- Email: [email protected]
Exemestane in metastatic breast cancer: Effective therapy after third-generation non-steroidal aromatase inhibitor failure
ARTICLE IN PRESS The Breast (2006) 15, 430–436
THE BREAST www.elsevier.com/locate/breast
SHORT REPORT
Exemestane in metastatic breast cancer: Effective therapy after third-generation non-steroidal aromatase inhibitor failure N. Steelea,, J. Zekrib, R. Colemanb, R. Leonardc, K. Dunnb, A. Bowmana, I. Manifoldb, I. Kunklera, O. Purohitb, D. Camerona a
Edinburgh Breast Unit, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK Weston Park Hospital, Whitham Road, Sheffield, South Yorkshire S10 2SJ, UK c South West Wales Cancer Centre, Singleton Hospital, Sketty, Swansea SA2 8QA, UK b
Received 18 April 2005; received in revised form 13 July 2005; accepted 24 August 2005
KEYWORDS Aromatase Inhibitor; Breast cancer; Exemestane
Summary Exemestane is a potent steroidal aromatase inhibitor (AI) with activity in post-menopausal women with metastatic breast cancer, with a reported clinical benefit (CB) rate of 24.3% after prior AI therapy. Data on 114 patients (112 female, 2 male) were obtained retrospectively at two cancer centres. Sixty-five percent of patients were confirmed as oestrogen receptor (ER) positive. All patients had received prior third-generation AI therapy. Responses were seen in 5% and the overall CB rate (CR+PR+SDX24 weeks) was 46%. Median PFS and OS were 18 and 61 weeks, respectively. In patients with visceral disease, the CBR was 33%. Patients with known ER-positive disease had a CBR of 47%, and a median TTP of 19 weeks. No benefit was seen in patients with known ER-negative disease. Survival was better in those with CB (median survival not reached in those with CB, 28 weeks in those without CB Po0:0001). Efficacy persisted in those patients who had received X3 prior lines of hormonal therapy, including adjuvant treatment. These data confirm exemestane to be an effective therapy after third-generation non-steroidal AI in post-menopausal ER-positive metastatic breast cancer, including visceral disease. & 2005 Elsevier Ltd. All rights reserved.
Introduction Corresponding author. Centre for Oncology and Applied
Pharmacology, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. Tel.: +44 141 3303509; fax: +44 141 3304127. E-mail address: [email protected] (N. Steele).
In post-menopausal women with advanced, oestrogen receptor (ER)-positive breast cancer, endocrine therapy remains the mainstay of initial treatment. Indeed, the development of newer, more effective hormonal agents may allow further prolongation of
0960-9776/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2005.08.032
ARTICLE IN PRESS Exemestane in metastatic breast cancer the interval between diagnosis of advanced breast cancer and the initiation of cytotoxic chemotherapy. With the exception of those patients who have rapidly progressive disease, endocrine therapy is an effective means of disease stabilisation and is better tolerated than cytotoxic chemotherapy. A recent improvement in survival in ER-positive metastatic breast cancer is thought to be due at least in part to the introduction of aromatase inhibitors (AIs) to routine clinical practice.1 The optimal use of available hormonal agents in this patient group therefore has important implications for patients’ survival and quality of life. In recent years, the non-steroidal third-generation AIs letrozole and anastrazole have found an established place in the initial treatment of hormone-sensitive metastatic breast cancer.2,3 These drugs bind reversibly to the aromatase enzyme, which catalyses the conversion of androstenedione to oestrone and testosterone to oestradiol. In post-menopausal women, this conversion occurs in the peripheral tissues (fat, skin, breast, skeletal muscle), and also within the breast cancer itself.4 The mechanism of action of these drugs is similar to the earlier non-steroidal AI, aminoglutethamide: the newer compounds have the advantage of improved specificity as well as fewer side effects and an oral administration route. Due to the reversible nature of the drug–enzyme interaction, continued oestrogen suppression requires continual presence of the drug. In contrast, the steroidal AI exemestane and its parenteral predecessor, formestane, are ‘‘suicide’’ inactivators, binding irreversibly to the substrate-binding site of the aromatase enzyme. Renewed oestrogen production therefore requires synthesis of new aromatase molecules. Data on the use of sequential aromatase inhibitors and inactivators are sparse although a number of small studies suggest a lack of clinical crossresistance between the two types of compounds. The first study to address this issue was published nearly a decade ago and reported successful treatment with the aromatase inactivator formestane in patients whose disease had become resistant to aminoglutethamide.5 In a more recent phase II study evaluating the activity of exemestane in those patients who had previously received non-steroidal AIs, including aminoglutethamide, the overall clinical benefit (CB) rate was 24.3%. In a subgroup of 105 patients who had received thirdgeneration non-steroidal AIs, the CB rate was 20%.6 A number of clinical trials have recently been published or are underway evaluating the use of exemestane in the first line treatment of metastatic breast cancer, as well as in the adjuvant
431 setting. Recent results of a phase III trial comparing exemestane with tamoxifen as first line therapy for metastatic breast cancer have shown a significant improvement in progression-free survival in those patients receiving exemestane.7 A small phase II trial has shown no difference between exemestane and anastrazole first line in patients with visceral disease.8 Large phase III adjuvant trials comparing the two types of AI are planned. Until larger trials report, the commonest use of exemestane will be in the setting of non-steroidal AI failure, despite the limited data to support this approach. The aim of this study is to report the experience of exemestane use in two regional cancer centres. The unselected population studied consists of all patients treated with exemestane who had been previously treated with third-generation AIs. There is therefore the opportunity to gain useful information about the efficacy of exemestane in this common clinical situation.
Patients and methods Patient data were obtained retrospectively from the case notes of all patients commencing exemestane therapy at the Edinburgh Breast Unit and Weston Park Hospital, Sheffield between June 2000 and February 2002. In both centres, all patients receiving exemestane were identified from pharmacy records. Of these, all patients who had received prior third-generation AIs were identified from case records and were included in this study. Data were collected between September 2002 and March 2003. Of the 114 patients studied, 112 were post-menopausal women and two were men. Male patients have been included in the overall analysis but are also described separately in the results section. Median follow-up from the date exemestane was started was 10 months (range 1–27 months). Fifty percent of patients studied had died at the time of analysis. All patients received exemestane at a dose of 25 mg daily. Patient characteristics are summarised in Table 1. Progression-free and overall survival was measured from the first day of exemestane treatment. Kaplan–Meier methods were used to analyse the duration of overall response and survival. Survival curves were generated using SPSSs 12.0 for windows.
Results Efficacy data are summarised in Table 2. As this was a retrospective study, responses could not be
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N. Steele et al.
Table 1 Demographic characteristics of 114 patients with advanced breast cancer. Characteristics Age o 60 years X60 years
No. of patients
39 61
9 105
8 92
ER status Positive Negative Unknown
74 5 35
65 4 31
Adjuvant endocrine therapy Yes No
62 52
54 46
Adjuvant third-generation aromatase inhibitor Yes 3 2 No 112 98 Disease extent at presentation of breast cancer Localised 61 54 Advanced/ metastatic 50 44 Unknown 2 2 Prior endocrine therapy for advanced disease None 2 2 1 line 39 34 2 lines 56 49 X3 lines 17 15 Sequence of prior endocrine therapy Tamoxifen-3rd gen AI 81 3rd gen AI -Tamoxifen 1 Tamoxifen -3rd gen AI 10 other(s) Tamoxifen -other(s) -3rd 17 gen AI 3rd gen AI only 3 Tamoxifen+3rd gen AI 2
71 1 9 15 2 2
Time from third-generation AI failureexemestane o 6 months 85 46 months 29
75 25
Visceral disease Yes No Unknown
42 57 1
48 65 1
Characteristics
%
44 70
Disease status Locally advanced Metastatic
Table 1 (continued )
Time from metastatic diagnosis to starting exemestane 420 months 36 32 p20 months 69 60 Locoregional disease only 9 8
Prior chemotherapy None Adjuvant Metastatic/advanced disease Both
No. of patients
%
66 16 22
58 14 19
10
9
formally assessed by RECIST criteria. Information on response was obtained from documentation in the clinical notes and, where available, appropriate imaging results. For a response or stable disease to be recorded, the response had to persist after 24 weeks of treatment or longer. These response criteria have been employed in clinical trials of endocrine therapies.9,10 Overall, the CB rate (CR+PR+SDX24 weeks) was 46%. Neither of the two male patients derived any benefit from exemestane treatment. Six patients were not evaluable for response: two patients were lost to follow-up prior to response assessment; three patients stopped exemestane due to intolerance prior to response assessment and one patient received exemestane following resection of all recurrent (soft tissue) disease. These patients have, however, been included in the survival analyses. Patients in whom ER was positive or unknown have been grouped for the purpose of analysis because, where ER score was not available, patients had to have had a previous favourable response to endocrine therapy for exemestane treatment to be considered. Three patients received exemestane following adjuvant therapy with a third-generation AI. Due to the small numbers involved, these have not been analysed separately. Formal toxicity data have not been collected due to the retrospective nature of this study; however, it should be noted that only four patients stopped exemestane due to poor tolerability. One of these patients experienced vomiting, anorexia and malaise, another stopped due to abdominal pain and nausea. No details are available as to why the other two patients stopped therapy. Median survival was 61 weeks, with a median progression-free survival time of 18 weeks. In patients who started exemestane 420 months after the diagnosis of metastases, overall survival was significantly better than those who started exemestane earlier in the course of their illness (PFS 19 vs. 18 weeks, P ¼ 0:35; OS 83 vs. 30 weeks,
ARTICLE IN PRESS Exemestane in metastatic breast cancer
433
Table 2 Efficacy of exemestane in 108 evaluable patients who had received prior third-generation aromatase inhibitor. Objective response (CR+PR)
Clinical benefit (CR+PR+SDX26 weeks)
Number of patients
%
Number of patients
%
6/103 2/70 4/33 0/5
6 3 12 0
50/103 33/70 17/33
48 47 48 0
No of prior hormonal therapies (including adjuvant) X3 3/36 o3 3/72
8 4
20/36 30/72
55 42
Prior chemotherapy for advanced disease Yes 1/32 No 5/76
3 7
14/32 36/76
44 47
Visceral disease Non-visceral disease
2 8
15/45 35/62
33 56
Time from metastases to exemestane 420 months 4/61 p20 months 1/37
7 3
34/61 12/37
56 32
All patients
5
50/108
46
ER +ve or unknown ER +ve ER Unknown ER ve
1/46 5/62
6/108
100
100
80
80
60
% PFS
% OS
60
40
40 20
20 0 0
0 0
50
100 Time (weeks)
Figure 1 Progression-free (n ¼ 114).
survival
in
150
50
100 Time (weeks)
150
200
Figure 2 Overall survival in all patients (n ¼ 114). all
patients
Discussion P ¼ 0:01). Those patients who achieved a response or prolonged disease stabilisation lived longer (PFS 43 vs. 10 weeks in those with CB P ¼ 0:0001; OS not reached in those with CB, 28 weeks in those without P ¼ 0:0001). Survival curves for all patients and subgroups with multiple prior therapies and visceral disease are shown in Figs. 1–4.
The results of this retrospective review confirm exemestane to be an effective therapy in postmenopausal patients with ER-positive advanced breast cancer. In our unselected, off-trial group of 108 evaluable patients previously treated with third-generation AIs, we have observed a CB rate of 46%. This is higher than the CB rate observed in a
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N. Steele et al.
phase II trial which recruited 241 patients from a similar population (overall CBR ¼ 24.3%).6 In that phase II study, 105 patients (43.6%) had received prior third-generation non-steroidal AIs, with a CBR in this subgroup of 20%. The first reported study of exemestane use following non-steroidal AIs was a phase II study, evaluating exemestane (at a dose 200 mg daily rather than the 25 mg dose now in common use) following progression on aminoglutethamide. That study reported a CBR of 26%.11 In this context, the results in our patient group are good, although the outcome of any retrospective study must be interpreted with caution. The CB rate in this group of patients may be higher than that achievable in a clinical trial for a number of reasons. There are often less frequent patient assessments in routine clinical practice with less strict criteria for disease progression than might be employed within a clinical trial. Despite these
100 80
Visceral
40 20 0
0
20
40 60 Time (weeks)
80
100
Figure 3 Progression-free survival by disease site.
100
80 < 3 regimens
% PFS
% PFS
Non-visceral 60
caveats, the achievement of such good results in a mixed, heavily pretreated group of patients is promising. In those patients who responded to exemestane or who had a prolonged period of disease stabilisation, survival was superior (median OS not reached in those who achieved CR, PR or SD X24 weeks, 28 weeks in those who did not). This real survival benefit, coupled with the observation that only four patients (3%) were intolerant of exemestane, supports the use of multiple lines of hormonal therapies for palliation in patients with slowly progressive disease. The widely held belief that patients with visceral metastases from breast cancer require chemotherapy as first line management is increasingly being challenged. A number of studies of AIs in ERpositive breast cancer in recent years have demonstrated that patients with visceral metastases can achieve disease stabilisation with AIs although the data remain fairly sparse. In a small randomised study comparing exemestane with anastrazole as first or second line therapy in patients with visceral metastases, there was no statistically significant difference between the two agents, with an overall CB rate using exemestane of 36% (38% in visceral sites).8 There are few studies where exemestane has been used in such a heavily pretreated population as ours. Our CB rate of 31% in patients with visceral metastases is therefore encouraging. Although the number of patients with known ERnegative disease was small,5 the failure of any of these patients to benefit from exemestane treatment is in keeping with the now established view that only patients with ER positive disease are suitable candidates for endocrine therapies.
≥ 3 regimens
60
40
20
0 0
50
100 Time (weeks)
150
Figure 4 Progression-free survival by number of prior hormonal regimens.
ARTICLE IN PRESS Exemestane in metastatic breast cancer We did not observe any significant difference in CB rate or progression-free survival in patients who had received more than three prior lines of hormonal therapy (including adjuvant therapy), as compared to those who had fewer prior endocrine therapies. Overall survival in this group of patients did not appear to be adversely affected (OS 55 weeks in patients with o3 previous endocrine agents, not reached in X3, P ¼ 0:05). In addition to this, those patients who had had metastatic disease for X20 months prior to commencing on exemestane had an improved overall survival compared to those who had a shorter disease history (median PFS 19 vs. 18 weeks P ¼ 0:49; median OS 83 vs. 30 weeks P ¼ 0:02). These two observations are likely to be related and, of course, may reflect the more indolent nature of these patients’ disease and/or their inherently greater hormone sensitivity. Nevertheless, despite the relatively small numbers, these data support the view that the administration of exemestane for metastatic disease in the third or subsequent line setting is a reasonable alternative to initiation of cytotoxic chemotherapy in patients with slowly progressive disease. The observation that even patients who have failed modern non-steroidal aromatase inhibition can respond to an aromatase inactivator suggests that resistance to the two groups of compounds does not completely overlap. This observation is supported by laboratory studies demonstrating differential sensitivity of individual tumours to type I and II inhibitors.12 In tracer studies which have examined in vivo aromatase inhibition by each class of compound, no significant difference between third-generation AIs and exemestane has been observed, with inhibition by both classes of drug consistently around 98% or better. The lack of cross-resistance between the compounds is therefore not explained by differences in circulating oestrogen levels.13 Whilst there may be differences in the inhibition of intra-tumoral aromatase, another possible explanation for the lack of crossresistance may be the androgenic effects of exemestane. 17-hydroexemestane, the major metabolite of exemestane, suppresses plasma sexhormone binding globulin in a dose-dependent manner, consistent with androgenic activity.14 In the clinical setting, this lack of cross resistance has mainly been studied in patients treated with aromatase inactivators following failure of AIs although one study has examined the reverse sequence of treatment, demonstrating activity of non-steroidal AIs in patients who have progressed on exemestane.15 In conclusion, the reason for the lack of cross-resistance between the two types of
435 compounds remains to be determined and the optimum sequence in which to use these drugs in the clinic is unclear and will be addressed in future studies. The data from this retrospective, ‘‘real-life’’ study support the view that exemestane is effective therapy in post-menopausal patients with metastatic, hormone-sensitive breast cancer. The benefits of exemestane treatment are seen in the subgroup of patients with visceral disease as well as in those patients in whom third-generation non-steroidal AI therapy has failed. Even though the data from the IES trial suggest that exemestane has a benefit in the adjuvant setting after tamoxifen,16 there are still many patients whose first exposure to this drug will be for advanced disease, and our results in this mixed group of heavily pre-treated patients reaffirm its efficacy in this common clinical setting.
References 1. Andre F, Slimane K, Bachelot T, Dunant A, Namer M, Barrelier A, et al. Breast cancer with synchronous metastases: trends in survival during a 14-year period. J Clin Oncol 2004;22(16): 3302–8. 2. Nabholtz JM, Bonneterre J, Buzdar A, Robertson JF, Thurlimann B. Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer 2003;39(12):1684–9. 3. Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the tamoxifen or arimidex randomized group efficacy and tolerability study. J Clin Oncol 2000;18(22):3748–57. 4. Miller WR, Mullen P, Telford J, Dixon JM. Clinical importance of intratumoral aromatase. Breast Cancer Res Treat 1998;49(Suppl 1):S27–32 (Discussion S33-7). 5. Murray R, Pitt P. Aromatase inhibition with 4-OHAndrostenedione after prior aromatase inhibition with aminoglutethimide in women with advanced breast cancer. Breast Cancer Res Treat 1995:249–53. 6. Lonning PE, Bajetta E, Murray R, Tubiana-Hulin M, Eisenberg PD, Mickiewicz E, et al. Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. J Clin Oncol 2000;18(11): 2234–44. 7. Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D, et al. Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol 2003;14(9):1391–8. 8. Cameron D, et al. A comparative study of exemestane vs. anastrazole in post-menopausal breast cancer subjects with visceral disease. Proc Asco 2004;628. 9. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, 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. J Clin Oncol 2001;19(10):2596–606.
ARTICLE IN PRESS 436 10. Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, 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. The Exemestane Study Group. J Clin Oncol 2000: 1399–411. 11. Thurlimann B, Paridaens R, Serin D, Bonneterre J, Roche H, Murray R, et al. Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on aminoglutethimide: a phase II multicentre multinational study. Exemestane Study Group. Eur J Cancer 1997;33(11):1767–73. 12. Miller WR, Anderson TJ, Evans DB, Krause A, Hampton G, Dixon JM. An integrated view of aromatase and its inhibition. J Steroid Biochem Mol Biol 2003;86(3-5):413–21.
N. Steele et al. 13. Lonning PE. Comparison between aromatase inhibitors and sequential use. J Steroid Biochem Mol Biol 2003; 86(3-5):275–82. 14. Johannessen DC, Engan T, Di Salle E, Zurlo MG, Paolini J, Ornati G, et al. Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study. Clin Cancer Res 1997;3(7):1101–8. 15. Bertelli G, et al. Sequential use of aromatase inhibitors and inactivators in advanced breast cancer. Proc Asco 2002. 16. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350(11):1081–92.
THE BREAST www.elsevier.com/locate/breast
SHORT REPORT
Exemestane in metastatic breast cancer: Effective therapy after third-generation non-steroidal aromatase inhibitor failure N. Steelea,, J. Zekrib, R. Colemanb, R. Leonardc, K. Dunnb, A. Bowmana, I. Manifoldb, I. Kunklera, O. Purohitb, D. Camerona a
Edinburgh Breast Unit, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK Weston Park Hospital, Whitham Road, Sheffield, South Yorkshire S10 2SJ, UK c South West Wales Cancer Centre, Singleton Hospital, Sketty, Swansea SA2 8QA, UK b
Received 18 April 2005; received in revised form 13 July 2005; accepted 24 August 2005
KEYWORDS Aromatase Inhibitor; Breast cancer; Exemestane
Summary Exemestane is a potent steroidal aromatase inhibitor (AI) with activity in post-menopausal women with metastatic breast cancer, with a reported clinical benefit (CB) rate of 24.3% after prior AI therapy. Data on 114 patients (112 female, 2 male) were obtained retrospectively at two cancer centres. Sixty-five percent of patients were confirmed as oestrogen receptor (ER) positive. All patients had received prior third-generation AI therapy. Responses were seen in 5% and the overall CB rate (CR+PR+SDX24 weeks) was 46%. Median PFS and OS were 18 and 61 weeks, respectively. In patients with visceral disease, the CBR was 33%. Patients with known ER-positive disease had a CBR of 47%, and a median TTP of 19 weeks. No benefit was seen in patients with known ER-negative disease. Survival was better in those with CB (median survival not reached in those with CB, 28 weeks in those without CB Po0:0001). Efficacy persisted in those patients who had received X3 prior lines of hormonal therapy, including adjuvant treatment. These data confirm exemestane to be an effective therapy after third-generation non-steroidal AI in post-menopausal ER-positive metastatic breast cancer, including visceral disease. & 2005 Elsevier Ltd. All rights reserved.
Introduction Corresponding author. Centre for Oncology and Applied
Pharmacology, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. Tel.: +44 141 3303509; fax: +44 141 3304127. E-mail address: [email protected] (N. Steele).
In post-menopausal women with advanced, oestrogen receptor (ER)-positive breast cancer, endocrine therapy remains the mainstay of initial treatment. Indeed, the development of newer, more effective hormonal agents may allow further prolongation of
0960-9776/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2005.08.032
ARTICLE IN PRESS Exemestane in metastatic breast cancer the interval between diagnosis of advanced breast cancer and the initiation of cytotoxic chemotherapy. With the exception of those patients who have rapidly progressive disease, endocrine therapy is an effective means of disease stabilisation and is better tolerated than cytotoxic chemotherapy. A recent improvement in survival in ER-positive metastatic breast cancer is thought to be due at least in part to the introduction of aromatase inhibitors (AIs) to routine clinical practice.1 The optimal use of available hormonal agents in this patient group therefore has important implications for patients’ survival and quality of life. In recent years, the non-steroidal third-generation AIs letrozole and anastrazole have found an established place in the initial treatment of hormone-sensitive metastatic breast cancer.2,3 These drugs bind reversibly to the aromatase enzyme, which catalyses the conversion of androstenedione to oestrone and testosterone to oestradiol. In post-menopausal women, this conversion occurs in the peripheral tissues (fat, skin, breast, skeletal muscle), and also within the breast cancer itself.4 The mechanism of action of these drugs is similar to the earlier non-steroidal AI, aminoglutethamide: the newer compounds have the advantage of improved specificity as well as fewer side effects and an oral administration route. Due to the reversible nature of the drug–enzyme interaction, continued oestrogen suppression requires continual presence of the drug. In contrast, the steroidal AI exemestane and its parenteral predecessor, formestane, are ‘‘suicide’’ inactivators, binding irreversibly to the substrate-binding site of the aromatase enzyme. Renewed oestrogen production therefore requires synthesis of new aromatase molecules. Data on the use of sequential aromatase inhibitors and inactivators are sparse although a number of small studies suggest a lack of clinical crossresistance between the two types of compounds. The first study to address this issue was published nearly a decade ago and reported successful treatment with the aromatase inactivator formestane in patients whose disease had become resistant to aminoglutethamide.5 In a more recent phase II study evaluating the activity of exemestane in those patients who had previously received non-steroidal AIs, including aminoglutethamide, the overall clinical benefit (CB) rate was 24.3%. In a subgroup of 105 patients who had received thirdgeneration non-steroidal AIs, the CB rate was 20%.6 A number of clinical trials have recently been published or are underway evaluating the use of exemestane in the first line treatment of metastatic breast cancer, as well as in the adjuvant
431 setting. Recent results of a phase III trial comparing exemestane with tamoxifen as first line therapy for metastatic breast cancer have shown a significant improvement in progression-free survival in those patients receiving exemestane.7 A small phase II trial has shown no difference between exemestane and anastrazole first line in patients with visceral disease.8 Large phase III adjuvant trials comparing the two types of AI are planned. Until larger trials report, the commonest use of exemestane will be in the setting of non-steroidal AI failure, despite the limited data to support this approach. The aim of this study is to report the experience of exemestane use in two regional cancer centres. The unselected population studied consists of all patients treated with exemestane who had been previously treated with third-generation AIs. There is therefore the opportunity to gain useful information about the efficacy of exemestane in this common clinical situation.
Patients and methods Patient data were obtained retrospectively from the case notes of all patients commencing exemestane therapy at the Edinburgh Breast Unit and Weston Park Hospital, Sheffield between June 2000 and February 2002. In both centres, all patients receiving exemestane were identified from pharmacy records. Of these, all patients who had received prior third-generation AIs were identified from case records and were included in this study. Data were collected between September 2002 and March 2003. Of the 114 patients studied, 112 were post-menopausal women and two were men. Male patients have been included in the overall analysis but are also described separately in the results section. Median follow-up from the date exemestane was started was 10 months (range 1–27 months). Fifty percent of patients studied had died at the time of analysis. All patients received exemestane at a dose of 25 mg daily. Patient characteristics are summarised in Table 1. Progression-free and overall survival was measured from the first day of exemestane treatment. Kaplan–Meier methods were used to analyse the duration of overall response and survival. Survival curves were generated using SPSSs 12.0 for windows.
Results Efficacy data are summarised in Table 2. As this was a retrospective study, responses could not be
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N. Steele et al.
Table 1 Demographic characteristics of 114 patients with advanced breast cancer. Characteristics Age o 60 years X60 years
No. of patients
39 61
9 105
8 92
ER status Positive Negative Unknown
74 5 35
65 4 31
Adjuvant endocrine therapy Yes No
62 52
54 46
Adjuvant third-generation aromatase inhibitor Yes 3 2 No 112 98 Disease extent at presentation of breast cancer Localised 61 54 Advanced/ metastatic 50 44 Unknown 2 2 Prior endocrine therapy for advanced disease None 2 2 1 line 39 34 2 lines 56 49 X3 lines 17 15 Sequence of prior endocrine therapy Tamoxifen-3rd gen AI 81 3rd gen AI -Tamoxifen 1 Tamoxifen -3rd gen AI 10 other(s) Tamoxifen -other(s) -3rd 17 gen AI 3rd gen AI only 3 Tamoxifen+3rd gen AI 2
71 1 9 15 2 2
Time from third-generation AI failureexemestane o 6 months 85 46 months 29
75 25
Visceral disease Yes No Unknown
42 57 1
48 65 1
Characteristics
%
44 70
Disease status Locally advanced Metastatic
Table 1 (continued )
Time from metastatic diagnosis to starting exemestane 420 months 36 32 p20 months 69 60 Locoregional disease only 9 8
Prior chemotherapy None Adjuvant Metastatic/advanced disease Both
No. of patients
%
66 16 22
58 14 19
10
9
formally assessed by RECIST criteria. Information on response was obtained from documentation in the clinical notes and, where available, appropriate imaging results. For a response or stable disease to be recorded, the response had to persist after 24 weeks of treatment or longer. These response criteria have been employed in clinical trials of endocrine therapies.9,10 Overall, the CB rate (CR+PR+SDX24 weeks) was 46%. Neither of the two male patients derived any benefit from exemestane treatment. Six patients were not evaluable for response: two patients were lost to follow-up prior to response assessment; three patients stopped exemestane due to intolerance prior to response assessment and one patient received exemestane following resection of all recurrent (soft tissue) disease. These patients have, however, been included in the survival analyses. Patients in whom ER was positive or unknown have been grouped for the purpose of analysis because, where ER score was not available, patients had to have had a previous favourable response to endocrine therapy for exemestane treatment to be considered. Three patients received exemestane following adjuvant therapy with a third-generation AI. Due to the small numbers involved, these have not been analysed separately. Formal toxicity data have not been collected due to the retrospective nature of this study; however, it should be noted that only four patients stopped exemestane due to poor tolerability. One of these patients experienced vomiting, anorexia and malaise, another stopped due to abdominal pain and nausea. No details are available as to why the other two patients stopped therapy. Median survival was 61 weeks, with a median progression-free survival time of 18 weeks. In patients who started exemestane 420 months after the diagnosis of metastases, overall survival was significantly better than those who started exemestane earlier in the course of their illness (PFS 19 vs. 18 weeks, P ¼ 0:35; OS 83 vs. 30 weeks,
ARTICLE IN PRESS Exemestane in metastatic breast cancer
433
Table 2 Efficacy of exemestane in 108 evaluable patients who had received prior third-generation aromatase inhibitor. Objective response (CR+PR)
Clinical benefit (CR+PR+SDX26 weeks)
Number of patients
%
Number of patients
%
6/103 2/70 4/33 0/5
6 3 12 0
50/103 33/70 17/33
48 47 48 0
No of prior hormonal therapies (including adjuvant) X3 3/36 o3 3/72
8 4
20/36 30/72
55 42
Prior chemotherapy for advanced disease Yes 1/32 No 5/76
3 7
14/32 36/76
44 47
Visceral disease Non-visceral disease
2 8
15/45 35/62
33 56
Time from metastases to exemestane 420 months 4/61 p20 months 1/37
7 3
34/61 12/37
56 32
All patients
5
50/108
46
ER +ve or unknown ER +ve ER Unknown ER ve
1/46 5/62
6/108
100
100
80
80
60
% PFS
% OS
60
40
40 20
20 0 0
0 0
50
100 Time (weeks)
Figure 1 Progression-free (n ¼ 114).
survival
in
150
50
100 Time (weeks)
150
200
Figure 2 Overall survival in all patients (n ¼ 114). all
patients
Discussion P ¼ 0:01). Those patients who achieved a response or prolonged disease stabilisation lived longer (PFS 43 vs. 10 weeks in those with CB P ¼ 0:0001; OS not reached in those with CB, 28 weeks in those without P ¼ 0:0001). Survival curves for all patients and subgroups with multiple prior therapies and visceral disease are shown in Figs. 1–4.
The results of this retrospective review confirm exemestane to be an effective therapy in postmenopausal patients with ER-positive advanced breast cancer. In our unselected, off-trial group of 108 evaluable patients previously treated with third-generation AIs, we have observed a CB rate of 46%. This is higher than the CB rate observed in a
ARTICLE IN PRESS 434
N. Steele et al.
phase II trial which recruited 241 patients from a similar population (overall CBR ¼ 24.3%).6 In that phase II study, 105 patients (43.6%) had received prior third-generation non-steroidal AIs, with a CBR in this subgroup of 20%. The first reported study of exemestane use following non-steroidal AIs was a phase II study, evaluating exemestane (at a dose 200 mg daily rather than the 25 mg dose now in common use) following progression on aminoglutethamide. That study reported a CBR of 26%.11 In this context, the results in our patient group are good, although the outcome of any retrospective study must be interpreted with caution. The CB rate in this group of patients may be higher than that achievable in a clinical trial for a number of reasons. There are often less frequent patient assessments in routine clinical practice with less strict criteria for disease progression than might be employed within a clinical trial. Despite these
100 80
Visceral
40 20 0
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20
40 60 Time (weeks)
80
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Figure 3 Progression-free survival by disease site.
100
80 < 3 regimens
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caveats, the achievement of such good results in a mixed, heavily pretreated group of patients is promising. In those patients who responded to exemestane or who had a prolonged period of disease stabilisation, survival was superior (median OS not reached in those who achieved CR, PR or SD X24 weeks, 28 weeks in those who did not). This real survival benefit, coupled with the observation that only four patients (3%) were intolerant of exemestane, supports the use of multiple lines of hormonal therapies for palliation in patients with slowly progressive disease. The widely held belief that patients with visceral metastases from breast cancer require chemotherapy as first line management is increasingly being challenged. A number of studies of AIs in ERpositive breast cancer in recent years have demonstrated that patients with visceral metastases can achieve disease stabilisation with AIs although the data remain fairly sparse. In a small randomised study comparing exemestane with anastrazole as first or second line therapy in patients with visceral metastases, there was no statistically significant difference between the two agents, with an overall CB rate using exemestane of 36% (38% in visceral sites).8 There are few studies where exemestane has been used in such a heavily pretreated population as ours. Our CB rate of 31% in patients with visceral metastases is therefore encouraging. Although the number of patients with known ERnegative disease was small,5 the failure of any of these patients to benefit from exemestane treatment is in keeping with the now established view that only patients with ER positive disease are suitable candidates for endocrine therapies.
≥ 3 regimens
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Figure 4 Progression-free survival by number of prior hormonal regimens.
ARTICLE IN PRESS Exemestane in metastatic breast cancer We did not observe any significant difference in CB rate or progression-free survival in patients who had received more than three prior lines of hormonal therapy (including adjuvant therapy), as compared to those who had fewer prior endocrine therapies. Overall survival in this group of patients did not appear to be adversely affected (OS 55 weeks in patients with o3 previous endocrine agents, not reached in X3, P ¼ 0:05). In addition to this, those patients who had had metastatic disease for X20 months prior to commencing on exemestane had an improved overall survival compared to those who had a shorter disease history (median PFS 19 vs. 18 weeks P ¼ 0:49; median OS 83 vs. 30 weeks P ¼ 0:02). These two observations are likely to be related and, of course, may reflect the more indolent nature of these patients’ disease and/or their inherently greater hormone sensitivity. Nevertheless, despite the relatively small numbers, these data support the view that the administration of exemestane for metastatic disease in the third or subsequent line setting is a reasonable alternative to initiation of cytotoxic chemotherapy in patients with slowly progressive disease. The observation that even patients who have failed modern non-steroidal aromatase inhibition can respond to an aromatase inactivator suggests that resistance to the two groups of compounds does not completely overlap. This observation is supported by laboratory studies demonstrating differential sensitivity of individual tumours to type I and II inhibitors.12 In tracer studies which have examined in vivo aromatase inhibition by each class of compound, no significant difference between third-generation AIs and exemestane has been observed, with inhibition by both classes of drug consistently around 98% or better. The lack of cross-resistance between the compounds is therefore not explained by differences in circulating oestrogen levels.13 Whilst there may be differences in the inhibition of intra-tumoral aromatase, another possible explanation for the lack of crossresistance may be the androgenic effects of exemestane. 17-hydroexemestane, the major metabolite of exemestane, suppresses plasma sexhormone binding globulin in a dose-dependent manner, consistent with androgenic activity.14 In the clinical setting, this lack of cross resistance has mainly been studied in patients treated with aromatase inactivators following failure of AIs although one study has examined the reverse sequence of treatment, demonstrating activity of non-steroidal AIs in patients who have progressed on exemestane.15 In conclusion, the reason for the lack of cross-resistance between the two types of
435 compounds remains to be determined and the optimum sequence in which to use these drugs in the clinic is unclear and will be addressed in future studies. The data from this retrospective, ‘‘real-life’’ study support the view that exemestane is effective therapy in post-menopausal patients with metastatic, hormone-sensitive breast cancer. The benefits of exemestane treatment are seen in the subgroup of patients with visceral disease as well as in those patients in whom third-generation non-steroidal AI therapy has failed. Even though the data from the IES trial suggest that exemestane has a benefit in the adjuvant setting after tamoxifen,16 there are still many patients whose first exposure to this drug will be for advanced disease, and our results in this mixed group of heavily pre-treated patients reaffirm its efficacy in this common clinical setting.
References 1. Andre F, Slimane K, Bachelot T, Dunant A, Namer M, Barrelier A, et al. Breast cancer with synchronous metastases: trends in survival during a 14-year period. J Clin Oncol 2004;22(16): 3302–8. 2. Nabholtz JM, Bonneterre J, Buzdar A, Robertson JF, Thurlimann B. Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer 2003;39(12):1684–9. 3. Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the tamoxifen or arimidex randomized group efficacy and tolerability study. J Clin Oncol 2000;18(22):3748–57. 4. Miller WR, Mullen P, Telford J, Dixon JM. Clinical importance of intratumoral aromatase. Breast Cancer Res Treat 1998;49(Suppl 1):S27–32 (Discussion S33-7). 5. Murray R, Pitt P. Aromatase inhibition with 4-OHAndrostenedione after prior aromatase inhibition with aminoglutethimide in women with advanced breast cancer. Breast Cancer Res Treat 1995:249–53. 6. Lonning PE, Bajetta E, Murray R, Tubiana-Hulin M, Eisenberg PD, Mickiewicz E, et al. Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. J Clin Oncol 2000;18(11): 2234–44. 7. Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D, et al. Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol 2003;14(9):1391–8. 8. Cameron D, et al. A comparative study of exemestane vs. anastrazole in post-menopausal breast cancer subjects with visceral disease. Proc Asco 2004;628. 9. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, 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. J Clin Oncol 2001;19(10):2596–606.
ARTICLE IN PRESS 436 10. Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, 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. The Exemestane Study Group. J Clin Oncol 2000: 1399–411. 11. Thurlimann B, Paridaens R, Serin D, Bonneterre J, Roche H, Murray R, et al. Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on aminoglutethimide: a phase II multicentre multinational study. Exemestane Study Group. Eur J Cancer 1997;33(11):1767–73. 12. Miller WR, Anderson TJ, Evans DB, Krause A, Hampton G, Dixon JM. An integrated view of aromatase and its inhibition. J Steroid Biochem Mol Biol 2003;86(3-5):413–21.
N. Steele et al. 13. Lonning PE. Comparison between aromatase inhibitors and sequential use. J Steroid Biochem Mol Biol 2003; 86(3-5):275–82. 14. Johannessen DC, Engan T, Di Salle E, Zurlo MG, Paolini J, Ornati G, et al. Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study. Clin Cancer Res 1997;3(7):1101–8. 15. Bertelli G, et al. Sequential use of aromatase inhibitors and inactivators in advanced breast cancer. Proc Asco 2002. 16. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350(11):1081–92.