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Impact of Body Mass Index on the Efficacy of Endocrine Therapy in Premenopausal Patients With Breast Cancer: An Analysis of the Prospective ABCSG-12 Trial
and 25.1 months, respectively, for the 500-mg group, whereas DoCB and OS were 13.9 and 22.8 months, respectively, in the 250-mg group. Fulvestrant 500 mg was well tolerated with no dose-dependent adverse events. QOL was similar for both arms. Conclusion.dFulvestrant 500 mg was associated with a statistically significant increase in PFS and not associated with increased toxicity, corresponding to a clinically meaningful improvement in benefit versus risk compared with fulvestrant 250 mg. Fulvestrant has had an unusually long gestation period. The concept of being able to develop a pure antiestrogen that would be effective as a second-line therapy following tamoxifen failure was demonstrated more than 20 years ago with the lead compound, ICI 164 384,1 followed by the first report of fulvestrant 2 years later.2 Getting the drug to the tumor’s estrogen receptors from the injection site has always been a problem, however,
Impact of Body Mass Index on the Efficacy of Endocrine Therapy in Premenopausal Patients With Breast Cancer: An Analysis of the Prospective ABCSG-12 Trial Pfeiler G, Königsberg R, Fesl C, et al (Med Univ of Vienna, Austria; Applied Cancer ReseInstitution for Translational Res Vienna (ACR-ITR Vienna), Austria; Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria; et al) J Clin Oncol 29:2653-2659, 2011
Purpose.dAromatase inhibitors are effective as endocrine treatment for patients with hormone receptorepositive
because of the low levels of fulvestrant in the body.3 This has consequences for the treatment of acquired drug resistance to antihormones following the report that fulvestrant in an environment of low-dose estrogen actually causes tumors to grow.4 There are 2 obvious strategies for avoiding this situation: either administer fulvestrant with an aromatase inhibitor5 or, as in this article by Di Leo and colleagues, double the dose of fulvestrant. It’s good to know that the basic principles of pharmacology and a knowledge of the biology of breast cancer with acquired resistance can come together to aid patients. V. C. Jordan, OBE, PhD, DSc, FMedSci
References
steroidal antiestrogens. Cancer Res. 1989;49:4090-4093. 2. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51:3867-3873. 3. Robertson JF, Erikstein B, Osborne KC, et al. Pharmacokinetic profile of intramuscular fulvestrant in advanced breast cancer. Clin Pharmacokinet. 2004;43: 529-538. 4. Osipo C, Gajdos C, Liu H, Chen B, Jordan VC. Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer. J Natl Cancer Inst. 2003;95:1597-1608. 5. Dodwell D, Coombes G, Bliss JM, Kilburn LS, Johnston S. Combining fulvestrant (Faslodex) with continued oestrogen suppression in endocrinesensitive advanced breast cancer: the SoFEA trial. Clin Oncol (R Coll Radiol). 2008;20:321-324.
1. Gottardis MM, Jiang SY, Jeng MH, Jordan VC. Inhibition of tamoxifenstimulated growth of an MCF-7 tumor variant in athymic mice by novel
breast cancer. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, we investigated the influence of body mass index (BMI) on the efficacy of adjuvant endocrine therapy in premenopausal patients in a retrospective analysis of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial. Patients and Methods.dABCSG12 examined the efficacy of ovarian suppression using goserelin (3.6 mg subcutaneously every 28 days) in combination with anastrozole or tamoxifen with or without zoledronic acid (4 mg intravenously every 6 months) in premenopausal women with endocrine-responsive breast cancer. BMI was calculated
using the prospectively collected data on patients’ height and weight at study entry. BMI categories have been differentiated according to the WHO definition. Results.dOverweight patients treated with anastrozole had a 60% increase in the risk of disease recurrence (hazard ratio [HR], 1.60; 95% CI, 1.06 to 2.41; P ¼.02) and more than a doubling in the risk of death (HR, 2.14; 95% CI, 1.17 to 3.92; P ¼ .01) compared with normal weight patients treated with anastrozole. In the overweight group, patients treated with anastrozole had a nearly 50% increase in the risk of disease recurrence (HR, 1.49; 95% CI, 0.93 to 2.38; P ¼ .08)
Breast Diseases: A Year BookÒ Quarterly Vol 23 No 2 2012
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TABLE 2.dEvents of Normal Weight and Overweight/Obese Patients Treated With Anastrozole Versus Tamoxifen Normal Weight Patients Tamoxifen (n ¼ 542)
Overweight and Obese Patients
Anastrozole (n ¼ 569)
Tamoxifen (n ¼ 294)
Anastrozole (n ¼ 279)
Event
No.
%
No.
%
No.
%
No.
%
All events Locoregional Distant Bone metastases Contralateral Secondary malignant conditions Death All Without previous recurrence
56 16 26 13 7 7
10.3 3.0 4.8 2.4 1.3 1.3
51 13 29 15 0 9
9.0 2.3 5.1 2.6 0.0 1.6
30 6 15 8 3 5
10.2 2.0 5.1 2.7 1.0 1.7
42 9 25 15 3 6
15.1 3.2 9.0 5.4 1.1 2.2
16 0
3.0 0.0
20 0
3.5 0.0
8 1
2.7 0.3
22 1
7.9 0.4
and a three-fold increase in the risk of death (HR, 3.03; 95% CI, 1.35 to 6.82; P ¼.004) compared with patients treated with tamoxifen. Conclusion.dBMI significantly impacts on the efficacy of anastrozole plus goserelin in premenopausal patients with breast cancer, probably through influencing aromatase availability and/ or ovarian suppression by goserelin. Obesity is very well known to be associated with breast cancer risk, albeit differently in pre- and postmenopausal women. The association may result from the peripheral conversion of androstenedione in adipose tissue to estrone, leading to higher levels of estrogen in overweight/obese women. However, nonestrogen-related factors, such as insulin and interleukins, may also play an important role in the relationship between breast cancer risk and obesity. In this very interesting article, Pfeiler and colleagues reported on the impact of BMI on the efficacy of anastrozole and tamoxifen in premenopausal women from the ABCSG-12 trial. Overall, overweight/obese women (BMI > 25 kg/m2) had a significantly higher risk of recurrence on anastrozole
192
compared to women with lower BMIs (<25 kg/m2). No impact of BMI was seen in women treated with tamoxifen. These findings raise important questions about the efficacy of anastrozole in heavier women. One interesting point is that the majority (N ¼ 1111 [66%]) of women in this cohort were normal weight, and only a third were either overweight or obese, which is not the pattern of obesity usually seen in early breast cancer trials. However, most breast cancer trials, specifically those involving an aromatase inhibitor, are performed in postmenopausal women, whereas this study was limited to premenopausal women. So the question arises, is the efficacy of anastrozole different in premenopausal women compared to postmenopausal women, since the results did not show a significant difference between tamoxifen and anastrozole treatment in normalweight premenopausal women (Table 2)? In contrast, an article from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) study1 not only showed that the efficacy of anastrozole in postmenopausal normal-weight women differed significantly from that
Breast Diseases: A Year BookÒ Quarterly Vol 23 No 2 2012
of tamoxifen but also found that the effect of anastrozole was not lessened in overweight/obese women, as was seen in the Pfeiler and colleagues study. Few studies have shown the importance of the reduced efficacy of anastrozole in overweight and obese women with breast cancer. Although premenopausal obesity is associated with a decreased risk of breast cancer, there is a clear need to understand the mechanisms of complete estrogen suppression with anastrozole (or any other aromatase inhibitor) in this overweight population and also, more importantly, in overweight/obese postmenopausal women who are routinely given aromatase inhibitors for breast cancer treatment. I. Sestak, PhD
Reference 1. Sestak I, Distler W, Forbes JF, Dowsett M, Howell A, Cuzick J. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial. J Clin Oncol. 2010;28: 3411-3415.
Impact of Body Mass Index on the Efficacy of Endocrine Therapy in Premenopausal Patients With Breast Cancer: An Analysis of the Prospective ABCSG-12 Trial Pfeiler G, Königsberg R, Fesl C, et al (Med Univ of Vienna, Austria; Applied Cancer ReseInstitution for Translational Res Vienna (ACR-ITR Vienna), Austria; Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria; et al) J Clin Oncol 29:2653-2659, 2011
Purpose.dAromatase inhibitors are effective as endocrine treatment for patients with hormone receptorepositive
because of the low levels of fulvestrant in the body.3 This has consequences for the treatment of acquired drug resistance to antihormones following the report that fulvestrant in an environment of low-dose estrogen actually causes tumors to grow.4 There are 2 obvious strategies for avoiding this situation: either administer fulvestrant with an aromatase inhibitor5 or, as in this article by Di Leo and colleagues, double the dose of fulvestrant. It’s good to know that the basic principles of pharmacology and a knowledge of the biology of breast cancer with acquired resistance can come together to aid patients. V. C. Jordan, OBE, PhD, DSc, FMedSci
References
steroidal antiestrogens. Cancer Res. 1989;49:4090-4093. 2. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res. 1991;51:3867-3873. 3. Robertson JF, Erikstein B, Osborne KC, et al. Pharmacokinetic profile of intramuscular fulvestrant in advanced breast cancer. Clin Pharmacokinet. 2004;43: 529-538. 4. Osipo C, Gajdos C, Liu H, Chen B, Jordan VC. Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer. J Natl Cancer Inst. 2003;95:1597-1608. 5. Dodwell D, Coombes G, Bliss JM, Kilburn LS, Johnston S. Combining fulvestrant (Faslodex) with continued oestrogen suppression in endocrinesensitive advanced breast cancer: the SoFEA trial. Clin Oncol (R Coll Radiol). 2008;20:321-324.
1. Gottardis MM, Jiang SY, Jeng MH, Jordan VC. Inhibition of tamoxifenstimulated growth of an MCF-7 tumor variant in athymic mice by novel
breast cancer. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, we investigated the influence of body mass index (BMI) on the efficacy of adjuvant endocrine therapy in premenopausal patients in a retrospective analysis of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial. Patients and Methods.dABCSG12 examined the efficacy of ovarian suppression using goserelin (3.6 mg subcutaneously every 28 days) in combination with anastrozole or tamoxifen with or without zoledronic acid (4 mg intravenously every 6 months) in premenopausal women with endocrine-responsive breast cancer. BMI was calculated
using the prospectively collected data on patients’ height and weight at study entry. BMI categories have been differentiated according to the WHO definition. Results.dOverweight patients treated with anastrozole had a 60% increase in the risk of disease recurrence (hazard ratio [HR], 1.60; 95% CI, 1.06 to 2.41; P ¼.02) and more than a doubling in the risk of death (HR, 2.14; 95% CI, 1.17 to 3.92; P ¼ .01) compared with normal weight patients treated with anastrozole. In the overweight group, patients treated with anastrozole had a nearly 50% increase in the risk of disease recurrence (HR, 1.49; 95% CI, 0.93 to 2.38; P ¼ .08)
Breast Diseases: A Year BookÒ Quarterly Vol 23 No 2 2012
191
TABLE 2.dEvents of Normal Weight and Overweight/Obese Patients Treated With Anastrozole Versus Tamoxifen Normal Weight Patients Tamoxifen (n ¼ 542)
Overweight and Obese Patients
Anastrozole (n ¼ 569)
Tamoxifen (n ¼ 294)
Anastrozole (n ¼ 279)
Event
No.
%
No.
%
No.
%
No.
%
All events Locoregional Distant Bone metastases Contralateral Secondary malignant conditions Death All Without previous recurrence
56 16 26 13 7 7
10.3 3.0 4.8 2.4 1.3 1.3
51 13 29 15 0 9
9.0 2.3 5.1 2.6 0.0 1.6
30 6 15 8 3 5
10.2 2.0 5.1 2.7 1.0 1.7
42 9 25 15 3 6
15.1 3.2 9.0 5.4 1.1 2.2
16 0
3.0 0.0
20 0
3.5 0.0
8 1
2.7 0.3
22 1
7.9 0.4
and a three-fold increase in the risk of death (HR, 3.03; 95% CI, 1.35 to 6.82; P ¼.004) compared with patients treated with tamoxifen. Conclusion.dBMI significantly impacts on the efficacy of anastrozole plus goserelin in premenopausal patients with breast cancer, probably through influencing aromatase availability and/ or ovarian suppression by goserelin. Obesity is very well known to be associated with breast cancer risk, albeit differently in pre- and postmenopausal women. The association may result from the peripheral conversion of androstenedione in adipose tissue to estrone, leading to higher levels of estrogen in overweight/obese women. However, nonestrogen-related factors, such as insulin and interleukins, may also play an important role in the relationship between breast cancer risk and obesity. In this very interesting article, Pfeiler and colleagues reported on the impact of BMI on the efficacy of anastrozole and tamoxifen in premenopausal women from the ABCSG-12 trial. Overall, overweight/obese women (BMI > 25 kg/m2) had a significantly higher risk of recurrence on anastrozole
192
compared to women with lower BMIs (<25 kg/m2). No impact of BMI was seen in women treated with tamoxifen. These findings raise important questions about the efficacy of anastrozole in heavier women. One interesting point is that the majority (N ¼ 1111 [66%]) of women in this cohort were normal weight, and only a third were either overweight or obese, which is not the pattern of obesity usually seen in early breast cancer trials. However, most breast cancer trials, specifically those involving an aromatase inhibitor, are performed in postmenopausal women, whereas this study was limited to premenopausal women. So the question arises, is the efficacy of anastrozole different in premenopausal women compared to postmenopausal women, since the results did not show a significant difference between tamoxifen and anastrozole treatment in normalweight premenopausal women (Table 2)? In contrast, an article from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) study1 not only showed that the efficacy of anastrozole in postmenopausal normal-weight women differed significantly from that
Breast Diseases: A Year BookÒ Quarterly Vol 23 No 2 2012
of tamoxifen but also found that the effect of anastrozole was not lessened in overweight/obese women, as was seen in the Pfeiler and colleagues study. Few studies have shown the importance of the reduced efficacy of anastrozole in overweight and obese women with breast cancer. Although premenopausal obesity is associated with a decreased risk of breast cancer, there is a clear need to understand the mechanisms of complete estrogen suppression with anastrozole (or any other aromatase inhibitor) in this overweight population and also, more importantly, in overweight/obese postmenopausal women who are routinely given aromatase inhibitors for breast cancer treatment. I. Sestak, PhD
Reference 1. Sestak I, Distler W, Forbes JF, Dowsett M, Howell A, Cuzick J. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial. J Clin Oncol. 2010;28: 3411-3415.