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Study Overview
Objective. To assess the effect of extending adjuvant therapy with an aromatase inhibitor beyond 5 years in postmenopausal women with breast cancer.
Design. Phase 3, randomized, double-blind, placebo-controlled trial.
Setting and participants. This was a North American Breast Cancer Group trial, coordinated by the Canadian Cancer Trials Group. The trial was originally designed as an extension of the MA.17 trial evaluating the role for 5 years of letrozole versus placebo after 5 years of tamoxifen, with re-randomization of letrozole-assigned patients to an additional 5 years of letrozole versus placebo. The trial was then extended to include additional postmenopausal women with stage I-III breast cancer who had been treated with 4.5 to 6 years of adjuvant therapy with any aromatase inhibitor with or without prior tamoxifen.
Most patients had received adjuvant treatment with tamoxifen before the aromatase inhibitor. Patients were randomized within 2 years after completing treatment with the aromatase inhibitor to either letrozole 2.5 mg or placebo orally once a day, for another 5 years. The criteria for stratification included lymph node status, prior receipt of adjuvant chemotherapy, the interval between the last dose of aromatase inhibitor and randomization, and the duration of prior use of tamoxifen. Eligibility criteria included patients who were disease-free after 4.5 to 6 years of aromatase inhibitor, hormone-positive tumors (and unknown receptor status for participants in the MA.17 trial), ECOG performance status of 0 to 2, and life expectancy of 5 or more years.
Main outcome measures. The primary endpoint was disease-free survival, defined as the time from randomization to recurrence or the development of new primary breast cancer. Secondary endpoints included overall survival, incidence of contralateral breast cancer, quality of life using the Medical Outcomes Study 36-Item Short-Form Heath Survey (SF-36) and the Menopause-Specific Quality of Life (MENQOL) questionnaire, and long-term safety. The investigators calculated that 196 events were required for the study to have 80% power to detect a 33% lower hazard of recurrence with letrozole as compared with placebo. At the 6-year point, only 176 events had been observed, and the study design was amended to have a time-based analysis instead of event-based. On 13 Nov 2015 the final database had 165 events, with 80% power to detect a hazard ratio for disease-free survival of 0.655. The analysis of time-to-event outcomes was performed utilizing a log-rank test with adjustment for stratification factors. Fisher’s exact test was used to assess binary outcomes, and Wilcoxon test, to assess continuous outcomes. Comparisons between the letrozole and the placebo groups were made using a 2-sided test with an alpha level of 5%.
Main results. A total of 1918 patients were randomized to receive either letrozole (n = 959) or placebo (n = 959). The rate of adherence to the study regimen was approximately 62% for both arms. The median duration of prior treatment with tamoxifen was 5 years; 20.7% of patients did not receive tamoxifen. The median duration of prior treatment with aromatase inhibitor was 5 years, and the median time interval between the last dose of aromatase inhibitor and randomization was less than 6 months. The median duration of the study regimen (letrozole or placebo) was 5 years, and the median follow-up was 6.3 years. Approximately 90% of patients had stage T1 or T2 tumors at diagnosis, and 94% of nodal stage were N0 or N1. Estrogen receptor, progesterone receptor or both were known to be positive in 98.8% of patients.
Disease recurrence or contralateral breast cancer occurred in 67 patients (7%) in the letrozole group and 98 patients (10.2%) in the placebo group. The hazard ratio for recurrence or occurrence of contralateral breast cancer was 0.66 (95% confidence interval [CI], 0.48–0.91, P = 0.01). In the letrozole group, 55 patients had disease recurrence and 13 patients had contralateral breast cancer. Among the patients in the placebo group, 68 had recurrence of disease and 31 had contralateral breast cancer. Both disease recurrence and contralateral breast cancer occurred in one patient in each group. Distant disease recurrence was 5.5% in the placebo group and 4.4% in the letrozole group.
Five-year disease-free survival, the primary endpoint of this study, was 95% in the letrozole group (95% CI, 93–96) and 91% in the placebo group (95% CI, 89–93). The rate of 5-year disease free-survival was higher in the letrozole group in all subgroups. A total of 200 deaths were observed, 100 in each group. The rate of 5-year overall survival was not statistically different between the 2 groups (93% in the letrozole group and 94% in the placebo group, HR 0.97, P = 0.83). The annual incidence rate of contralateral breast cancer favored the letrozole group, with a rate of 0.21% in comparison with 0.49% in the placebo group (HR 0.42, P = 0.007).
Discontinuation of treatment occurred in 5.4% of patients in the letrozole group and 3.7% in the placebo group. The majority of toxic effects had a similar incidence in both groups, however bone-related side effects were more common in the letrozole group. Bone fractures occurred in 14% of patients in the letrozole group and 9% in the placebo group (P = 0.001). New-onset osteoporosis was also more common in the letrozole group (11% versus 6%, P < 0.001). Of note, 5 patients developed a hip fracture after discontinuation of letrozole. In regards to quality of life, patients receiving letrozole had a greater reduction in scores in the role-physical subscale of the SF-36 survey, indicating worse quality of life, but the difference was less than the minimum clinically important difference. There were no differences in the MENQOL questionnaire subscales.
Conclusion. Treatment with an aromatase inhibitor for additional 4.5 to 6 years was beneficial in preventing disease recurrence. There was no difference in overall survival.
Commentary
Adjuvant endocrine therapy reduces the risk of recurrence and increases survival in women with hormone receptor–positive breast cancer. The use of tamoxifen as adjuvant therapy for women with early stage breast cancer has been extensively studied. A metanalysis performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTG) demonstrated that tamoxifen reduces breast cancer mortality by a third when given as adjuvant therapy for women with hormone positive breast cancer [1].
Two important studies published in the last decade demonstrated that extending therapy with tamoxifen beyond 5 years reduces the chance of recurrence and improves survival. In the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial, women with early stage breast cancer who had completed 5 years of adjuvant tamoxifen were randomized to stop therapy or to continue tamoxifen for 5 additional years. Among patients with estrogen receptor (ER)–positive disease, the results demonstrated an absolute recurrence reduction of 3.7% and an absolute mortality reduction of 2.8% in 15 years after diagnosis [2].The aTTom trial randomized 6953 women with ER-positive breast cancer to discontinue tamoxifen after 5 years or to continue to complete 10 years of treatment and confirmed a benefit in recurrence rates and breast cancer mortality with 10 years of adjuvant tamoxifen [3].
Although tamoxifen is active in both pre- and postmenopausal patients, therapy with an aromatase inhibitor either as first-line or following treatment with tamoxifen has been demonstrated to be superior to tamoxifen alone in hormone receptor–positive postmenopausal women. In the ATAC (The Arimidex, Tamoxifen, Alone or in Combination) trial, postmenopausal patients were randomized to receive 5 years of either tamoxifen or anastrozole as adjuvant therapy. The anastrozole group had higher disease-free survival, time to recurrence and time to distant recurrence [4].In the Breast Intergroup (BIG) 1-98 trial, postmenopausal women were assigned to 4 different arms: 5 years of letrozole, 5 years of tamoxifen, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. The 2 groups assigned to receive letrozole initially were compared to the 2 groups assigned to receive tamoxifen initially. Compared with tamoxifen, letrozole significantly decrease the risk of recurrence [5].The MA-17 trial demonstrated a disease-free survival advantage with 5 years of letrozole compared with placebo in women who had been treated with tamoxifen for 5 years [6]. Based on these data, current guidelines for adjuvant endocrine therapy for postmenopausal women recommend an aromatase inhibitor for 5 years as primary therapy or after 2 to 3 years of tamoxifen [7].
Results from studies with extended endocrine therapy, either 10 years of tamoxifen or 5 years of aromatase inhibitor after up to 5 years of tamoxifen, provide rationale to study the effect of therapy with aromatase inhibitor beyond 5 years. The current study by Goss et al (the MA 17.R trial) addresses the relevant question of whether extended adjuvant therapy with an aromatase inhibitor in post-menopausal women beyond 5 years provides additional benefit. The design of this study has several strengths including being randomized, phase 3, placebo-controlled and double-blind. Another strength was the large number of patients enrolled. The choice of disease-free survival as the primary endpoint is in accordance with the natural course of ER-positive breast cancer, which has a prolonged rate of recurrence. The study results showed that patients who received 10 years of letrozole had a 34% lower risk of recurrence, with an absolute improvement of 4% in disease-free survival. However, no overall survival benefit was demonstrated at a median follow-up of 6.3 years. This might be a result of the fact that the highest proportional benefit was reduction in incidence of contralateral breast cancer. It is also possible that an overall survival benefit would be observed with a longer follow-up.
As highlighted by the authors, the benefit of extended adjuvant therapy is higher in the first years. Given that the majority of patients enrolled in this study had received prior tamoxifen, it is possible that patients who receive only an aromatase inhibitor for 5 years without prior tamoxifen would benefit even more from extended aromatase inhibitor therapy. On the other hand, the 1.1% numerical advantage observed in reducing distant recurrence is quite modest, with the majority of the disease-free survival advantage seen with extended aromatase inhibition being due to a reduction in local recurrence and contralateral new concerns.
The quality of life assessment enhanced this trial, since adherence to adjuvant endocrine therapy remains a challenge. It should be noted, however, that patients willing to participate in a trial of extended therapy are likely to be those who have tolerated therapy reasonably well. The increase in body pain and differences in the role-emotional subscale in the letrozole reflect side effects of aromatase inhibitors that are seen in clinical practice. The higher rates of new-onset osteoporosis and bone fractures underscore the need to balance potential benefits and risks with extended aromatase inhibitor therapy.
Results from other trials evaluating extended adjuvant therapy will be helpful. The NSABP B-42 study randomized ER-positive postmenopausal patients to receive 5 years of letrozole or placebo after completing 5 years of hormonal therapy with an aromatase inhibitor for 5 years or ≤ 3 years of tamoxifen followed by an aromatase inhibitor. This study has completed enrollment and should provide additional insight regarding duration of therapy with aromatase inhibitors.
Applications for Clinical Practice
These trial results showed a benefit with extended aromatase inhibitor therapy; however, the magnitude of benefit was relatively small, particularly with respect to impacting distant recurrence risk. Given that extended therapy has potential side effects, it is appropriate to have a detailed discussion with patients regarding potential benefits and risks. A reasonable clinical strategy is to discuss extended therapy with patients who have a higher chance of relapse and those who are motivated to continue therapy to reduce new breast cancer events.
—Leticia Varella, MD, and Halle Moore, MD,
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–717.
2. Davies C, Pan H, Godwin J, at al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805–16.
3. Gray RG, Rea D, Handley K, et al. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 2013;31(suppl;abstr 5).
4. Cuzick J, Sestak I, Baum M, et al; ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010;11:113541.
5. Breast International Group (BIG) 1-98 Collaborative Group, Thürlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747–57.
6. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–802.
7. Burstein HJ, Prestrud AA, Seidenfeld J, et al; American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010;28:3784–96.
Study Overview
Objective. To assess the effect of extending adjuvant therapy with an aromatase inhibitor beyond 5 years in postmenopausal women with breast cancer.
Design. Phase 3, randomized, double-blind, placebo-controlled trial.
Setting and participants. This was a North American Breast Cancer Group trial, coordinated by the Canadian Cancer Trials Group. The trial was originally designed as an extension of the MA.17 trial evaluating the role for 5 years of letrozole versus placebo after 5 years of tamoxifen, with re-randomization of letrozole-assigned patients to an additional 5 years of letrozole versus placebo. The trial was then extended to include additional postmenopausal women with stage I-III breast cancer who had been treated with 4.5 to 6 years of adjuvant therapy with any aromatase inhibitor with or without prior tamoxifen.
Most patients had received adjuvant treatment with tamoxifen before the aromatase inhibitor. Patients were randomized within 2 years after completing treatment with the aromatase inhibitor to either letrozole 2.5 mg or placebo orally once a day, for another 5 years. The criteria for stratification included lymph node status, prior receipt of adjuvant chemotherapy, the interval between the last dose of aromatase inhibitor and randomization, and the duration of prior use of tamoxifen. Eligibility criteria included patients who were disease-free after 4.5 to 6 years of aromatase inhibitor, hormone-positive tumors (and unknown receptor status for participants in the MA.17 trial), ECOG performance status of 0 to 2, and life expectancy of 5 or more years.
Main outcome measures. The primary endpoint was disease-free survival, defined as the time from randomization to recurrence or the development of new primary breast cancer. Secondary endpoints included overall survival, incidence of contralateral breast cancer, quality of life using the Medical Outcomes Study 36-Item Short-Form Heath Survey (SF-36) and the Menopause-Specific Quality of Life (MENQOL) questionnaire, and long-term safety. The investigators calculated that 196 events were required for the study to have 80% power to detect a 33% lower hazard of recurrence with letrozole as compared with placebo. At the 6-year point, only 176 events had been observed, and the study design was amended to have a time-based analysis instead of event-based. On 13 Nov 2015 the final database had 165 events, with 80% power to detect a hazard ratio for disease-free survival of 0.655. The analysis of time-to-event outcomes was performed utilizing a log-rank test with adjustment for stratification factors. Fisher’s exact test was used to assess binary outcomes, and Wilcoxon test, to assess continuous outcomes. Comparisons between the letrozole and the placebo groups were made using a 2-sided test with an alpha level of 5%.
Main results. A total of 1918 patients were randomized to receive either letrozole (n = 959) or placebo (n = 959). The rate of adherence to the study regimen was approximately 62% for both arms. The median duration of prior treatment with tamoxifen was 5 years; 20.7% of patients did not receive tamoxifen. The median duration of prior treatment with aromatase inhibitor was 5 years, and the median time interval between the last dose of aromatase inhibitor and randomization was less than 6 months. The median duration of the study regimen (letrozole or placebo) was 5 years, and the median follow-up was 6.3 years. Approximately 90% of patients had stage T1 or T2 tumors at diagnosis, and 94% of nodal stage were N0 or N1. Estrogen receptor, progesterone receptor or both were known to be positive in 98.8% of patients.
Disease recurrence or contralateral breast cancer occurred in 67 patients (7%) in the letrozole group and 98 patients (10.2%) in the placebo group. The hazard ratio for recurrence or occurrence of contralateral breast cancer was 0.66 (95% confidence interval [CI], 0.48–0.91, P = 0.01). In the letrozole group, 55 patients had disease recurrence and 13 patients had contralateral breast cancer. Among the patients in the placebo group, 68 had recurrence of disease and 31 had contralateral breast cancer. Both disease recurrence and contralateral breast cancer occurred in one patient in each group. Distant disease recurrence was 5.5% in the placebo group and 4.4% in the letrozole group.
Five-year disease-free survival, the primary endpoint of this study, was 95% in the letrozole group (95% CI, 93–96) and 91% in the placebo group (95% CI, 89–93). The rate of 5-year disease free-survival was higher in the letrozole group in all subgroups. A total of 200 deaths were observed, 100 in each group. The rate of 5-year overall survival was not statistically different between the 2 groups (93% in the letrozole group and 94% in the placebo group, HR 0.97, P = 0.83). The annual incidence rate of contralateral breast cancer favored the letrozole group, with a rate of 0.21% in comparison with 0.49% in the placebo group (HR 0.42, P = 0.007).
Discontinuation of treatment occurred in 5.4% of patients in the letrozole group and 3.7% in the placebo group. The majority of toxic effects had a similar incidence in both groups, however bone-related side effects were more common in the letrozole group. Bone fractures occurred in 14% of patients in the letrozole group and 9% in the placebo group (P = 0.001). New-onset osteoporosis was also more common in the letrozole group (11% versus 6%, P < 0.001). Of note, 5 patients developed a hip fracture after discontinuation of letrozole. In regards to quality of life, patients receiving letrozole had a greater reduction in scores in the role-physical subscale of the SF-36 survey, indicating worse quality of life, but the difference was less than the minimum clinically important difference. There were no differences in the MENQOL questionnaire subscales.
Conclusion. Treatment with an aromatase inhibitor for additional 4.5 to 6 years was beneficial in preventing disease recurrence. There was no difference in overall survival.
Commentary
Adjuvant endocrine therapy reduces the risk of recurrence and increases survival in women with hormone receptor–positive breast cancer. The use of tamoxifen as adjuvant therapy for women with early stage breast cancer has been extensively studied. A metanalysis performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTG) demonstrated that tamoxifen reduces breast cancer mortality by a third when given as adjuvant therapy for women with hormone positive breast cancer [1].
Two important studies published in the last decade demonstrated that extending therapy with tamoxifen beyond 5 years reduces the chance of recurrence and improves survival. In the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial, women with early stage breast cancer who had completed 5 years of adjuvant tamoxifen were randomized to stop therapy or to continue tamoxifen for 5 additional years. Among patients with estrogen receptor (ER)–positive disease, the results demonstrated an absolute recurrence reduction of 3.7% and an absolute mortality reduction of 2.8% in 15 years after diagnosis [2].The aTTom trial randomized 6953 women with ER-positive breast cancer to discontinue tamoxifen after 5 years or to continue to complete 10 years of treatment and confirmed a benefit in recurrence rates and breast cancer mortality with 10 years of adjuvant tamoxifen [3].
Although tamoxifen is active in both pre- and postmenopausal patients, therapy with an aromatase inhibitor either as first-line or following treatment with tamoxifen has been demonstrated to be superior to tamoxifen alone in hormone receptor–positive postmenopausal women. In the ATAC (The Arimidex, Tamoxifen, Alone or in Combination) trial, postmenopausal patients were randomized to receive 5 years of either tamoxifen or anastrozole as adjuvant therapy. The anastrozole group had higher disease-free survival, time to recurrence and time to distant recurrence [4].In the Breast Intergroup (BIG) 1-98 trial, postmenopausal women were assigned to 4 different arms: 5 years of letrozole, 5 years of tamoxifen, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. The 2 groups assigned to receive letrozole initially were compared to the 2 groups assigned to receive tamoxifen initially. Compared with tamoxifen, letrozole significantly decrease the risk of recurrence [5].The MA-17 trial demonstrated a disease-free survival advantage with 5 years of letrozole compared with placebo in women who had been treated with tamoxifen for 5 years [6]. Based on these data, current guidelines for adjuvant endocrine therapy for postmenopausal women recommend an aromatase inhibitor for 5 years as primary therapy or after 2 to 3 years of tamoxifen [7].
Results from studies with extended endocrine therapy, either 10 years of tamoxifen or 5 years of aromatase inhibitor after up to 5 years of tamoxifen, provide rationale to study the effect of therapy with aromatase inhibitor beyond 5 years. The current study by Goss et al (the MA 17.R trial) addresses the relevant question of whether extended adjuvant therapy with an aromatase inhibitor in post-menopausal women beyond 5 years provides additional benefit. The design of this study has several strengths including being randomized, phase 3, placebo-controlled and double-blind. Another strength was the large number of patients enrolled. The choice of disease-free survival as the primary endpoint is in accordance with the natural course of ER-positive breast cancer, which has a prolonged rate of recurrence. The study results showed that patients who received 10 years of letrozole had a 34% lower risk of recurrence, with an absolute improvement of 4% in disease-free survival. However, no overall survival benefit was demonstrated at a median follow-up of 6.3 years. This might be a result of the fact that the highest proportional benefit was reduction in incidence of contralateral breast cancer. It is also possible that an overall survival benefit would be observed with a longer follow-up.
As highlighted by the authors, the benefit of extended adjuvant therapy is higher in the first years. Given that the majority of patients enrolled in this study had received prior tamoxifen, it is possible that patients who receive only an aromatase inhibitor for 5 years without prior tamoxifen would benefit even more from extended aromatase inhibitor therapy. On the other hand, the 1.1% numerical advantage observed in reducing distant recurrence is quite modest, with the majority of the disease-free survival advantage seen with extended aromatase inhibition being due to a reduction in local recurrence and contralateral new concerns.
The quality of life assessment enhanced this trial, since adherence to adjuvant endocrine therapy remains a challenge. It should be noted, however, that patients willing to participate in a trial of extended therapy are likely to be those who have tolerated therapy reasonably well. The increase in body pain and differences in the role-emotional subscale in the letrozole reflect side effects of aromatase inhibitors that are seen in clinical practice. The higher rates of new-onset osteoporosis and bone fractures underscore the need to balance potential benefits and risks with extended aromatase inhibitor therapy.
Results from other trials evaluating extended adjuvant therapy will be helpful. The NSABP B-42 study randomized ER-positive postmenopausal patients to receive 5 years of letrozole or placebo after completing 5 years of hormonal therapy with an aromatase inhibitor for 5 years or ≤ 3 years of tamoxifen followed by an aromatase inhibitor. This study has completed enrollment and should provide additional insight regarding duration of therapy with aromatase inhibitors.
Applications for Clinical Practice
These trial results showed a benefit with extended aromatase inhibitor therapy; however, the magnitude of benefit was relatively small, particularly with respect to impacting distant recurrence risk. Given that extended therapy has potential side effects, it is appropriate to have a detailed discussion with patients regarding potential benefits and risks. A reasonable clinical strategy is to discuss extended therapy with patients who have a higher chance of relapse and those who are motivated to continue therapy to reduce new breast cancer events.
—Leticia Varella, MD, and Halle Moore, MD,
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
Study Overview
Objective. To assess the effect of extending adjuvant therapy with an aromatase inhibitor beyond 5 years in postmenopausal women with breast cancer.
Design. Phase 3, randomized, double-blind, placebo-controlled trial.
Setting and participants. This was a North American Breast Cancer Group trial, coordinated by the Canadian Cancer Trials Group. The trial was originally designed as an extension of the MA.17 trial evaluating the role for 5 years of letrozole versus placebo after 5 years of tamoxifen, with re-randomization of letrozole-assigned patients to an additional 5 years of letrozole versus placebo. The trial was then extended to include additional postmenopausal women with stage I-III breast cancer who had been treated with 4.5 to 6 years of adjuvant therapy with any aromatase inhibitor with or without prior tamoxifen.
Most patients had received adjuvant treatment with tamoxifen before the aromatase inhibitor. Patients were randomized within 2 years after completing treatment with the aromatase inhibitor to either letrozole 2.5 mg or placebo orally once a day, for another 5 years. The criteria for stratification included lymph node status, prior receipt of adjuvant chemotherapy, the interval between the last dose of aromatase inhibitor and randomization, and the duration of prior use of tamoxifen. Eligibility criteria included patients who were disease-free after 4.5 to 6 years of aromatase inhibitor, hormone-positive tumors (and unknown receptor status for participants in the MA.17 trial), ECOG performance status of 0 to 2, and life expectancy of 5 or more years.
Main outcome measures. The primary endpoint was disease-free survival, defined as the time from randomization to recurrence or the development of new primary breast cancer. Secondary endpoints included overall survival, incidence of contralateral breast cancer, quality of life using the Medical Outcomes Study 36-Item Short-Form Heath Survey (SF-36) and the Menopause-Specific Quality of Life (MENQOL) questionnaire, and long-term safety. The investigators calculated that 196 events were required for the study to have 80% power to detect a 33% lower hazard of recurrence with letrozole as compared with placebo. At the 6-year point, only 176 events had been observed, and the study design was amended to have a time-based analysis instead of event-based. On 13 Nov 2015 the final database had 165 events, with 80% power to detect a hazard ratio for disease-free survival of 0.655. The analysis of time-to-event outcomes was performed utilizing a log-rank test with adjustment for stratification factors. Fisher’s exact test was used to assess binary outcomes, and Wilcoxon test, to assess continuous outcomes. Comparisons between the letrozole and the placebo groups were made using a 2-sided test with an alpha level of 5%.
Main results. A total of 1918 patients were randomized to receive either letrozole (n = 959) or placebo (n = 959). The rate of adherence to the study regimen was approximately 62% for both arms. The median duration of prior treatment with tamoxifen was 5 years; 20.7% of patients did not receive tamoxifen. The median duration of prior treatment with aromatase inhibitor was 5 years, and the median time interval between the last dose of aromatase inhibitor and randomization was less than 6 months. The median duration of the study regimen (letrozole or placebo) was 5 years, and the median follow-up was 6.3 years. Approximately 90% of patients had stage T1 or T2 tumors at diagnosis, and 94% of nodal stage were N0 or N1. Estrogen receptor, progesterone receptor or both were known to be positive in 98.8% of patients.
Disease recurrence or contralateral breast cancer occurred in 67 patients (7%) in the letrozole group and 98 patients (10.2%) in the placebo group. The hazard ratio for recurrence or occurrence of contralateral breast cancer was 0.66 (95% confidence interval [CI], 0.48–0.91, P = 0.01). In the letrozole group, 55 patients had disease recurrence and 13 patients had contralateral breast cancer. Among the patients in the placebo group, 68 had recurrence of disease and 31 had contralateral breast cancer. Both disease recurrence and contralateral breast cancer occurred in one patient in each group. Distant disease recurrence was 5.5% in the placebo group and 4.4% in the letrozole group.
Five-year disease-free survival, the primary endpoint of this study, was 95% in the letrozole group (95% CI, 93–96) and 91% in the placebo group (95% CI, 89–93). The rate of 5-year disease free-survival was higher in the letrozole group in all subgroups. A total of 200 deaths were observed, 100 in each group. The rate of 5-year overall survival was not statistically different between the 2 groups (93% in the letrozole group and 94% in the placebo group, HR 0.97, P = 0.83). The annual incidence rate of contralateral breast cancer favored the letrozole group, with a rate of 0.21% in comparison with 0.49% in the placebo group (HR 0.42, P = 0.007).
Discontinuation of treatment occurred in 5.4% of patients in the letrozole group and 3.7% in the placebo group. The majority of toxic effects had a similar incidence in both groups, however bone-related side effects were more common in the letrozole group. Bone fractures occurred in 14% of patients in the letrozole group and 9% in the placebo group (P = 0.001). New-onset osteoporosis was also more common in the letrozole group (11% versus 6%, P < 0.001). Of note, 5 patients developed a hip fracture after discontinuation of letrozole. In regards to quality of life, patients receiving letrozole had a greater reduction in scores in the role-physical subscale of the SF-36 survey, indicating worse quality of life, but the difference was less than the minimum clinically important difference. There were no differences in the MENQOL questionnaire subscales.
Conclusion. Treatment with an aromatase inhibitor for additional 4.5 to 6 years was beneficial in preventing disease recurrence. There was no difference in overall survival.
Commentary
Adjuvant endocrine therapy reduces the risk of recurrence and increases survival in women with hormone receptor–positive breast cancer. The use of tamoxifen as adjuvant therapy for women with early stage breast cancer has been extensively studied. A metanalysis performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTG) demonstrated that tamoxifen reduces breast cancer mortality by a third when given as adjuvant therapy for women with hormone positive breast cancer [1].
Two important studies published in the last decade demonstrated that extending therapy with tamoxifen beyond 5 years reduces the chance of recurrence and improves survival. In the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial, women with early stage breast cancer who had completed 5 years of adjuvant tamoxifen were randomized to stop therapy or to continue tamoxifen for 5 additional years. Among patients with estrogen receptor (ER)–positive disease, the results demonstrated an absolute recurrence reduction of 3.7% and an absolute mortality reduction of 2.8% in 15 years after diagnosis [2].The aTTom trial randomized 6953 women with ER-positive breast cancer to discontinue tamoxifen after 5 years or to continue to complete 10 years of treatment and confirmed a benefit in recurrence rates and breast cancer mortality with 10 years of adjuvant tamoxifen [3].
Although tamoxifen is active in both pre- and postmenopausal patients, therapy with an aromatase inhibitor either as first-line or following treatment with tamoxifen has been demonstrated to be superior to tamoxifen alone in hormone receptor–positive postmenopausal women. In the ATAC (The Arimidex, Tamoxifen, Alone or in Combination) trial, postmenopausal patients were randomized to receive 5 years of either tamoxifen or anastrozole as adjuvant therapy. The anastrozole group had higher disease-free survival, time to recurrence and time to distant recurrence [4].In the Breast Intergroup (BIG) 1-98 trial, postmenopausal women were assigned to 4 different arms: 5 years of letrozole, 5 years of tamoxifen, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. The 2 groups assigned to receive letrozole initially were compared to the 2 groups assigned to receive tamoxifen initially. Compared with tamoxifen, letrozole significantly decrease the risk of recurrence [5].The MA-17 trial demonstrated a disease-free survival advantage with 5 years of letrozole compared with placebo in women who had been treated with tamoxifen for 5 years [6]. Based on these data, current guidelines for adjuvant endocrine therapy for postmenopausal women recommend an aromatase inhibitor for 5 years as primary therapy or after 2 to 3 years of tamoxifen [7].
Results from studies with extended endocrine therapy, either 10 years of tamoxifen or 5 years of aromatase inhibitor after up to 5 years of tamoxifen, provide rationale to study the effect of therapy with aromatase inhibitor beyond 5 years. The current study by Goss et al (the MA 17.R trial) addresses the relevant question of whether extended adjuvant therapy with an aromatase inhibitor in post-menopausal women beyond 5 years provides additional benefit. The design of this study has several strengths including being randomized, phase 3, placebo-controlled and double-blind. Another strength was the large number of patients enrolled. The choice of disease-free survival as the primary endpoint is in accordance with the natural course of ER-positive breast cancer, which has a prolonged rate of recurrence. The study results showed that patients who received 10 years of letrozole had a 34% lower risk of recurrence, with an absolute improvement of 4% in disease-free survival. However, no overall survival benefit was demonstrated at a median follow-up of 6.3 years. This might be a result of the fact that the highest proportional benefit was reduction in incidence of contralateral breast cancer. It is also possible that an overall survival benefit would be observed with a longer follow-up.
As highlighted by the authors, the benefit of extended adjuvant therapy is higher in the first years. Given that the majority of patients enrolled in this study had received prior tamoxifen, it is possible that patients who receive only an aromatase inhibitor for 5 years without prior tamoxifen would benefit even more from extended aromatase inhibitor therapy. On the other hand, the 1.1% numerical advantage observed in reducing distant recurrence is quite modest, with the majority of the disease-free survival advantage seen with extended aromatase inhibition being due to a reduction in local recurrence and contralateral new concerns.
The quality of life assessment enhanced this trial, since adherence to adjuvant endocrine therapy remains a challenge. It should be noted, however, that patients willing to participate in a trial of extended therapy are likely to be those who have tolerated therapy reasonably well. The increase in body pain and differences in the role-emotional subscale in the letrozole reflect side effects of aromatase inhibitors that are seen in clinical practice. The higher rates of new-onset osteoporosis and bone fractures underscore the need to balance potential benefits and risks with extended aromatase inhibitor therapy.
Results from other trials evaluating extended adjuvant therapy will be helpful. The NSABP B-42 study randomized ER-positive postmenopausal patients to receive 5 years of letrozole or placebo after completing 5 years of hormonal therapy with an aromatase inhibitor for 5 years or ≤ 3 years of tamoxifen followed by an aromatase inhibitor. This study has completed enrollment and should provide additional insight regarding duration of therapy with aromatase inhibitors.
Applications for Clinical Practice
These trial results showed a benefit with extended aromatase inhibitor therapy; however, the magnitude of benefit was relatively small, particularly with respect to impacting distant recurrence risk. Given that extended therapy has potential side effects, it is appropriate to have a detailed discussion with patients regarding potential benefits and risks. A reasonable clinical strategy is to discuss extended therapy with patients who have a higher chance of relapse and those who are motivated to continue therapy to reduce new breast cancer events.
—Leticia Varella, MD, and Halle Moore, MD,
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–717.
2. Davies C, Pan H, Godwin J, at al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805–16.
3. Gray RG, Rea D, Handley K, et al. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 2013;31(suppl;abstr 5).
4. Cuzick J, Sestak I, Baum M, et al; ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010;11:113541.
5. Breast International Group (BIG) 1-98 Collaborative Group, Thürlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747–57.
6. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–802.
7. Burstein HJ, Prestrud AA, Seidenfeld J, et al; American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010;28:3784–96.
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–717.
2. Davies C, Pan H, Godwin J, at al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805–16.
3. Gray RG, Rea D, Handley K, et al. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 2013;31(suppl;abstr 5).
4. Cuzick J, Sestak I, Baum M, et al; ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010;11:113541.
5. Breast International Group (BIG) 1-98 Collaborative Group, Thürlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747–57.
6. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–802.
7. Burstein HJ, Prestrud AA, Seidenfeld J, et al; American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010;28:3784–96.