August 23, 2011 — Aromatase inhibitors have provided an alternative form of adjuvant endocrine treatment for breast cancer and are associated with reduced recurrence rates and improved disease-free survival. But when they are used as an up-front therapy, an overall survival benefit has not been observed.
The results of a new meta-analysis, however, suggest that the toxicities associated with aromatase inhibitors may explain the lack of overall survival improvement as compared with tamoxifen.
The new findings are reported in the Journal of the National Cancer Institute.
Although aromatase inhibitors have been gaining in popularity at the expense of tamoxifen for this indication and are now often used in its place, the results from this study and a previous meta-analysis suggest that switching strategies — in which both types of drugs are used sequentially — is also rational and effective, breast cancer experts comment in an accompanying editorial. "We should not 'ditch the switch,'" they write.
Cumulative Toxicity
The meta-analysis showed that a longer duration of aromatase inhibitor use was associated with higher odds of developing cardiovascular disease (odds ratio [OR], 1.26; P < .001), as well as bone fractures (OR, 1.47; P < .001). Use of these agents was also associated with decreased odds of venous thrombosis (OR, 0.55; P < .001) and endometrial carcinoma (OR, 0.34; P < .001).
"Of interest, we found a consistent decrease in the risk of death without breast cancer recurrence for those patients treated with a switch from tamoxifen to aromatase inhibitors, compared with those treated with either aromatase inhibitors or tamoxifen alone," said lead author Eitan Amir, MB, ChB, from the Division of Medical Oncology and Hematology at the Princess Margaret Hospital, Toronto, Ontario, Canada.
"This finding may be explained by a reduction of cumulative toxicity associated with these individual agents when they are each given for 2 to 3 years rather than for 5 years," he said.
Overall, treatment for 5 years with aromatase inhibitors was associated with a non–statistically significant increased odds of death, without disease recurrence, vs 5 years of tamoxifen alone or tamoxifen for 2 to 3 years and then followed by an aromatase inhibitor for 2 to 3 years (OR, 1.11; P = .09).
"We did find statistically significant, but small, absolute increases in risk of cardiovascular events and bone fractures and corresponding small absolute decreases in risk of venous thrombosis and endometrial carcinoma," Dr. Amir told Medscape Medical News. "And while in an unselected population the differences in risks were small, it is highly likely that in certain high-risk patients the risks are higher."
Dr. Amir pointed out that this was a finding in the ATAC trial, which showed that patients with baseline ischemic heart disease had a very large increase in risk of developing cardiovascular events if treated with anastrozole compared with tamoxifen.
The authors note that although several large randomized trials have examined the benefit of the third-generation aromatase inhibitors anastrozole, letrozole, and exemestane, as compared with 5 years of tamoxifen, they have failed to demonstrate a statistically significant improvement in overall survival.
A previous meta-analysis of the randomized trials conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) confirmed that the use of aromatase inhibitors was associated with improved disease-free survival (J Clin Oncol. 2010;28:509-518). However, it also showed a modest but statistically significant improvement in overall survival, but only for patients who took aromatase inhibitors for 2 to 3 years after receiving tamoxifen therapy for the same length of time.
"We therefore postulated that as switching from tamoxifen to aromatase inhibitors is equivalent to upfront use of aromatase inhibitors in terms of reduction in the risk of breast cancer recurrence, and switching reduces the risk of non-breast cancer death, this strategy may be the optimal endocrine therapy strategy in post-menopausal women," he added.
Although it is possible that with longer follow-up, aromatase inhibitors may lead to a survival advantage, current data do not support this hypothesis, Dr. Amir explained. "Indeed, in the most recent update of the ATAC trial which now has a median follow-up of 10 years, there remains no evidence of any survival benefit with anastrozole."
Do Not "Ditch the Switch"
The use of tamoxifen in postmenopausal women has recently been eclipsed by enthusiasm about aromatase inhibitors, and numerous studies have documented a greater reduction in breast cancer recurrence and a seemingly more favorable toxicity profile, notes the accompanying editorial. This is despite the fact that an overall survival benefit with these agents has not been observed.
"What we lack today is a predictive model that integrates cardiovascular and bone risks with the risk of breast cancer recurrence to facilitate a personalized selection of therapy," write Nancy E. Davidson, MD, Shannon Puhalla, MD, and Rachel C. Jankowitz, MD, all from the University of Pittsburgh Cancer Institute and UPMC Cancer Centers, Pittsburgh, Pennsylvania.
They point out that the ability to incorporate cardiovascular and bone health into a model that is intuitive and easy to use would be very helpful to both providers and patients. "We hope that, with time, more sophisticated prognostic and predictive testing for breast cancer and non-breast cancer–related endpoints will become the norm," they say.
The editorialists also emphasize that the provocative findings from both the current study and EBCTCG meta-analyses are far from mature given that the length of follow-up of trials of adjuvant aromatase inhibitors is still relatively short.
"Notably, survival benefits with adjuvant tamoxifen were not truly evident until after 5 years of follow-up," they write. "Thus, it is conceivable that a late survival advantage with aromatase inhibitors over tamoxifen may also emerge over time. Moreover, although it appears that the risk of fracture reverts to baseline after cessation of aromatase inhibitors, it is uncertain whether cardiovascular risk will also evolve over time."
The editorialists conclude that in the meantime, a practical approach would be to "choose initial endocrine therapy for the individual patient with careful attention to the risk of breast cancer recurrence, the risk of toxicity, and comorbidities."
"Ultimately, results of the meta-analysis by Amir et al as well as those from the EBCTCG meta-analysis suggest that switching strategies are also rational and effective, leading us to conclude that we should not 'ditch the switch,'" they write.
Study Details
Dr. Amir and colleagues conducted a systematic review to identify randomized, controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women. A total of 7 trials with a total of 30,023 patients met the inclusion criteria.
Longer durations of aromatase inhibitor use were associated with increased odds of cardiovascular disease when compared with tamoxifen. In absolute terms, 4.2% of patients using aromatase inhibitors and 3.4% of patients in the tamoxifen group experienced a cardiovascular event.
The odds of a cardiovascular event were increased in the aromatase inhibitor group compared with the tamoxifen group and were observed in all treatment cohorts; however, the magnitude was numerically, but not statistically significantly, lower among patients who received aromatase inhibitors after 2 to 3 years of treatment with tamoxifen (ORs of 1.15 vs 1.30 and 1.37; test of subgroup differences, P = .53).
Cerebrovascular events were similar in both treatment groups, and neither the individual studies nor the pooled data showed any statistically significant difference. It was an uncommon adverse event, occurring in 1.4% of patients in the aromatase inhibitor group and in 1.5% of patients in the tamoxifen group.
Longer use of aromatase inhibitors were also associated with increased odds of bone fractures as compared with tamoxifen. The pooled analysis showed that a longer duration of aromatase inhibitor use was associated with a 47% increase in the odds of bone fractures compared with tamoxifen (OR, 1.47; P < .001). In absolute terms, the incidence of fractures was 7.5% in the aromatase inhibitor group and 5.2% in the tamoxifen group.
As compared with tamoxifen, longer use of aromatase inhibitors was associated with decreased odds of venous thrombosis. The pooled analysis showed a 45% (OR, 1.47; P < .001) reduction in the relative odds of venous thrombosis for aromatase inhibitor users compared with the tamoxifen group.
Similarly, there was a 66% reduction in the relative odds of endometrial carcinoma with longer duration of aromatase inhibitor use as compared with tamoxifen (OR, 0.34; P < .001). The authors note that overall, endometrial carcinoma was a very rare event, occurring in only 0.1% of patients in the aromatase inhibitor group and in 0.5% of the tamoxifen group.
The study was funded by the Asociación Española Contra el Cáncer and Fondo de Investigaciones Sanitarias. The authors and editorialists have disclosed no relevant financial relationships.
J Natl Cancer Inst. 2011;103:1-11. Abstract
The results of a new meta-analysis, however, suggest that the toxicities associated with aromatase inhibitors may explain the lack of overall survival improvement as compared with tamoxifen.
The new findings are reported in the Journal of the National Cancer Institute.
Although aromatase inhibitors have been gaining in popularity at the expense of tamoxifen for this indication and are now often used in its place, the results from this study and a previous meta-analysis suggest that switching strategies — in which both types of drugs are used sequentially — is also rational and effective, breast cancer experts comment in an accompanying editorial. "We should not 'ditch the switch,'" they write.
Cumulative Toxicity
The meta-analysis showed that a longer duration of aromatase inhibitor use was associated with higher odds of developing cardiovascular disease (odds ratio [OR], 1.26; P < .001), as well as bone fractures (OR, 1.47; P < .001). Use of these agents was also associated with decreased odds of venous thrombosis (OR, 0.55; P < .001) and endometrial carcinoma (OR, 0.34; P < .001).
"Of interest, we found a consistent decrease in the risk of death without breast cancer recurrence for those patients treated with a switch from tamoxifen to aromatase inhibitors, compared with those treated with either aromatase inhibitors or tamoxifen alone," said lead author Eitan Amir, MB, ChB, from the Division of Medical Oncology and Hematology at the Princess Margaret Hospital, Toronto, Ontario, Canada.
"This finding may be explained by a reduction of cumulative toxicity associated with these individual agents when they are each given for 2 to 3 years rather than for 5 years," he said.
Overall, treatment for 5 years with aromatase inhibitors was associated with a non–statistically significant increased odds of death, without disease recurrence, vs 5 years of tamoxifen alone or tamoxifen for 2 to 3 years and then followed by an aromatase inhibitor for 2 to 3 years (OR, 1.11; P = .09).
"We did find statistically significant, but small, absolute increases in risk of cardiovascular events and bone fractures and corresponding small absolute decreases in risk of venous thrombosis and endometrial carcinoma," Dr. Amir told Medscape Medical News. "And while in an unselected population the differences in risks were small, it is highly likely that in certain high-risk patients the risks are higher."
Dr. Amir pointed out that this was a finding in the ATAC trial, which showed that patients with baseline ischemic heart disease had a very large increase in risk of developing cardiovascular events if treated with anastrozole compared with tamoxifen.
The authors note that although several large randomized trials have examined the benefit of the third-generation aromatase inhibitors anastrozole, letrozole, and exemestane, as compared with 5 years of tamoxifen, they have failed to demonstrate a statistically significant improvement in overall survival.
A previous meta-analysis of the randomized trials conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) confirmed that the use of aromatase inhibitors was associated with improved disease-free survival (J Clin Oncol. 2010;28:509-518). However, it also showed a modest but statistically significant improvement in overall survival, but only for patients who took aromatase inhibitors for 2 to 3 years after receiving tamoxifen therapy for the same length of time.
"We therefore postulated that as switching from tamoxifen to aromatase inhibitors is equivalent to upfront use of aromatase inhibitors in terms of reduction in the risk of breast cancer recurrence, and switching reduces the risk of non-breast cancer death, this strategy may be the optimal endocrine therapy strategy in post-menopausal women," he added.
Although it is possible that with longer follow-up, aromatase inhibitors may lead to a survival advantage, current data do not support this hypothesis, Dr. Amir explained. "Indeed, in the most recent update of the ATAC trial which now has a median follow-up of 10 years, there remains no evidence of any survival benefit with anastrozole."
Do Not "Ditch the Switch"
The use of tamoxifen in postmenopausal women has recently been eclipsed by enthusiasm about aromatase inhibitors, and numerous studies have documented a greater reduction in breast cancer recurrence and a seemingly more favorable toxicity profile, notes the accompanying editorial. This is despite the fact that an overall survival benefit with these agents has not been observed.
"What we lack today is a predictive model that integrates cardiovascular and bone risks with the risk of breast cancer recurrence to facilitate a personalized selection of therapy," write Nancy E. Davidson, MD, Shannon Puhalla, MD, and Rachel C. Jankowitz, MD, all from the University of Pittsburgh Cancer Institute and UPMC Cancer Centers, Pittsburgh, Pennsylvania.
They point out that the ability to incorporate cardiovascular and bone health into a model that is intuitive and easy to use would be very helpful to both providers and patients. "We hope that, with time, more sophisticated prognostic and predictive testing for breast cancer and non-breast cancer–related endpoints will become the norm," they say.
The editorialists also emphasize that the provocative findings from both the current study and EBCTCG meta-analyses are far from mature given that the length of follow-up of trials of adjuvant aromatase inhibitors is still relatively short.
"Notably, survival benefits with adjuvant tamoxifen were not truly evident until after 5 years of follow-up," they write. "Thus, it is conceivable that a late survival advantage with aromatase inhibitors over tamoxifen may also emerge over time. Moreover, although it appears that the risk of fracture reverts to baseline after cessation of aromatase inhibitors, it is uncertain whether cardiovascular risk will also evolve over time."
The editorialists conclude that in the meantime, a practical approach would be to "choose initial endocrine therapy for the individual patient with careful attention to the risk of breast cancer recurrence, the risk of toxicity, and comorbidities."
"Ultimately, results of the meta-analysis by Amir et al as well as those from the EBCTCG meta-analysis suggest that switching strategies are also rational and effective, leading us to conclude that we should not 'ditch the switch,'" they write.
Study Details
Dr. Amir and colleagues conducted a systematic review to identify randomized, controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women. A total of 7 trials with a total of 30,023 patients met the inclusion criteria.
Longer durations of aromatase inhibitor use were associated with increased odds of cardiovascular disease when compared with tamoxifen. In absolute terms, 4.2% of patients using aromatase inhibitors and 3.4% of patients in the tamoxifen group experienced a cardiovascular event.
The odds of a cardiovascular event were increased in the aromatase inhibitor group compared with the tamoxifen group and were observed in all treatment cohorts; however, the magnitude was numerically, but not statistically significantly, lower among patients who received aromatase inhibitors after 2 to 3 years of treatment with tamoxifen (ORs of 1.15 vs 1.30 and 1.37; test of subgroup differences, P = .53).
Cerebrovascular events were similar in both treatment groups, and neither the individual studies nor the pooled data showed any statistically significant difference. It was an uncommon adverse event, occurring in 1.4% of patients in the aromatase inhibitor group and in 1.5% of patients in the tamoxifen group.
Longer use of aromatase inhibitors were also associated with increased odds of bone fractures as compared with tamoxifen. The pooled analysis showed that a longer duration of aromatase inhibitor use was associated with a 47% increase in the odds of bone fractures compared with tamoxifen (OR, 1.47; P < .001). In absolute terms, the incidence of fractures was 7.5% in the aromatase inhibitor group and 5.2% in the tamoxifen group.
As compared with tamoxifen, longer use of aromatase inhibitors was associated with decreased odds of venous thrombosis. The pooled analysis showed a 45% (OR, 1.47; P < .001) reduction in the relative odds of venous thrombosis for aromatase inhibitor users compared with the tamoxifen group.
Similarly, there was a 66% reduction in the relative odds of endometrial carcinoma with longer duration of aromatase inhibitor use as compared with tamoxifen (OR, 0.34; P < .001). The authors note that overall, endometrial carcinoma was a very rare event, occurring in only 0.1% of patients in the aromatase inhibitor group and in 0.5% of the tamoxifen group.
The study was funded by the Asociación Española Contra el Cáncer and Fondo de Investigaciones Sanitarias. The authors and editorialists have disclosed no relevant financial relationships.
J Natl Cancer Inst. 2011;103:1-11. Abstract
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