMATASE INHIBITORS With studies of AIs showing advantages over tamoxifen, the potential adverse events resulting from oestrogen–lowering effects becomes an important consideration in clinical decision making. Most of the adjuvant AI trials assessed safety profiles in comparison with tamoxifen. Only the MA.17 trial directly compared an AI with placebo, although the exposure to tamoxifen for five years prior to randomisation will affect the findings. The impact of AIs on bone and lipid metabolism and vascular and gynaecological complications have been evaluated. © 2009 Surgeon 7; 1: 42-55

Skeletal adverse effects In the ATAC trial, bone fractures were shown to be significantly less common with tamoxifen than with anastrozole after a median follow-up of 68 months (Table 5).43 The incidence of hip fractures was low and similar in both groups; however, the incidence of vertebral fractures was significantly higher in the anastrozole group (1.5% vs 0.9%; p=0.03). Recent data from 100-month follow-up has confirmed the above results.44 However, the increased yearly episode rate noted during treatment did not continue into the post-treatment follow-up period, where the rate on anastrozole was very similar to that with tamoxifen. In a bone substudy of the ATAC trial, 308 patients were evaluated.90 The study showed that anastrozole was associated with significant bone mass density (BMD) loss with a small increase in bone turnover, whereas the reverse was true for tamoxifen after one and two years of treatment. Updated data after five years of treatment showed a slow decrease in BMD in the lumbar spine during year two to five in the anastrozole group.91 No patients with a normal BMD at baseline developed osteoporosis following five years of anastrozole. Similarly, in the ABCSG 8/ARNO 95 trial, there were more fractures in patients switching to anastrozole than in those remaining on tamoxifen (2% vs 1%; p=0.02).57 In the BIG 1-98 trial, the fractures were significantly more frequent with letrozole after a median follow-up of 51 months (Table 5).49 A bone substudy is ongoing. A randomised study comparing exemestane with placebo in premenopausal women with breast cancer, showed no difference in BMD loss in the lumbar spine between the two groups.92 However, there was a significantly higher BMD loss in the femoral neck with exemestane, compared with placebo (2.7% vs 1.5%; p = 0.02). Although exemestane seems to have fewer adverse skeletal effects, the results from the IES trial showed that clinically relevant fractures and osteoporosis were significantly higher in the switching arm than the tamoxifen alone arm (Table 5).54 The bone substudy of 206 patients revealed significant reduction in BMD in both the lumbar spine and hip within six months of switching to exemestane.93 Thereafter, the change in BMD appeared to be slow but remained significantly higher in the switching arm. No patients with a normal BMD at baseline developed osteoporosis. In the MA.17 trial, there was a nonsignificant difference in fractures between the letrozole and placebo groups (Table 5).62 However, new diagnoses of osteoporosis were significantly higher in the letrozole group (8.1% vs 6%; p=0.003). The MA.17 bone substudy of 226 women revealed that patients receiving letrozole had a significant decrease in total hip and lumbar spine BMD at 24 months.94 The changes in bone turnover biomarkers were also increased in the patients receiving letrozole. Role of bisphosphonates in preventing bone loss All third-generation AIs have significant adverse effects on bone metabolism reflecting clinical skeletal morbidity, particularly osteoporosis and bone fractures. Based on these data, the 2003 ASCO clinical practice guideline panel on bisphosphonates and bone health in women with breast cancer advised routine and regular assessment of BMD in women on AIs.95 The optimal use of bisphosphonates in preventing fractures and loss of BMD in early breast cancer patients receiving an AI is under evaluation. The ABCSG Trial 12 evaluating the efficacy of the LHRH agonist goserelin with either tamoxifen or anastrozole in pre-menopausal women randomised half of the women to receive zoledronic acid (ZA) every six months.96

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The results showed an increase in BMD loss with increasing treatment duration, being more severe in patients receiving goserelin/anastrozole. After 36 months of treatment, only patients receiving goserelin/anastrozole (24%) met the clinical definition for osteoporosis, and another 50% were osteopenic, while 46% of patients receiving goserelin/tamoxifen were osteopenic. The addition of ZA to both treatment groups inhibited loss of BMD and effectively stabilised bone density at baseline level. No fractures have been reported in either group. Updated data at 60 months of follow-up (two years after completion of treatment) have shown some recovery in BMD loss in patients who did not receive ZA and increased BMD in those who received ZA.97 The study concluded that 4 mg of ZA, given every six months for three years, completely inhibited cancer treatment-induced bone loss and led to an improvement in BMD at five years. The Zometa-Femara Adjuvant Synergy Trial (Z-FAST) randomised 602 post-menopausal women with early breast cancer, with T scores >-2.0 receiving five years of letrozole, to receive either upfront ZA every six months or delayed ZA (to start only if T scores decreased below -2.0 or if a non-traumatic clinical fracture occurred).98 At the end of one year, BMD was significantly higher in the up front zoledronic acid group for both the lumbar spine and hip. Only 8.3% of patients on the delayed treatment arm had been started on ZA. For the patients who enrolled with normal BMD at baseline, more patients in the delayed group had T scores decreased below -1.0, compared with the up front arm (13% vs 3%). For patients with osteopenia at baseline, more patients in the delayed group had T scores decreased below -2.0, compared with the up front arm (15% vs 1%). Nontraumatic and traumatic fractures rates were low, with there being no difference between the treatment groups. Updated data at 36 months of follow-up have shown that the overall differences in the percentage change in BMD between the upfront (increased BMD) and delayed (decreased BMD) ZA treatment groups, in both the lumbar spine and the hip, progressively increased from baseline through 36 months.99 These data confirmed the efficacy of ZA in preventing bone loss

associated with adjuvant AI therapy in postmenopausal women with early breast cancer. Comparable results from the similarly designed international ZOmeta-Femara Adjuvant Synergy Trial (ZO-FAST) have also been reported.100 ZA, given six monthly, therefore, is effective in preventing cancer treatment-associated BMD loss both in pre- and post-menopausal women. However, long-term follow-up is needed and the role of the oral forms has yet to be defined. The ASCO recommended a baseline dual-energy x-ray absorptiometry (DEXA) scan with annual DEXA follow-up for breast cancer patients receiving OFS and/or AIs due to a higher risk for osteoporosis.101 In the UK, DEXA scans are usually performed at baseline on commencement of AIs and two to three years subsequently. The other recommendations for bone health, in addition to bisphosphonates, include adequate calcium and vitamin D intake, weight-bearing exercise and avoidance of smoking.101,102 Lipid metabolism and cardiovascular events Tamoxifen has been shown to have a favourable influence on lipid metabolism. However, it remains unclear whether this can translate into a reduction in cardiovascular disease (CVD). A small number of studies have evaluated the effect of AIs on lipid metabolism as well as the impact on CVD. There were no data from the ATAC and ABCSG 8/ARNO 95 trials on lipid profiles. The incidence of ischaemic heart disease (IHD) was higher in the anastrozole group, compared with the tamoxifen group in the ATAC trial (Table 5).43 However, myocardial infarctions were similar in the two treatment groups, both during treatment and after its completion.44 No difference in the rate of myocardial infarction was seen in the ABCSG 8/ARNO 95 trial.57 Changes in lipid profiles have been reported in the BIG 1-98 trial. Low-grade hypercholesterolaemia was significantly higher with letrozole.49 This result may be related to the lipid-lowering effect of tamoxifen. There were no differences in IHD and cardiac failure between the two groups; however, the incidence of grade 3-5 cardiac events was significantly higher in the

Table 5. Summary of adverse events from adjuvant trials of aromatase inhibitors (compared with tamoxifen or placebo) in post-menopausal women with breast cancer Hypercholesterolaemia (%)

IHD (%)

CVA/TIA (%)

Thromboembolic events (%)

Vaginal bleeding (%)

Hot ushes (%)

N/A

4.1 vs 3.4 (p = 0.1)

2.0 vs 2.8 (p = 0.03)

2.8 vs 4.5 (p = 0.0004)

5.4 vs 10.2 (p < 0.001)

35.7 vs 40.9 (p < 0.001)

N/A

50.6 vs 24.6 (p < 0.001)

2.2 vs 1.7 (p = 0.2)

1.4 vs 1.4 (p = 0.9)

2.0 vs 3.8 (p < 0.001)

3.8 vs 8.3 (p < 0.001)

32.8 vs 37.4 (p < 0.001)

4.3 vs 3.1 (p = 0.03)

7.3 vs 5.5 (p = 0.01)

7.2 vs 6.0 (p = 0.1)

8.0 vs 6.9 (p = 0.2)

N/A

1.2 vs 2.3 (p = 0.004)

4.6 vs 6.5 (p = 0.008)

41.3 vs 38.6 (p = 0.07)

5.3 vs 4.6 (p = 0.25)

8.1 vs 6.0 16.0 vs 16.0 (p = 0.8) (p = 0.003)

5.8 vs 5.6 (p = 0.8)

0.7 vs 0.6 (p > 0.05)

0.4 vs 0.2 (p = 0.8)

6.0 vs 8.0 (p = 0.005)

58.0 vs 54.0 (p = 0.003)

Osteoporosis (%)

Study

Follow-up (months)

Bone fractures (%)

ATAC43

68

11.0 vs 7.7 N/A (p < 0.0001)

BIG 1-9849

51

8.6 vs 5.8 (p < 0.001)

IES54

55.7

MA.1762

30

Abbreviations: ATAC, Anastrozole or Tamoxifen Alone or in Combination; BIG 1-98, Breast International Group; IES, Intergroup Exemestane Study; MA.17, National Cancer Institute of Canada Clinical Trial Group MA.17; IHD, ischaemic heart disease; CVA/TIA, cerebrovascular accident/transient ischaemic attack; N/A, not applicable

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letrozole group (p<0.001). No differences in cardiac events and IHD were observed in the IES trial.54 The results from the study comparing exemestane with placebo showed no major effects on lipid profiles, except a modest reduction in high-density lipoprotein cholesterol (p < 0.001) and apolipoprotein A1 (p = 0.004) in the exemestane group.92 The MA.17 trial showed no differences in hypercholesterolaemia and CVD.62 The lipid substudy of 347 women did not show any differences in the lipid profiles between the two groups.103 Despite some concerns about the potential adverse cardiovascular events with the use of AIs, the current consensus is that they have no major effect on lipid metabolism and little if any effect on overall cardiovascular morbidity.

results in terms of clinical efficacy and patient safety. The third-generation AIs, therefore, have become standard first-line therapy for MBC, and are frequently prescribed in the neoadjuvant setting. The improved efficacy of AIs compared with tamoxifen as adjuvant treatment has been well documented. Several guidelines support the use of AIs in post-menopausal women with ER expressing breast cancer, either as initial monotherapy or after a period of tamoxifen administration. However, the optimal schedule and duration remain under evaluation. Long-term follow-up of these trials will provide important information on the benefits and safety profiles, and will lead to further improvement in survival of post-menopausal women with breast cancer.

Thromboembolic events The results from the ATAC, BIG 1-98 and IES trials showed that the rate of thromboembolic events was significantly higher in the tamoxifen alone arm (Table 5).43,49,54 Thromboembolic events were similar in both patient groups receiving either letrozole or placebo in the MA.17 trial.62 These studies confirm the findings of the increased risk of thromboembolic disorders with the use of tamoxifen and the reduced risk with AI therapy.

Copyright © 22 February 2008

Gynaecological adverse effects In the ATAC trial, treatment with anastrozole was associated with significantly fewer hot flushes, vaginal bleeding, vaginal discharge and endometrial cancer, compared with tamoxifen (Table 5).43,44 The BIG 1-98 trial also demonstrated significantly fewer hot flushes and vaginal bleeding, and less endometrial cancer in the letrozole group.49 Vaginal bleeding and discharge, and the incidence of endometrial hyperplasia, were significantly higher with the use of tamoxifen in the IES trial.54 In the MA.17 trial, patients receiving letrozole experienced significantly increased frequency of hot flushes but not vaginal bleeding.62 These studies have confirmed that gynaecological symptoms and the incidence of endometrial cancer are increased with prolonged tamoxifen usage.

QUALITY OF LIFE Due to the long duration and adverse effects of therapy, quality of life (QoL) has been assessed in patients receiving the AIs. In the MA.17 trial, letrozole did not have an adverse impact on overall QoL, although there were effects associated with oestrogen depletion.104 No difference in QoL was found between patients on tamoxifen alone and those switching to exemestane in the IES trial.105 The recent report from the ATAC trial has also shown no significant difference in QoL between the two groups.106

COST-EFFECTIVENESS Tamoxifen is less expensive than the AIs. With favourable results in efficacy and safety of AI therapy, the cost-effectiveness of the AIs compared with tamoxifen has been evaluated. The NICE Assessment Group evaluated the cost-effectiveness of the AIs, using the Markov model and data from large, randomised adjuvant trials.72 The group concluded that the incremental cost/QALY gained for AIs, compared with tamoxifen, was less than £20,000, the limiting cost determination for cost-effectiveness, for all treatment strategies. The incremental cost/ QALY gained did not increase more than £20,000 when the predicted fracture risk was increased. It also concluded that in extended adjuvant treatment letrozole is cost-effective, compared with placebo.

CONCLUSION The treatment of ER/PgR expressing breast cancers in post-menopausal women has undergone significant changes over the last ten years. The data from large trials with the third-generation AIs has shown promising © 2009 Surgeon 7; 1: 42-55

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