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CHICAGO – Adjuvant exemestane is more effective at preventing recurrence than tamoxifen is when either is given with ovarian function suppression in premenopausal women with hormone-sensitive breast cancers, according to a joint analysis of the phase III TEXT and SOFT trials.
"Exemestane plus OFS [ovarian function suppression] significantly improves disease-free survival, breast cancer free–interval, and distant recurrence free–interval and is a new treatment option for premenopausal women with hormone receptor-positive early breast cancer," lead study author Dr. Olivia Pagani said during a plenary session at the annual meeting of the American Society of Clinical Oncology.
The results were consistent in TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial), and in women who did and did not receive chemotherapy, said Dr. Pagani, clinical director of the breast unit at the Oncology Institute of Southern Switzerland, Bellinzona.
Among the 43% of women who did not receive chemotherapy, 97.6% of these women in TEXT and 97.5% in SOFT who received the aromatase inhibitor exemestane (Aromasin) remained free from breast cancer at 5 years.
On average, these women had lower-risk features such as older age and smaller tumors, however, 21% of them in TEXT and 8% in SOFT had node-positive disease, she observed. After 5.7 years median follow-up, there were very few distant recurrences in this subgroup, only 1% in the exemestane group.
"These results suggest that some premenopausal women have an excellent prognosis with highly effective endocrine therapy without chemotherapy," Dr. Pagani said.
Invited discussant Dr. Nancy E. Davidson, director of the University of Pittsburgh Cancer Institute, said, "We should remember the power of endocrine therapy in properly selected patients of all ages. Not every premenopausal patient needs chemotherapy."
Dr. Davidson said the results show that the combination of ovarian suppression and an aromatase inhibitor (AI) is "an evidence-based approach and may provide support to use the combination in women who cannot take tamoxifen or perhaps in those at very high risk, especially if they don’t take chemotherapy."
She went on to say, however, that "For now, I’m waiting for the results of SOFT to finalize my approach."
Currently, the standard adjuvant endocrine therapy for premenopausal women is 5 years of tamoxifen, while aromatase inhibitors are primarily used in postmenopausal women, where they have been shown to improve outcomes over tamoxifen.
Physicians in some countries, typically outside the United States, however, recommend adding OFS to tamoxifen in high-risk younger women, but the benefit of this strategy is uncertain. SOFT included a third treatment arm of tamoxifen alone to address the role of OFS for women receiving tamoxifen, but those results are not expected until late 2014.
Study details
The joint analysis, simultaneously published online in the New England Journal of Medicine, included 4,690 premenopausal women with early hormone-sensitive breast cancer, who were randomly assigned to exemestane 25 mg daily or tamoxifen 20 mg daily for 5 years (2014 [doi:10.1056/NEJMoa1404037]).
Randomization occurred within 12 weeks of surgery for all women in TEXT and women in SOFT who did not receive chemotherapy. Women in SOFT who received prior (neo)adjuvant chemotherapy were randomized within 8 months of chemotherapy completion when premenopausal status was demonstrated.
OFS in both trials was achieved through monthly injections of the gonadotropin-releasing hormone agonist triptorelin pamoate (Trelstar Depot), bilateral oophorectomy, or ovarian radiation.
Routine use of bisphosphonates was not permitted, but adjuvant trastuzumab was allowed, if indicated.
Overall, 42% of women were lymph node–positive, 36% had tumors larger than 2 cm, and 12% had human epidermal growth factor receptor 2–positive breast cancer. Their median age was 43 years.
Outcomes
At 5 years, exemestane plus OFS significantly improved the primary endpoint of disease-free survival from 87.3% with tamoxifen plus OFS to 91.1% (hazard ratio, 0.72; P = .0002), Dr. Pagani said.
No striking heterogeneity of treatment effect was observed in prospectively planned subgroup analyses including the cohorts defined by trial, chemotherapy stratum, and node status.
"The relative and absolute differences at 5 years compare favorably with those reported in the practice-changing BIG 1-98 and ATAC [Arimidex, Tamoxifen, Alone or in Combination] trials of aromatase inhibitors vs. tamoxifen in postmenopausal women," she said.
At 5 years, 92.8% of women assigned to receive exemestane plus ovarian suppression were free from breast cancer vs. 88.8% of those given tamoxifen plus ovarian suppression (HR, 0.66; P less than .0001).
The rate of freedom from distant recurrence at 5 years was also superior in the exemestane group (93.8% vs. 92%; HR, 0.78; P = .02). In all, 60% of first events involved distant sites.
These benefits, however, have yet to translate into a significant overall survival benefit at 5 years for exemestane plus ovarian suppression, compared with tamoxifen plus ovarian suppression (95.9% vs. 96.9%; HR, 1.14; P = .37), said Dr. Pagani, who added that conclusions about long-term survival are premature at this early follow-up.
Where do we go from here?
ASCO immediate past-president Dr. Clifford Hudis said in a press briefing that the joint analysis provides long-awaited and actionable information on how best to treat premenopausal women with hormone-sensitive breast cancer who appear cured after surgery, but that data from the tamoxifen-alone arm in SOFT are needed to change practice for those unconvinced about the need for ovarian suppression.
Dr. Davidson said she’s left pondering how the results will be integrated into practice. Will clinicians use 10 years of tamoxifen, as supported by the ATLAS and aTTOM trials, or will they use an extended adjuvant approach of 5 years of tamoxifen followed by a switch to 5 years of AI for women who become postmenopausal during their tamoxifen, as supported by the MA 17 trial? It’s also possible some will follow the lead set by TEXT/SOFT and use 5 years of ovarian suppression and AI.
"If the benefits of OFS with AI hold up, we may want to revisit the role of oophorectomy in selected patients, who want to avoid injections and have a permanent menopause," she added. "We will need to make sure we maximize bisphosphonates for bone health, but I’m not prepared to use bisphosphonates as a routine form of adjuvant therapy in these women just yet."
Finally, Dr. Davidson said long-term follow-up of TEXT/SOFT is vital for both benefit and toxicity. Though overall compliance was good, she noted earlier in her talk that 16% of women on exemestane plus OFS prematurely stopped therapy vs. 11% on tamoxifen plus OFS. "Financial toxicity" is also an issue, with the wholesale acquisition cost at her institution for 1 year of exemestane 25 mg daily at $7,344 vs. $1,369 for tamoxifen, she said.
Dr. Pagani stressed during the press briefing that the results do not mean all premenopausal women should be given an AI plus ovarian suppression, but that the decision should be individualized with input from the physician and patient.
The research was supported in part by Pfizer, Ipsen, the International Breast Cancer Study Group, and the National Cancer Institute (NCI). Dr. Pagani reported research funding from Ipsen and Pfizer. Dr. Davidson reported research funding from the Breast Cancer Research Foundation and National Institutes of Health (NIH).
CHICAGO – Adjuvant exemestane is more effective at preventing recurrence than tamoxifen is when either is given with ovarian function suppression in premenopausal women with hormone-sensitive breast cancers, according to a joint analysis of the phase III TEXT and SOFT trials.
"Exemestane plus OFS [ovarian function suppression] significantly improves disease-free survival, breast cancer free–interval, and distant recurrence free–interval and is a new treatment option for premenopausal women with hormone receptor-positive early breast cancer," lead study author Dr. Olivia Pagani said during a plenary session at the annual meeting of the American Society of Clinical Oncology.
The results were consistent in TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial), and in women who did and did not receive chemotherapy, said Dr. Pagani, clinical director of the breast unit at the Oncology Institute of Southern Switzerland, Bellinzona.
Among the 43% of women who did not receive chemotherapy, 97.6% of these women in TEXT and 97.5% in SOFT who received the aromatase inhibitor exemestane (Aromasin) remained free from breast cancer at 5 years.
On average, these women had lower-risk features such as older age and smaller tumors, however, 21% of them in TEXT and 8% in SOFT had node-positive disease, she observed. After 5.7 years median follow-up, there were very few distant recurrences in this subgroup, only 1% in the exemestane group.
"These results suggest that some premenopausal women have an excellent prognosis with highly effective endocrine therapy without chemotherapy," Dr. Pagani said.
Invited discussant Dr. Nancy E. Davidson, director of the University of Pittsburgh Cancer Institute, said, "We should remember the power of endocrine therapy in properly selected patients of all ages. Not every premenopausal patient needs chemotherapy."
Dr. Davidson said the results show that the combination of ovarian suppression and an aromatase inhibitor (AI) is "an evidence-based approach and may provide support to use the combination in women who cannot take tamoxifen or perhaps in those at very high risk, especially if they don’t take chemotherapy."
She went on to say, however, that "For now, I’m waiting for the results of SOFT to finalize my approach."
Currently, the standard adjuvant endocrine therapy for premenopausal women is 5 years of tamoxifen, while aromatase inhibitors are primarily used in postmenopausal women, where they have been shown to improve outcomes over tamoxifen.
Physicians in some countries, typically outside the United States, however, recommend adding OFS to tamoxifen in high-risk younger women, but the benefit of this strategy is uncertain. SOFT included a third treatment arm of tamoxifen alone to address the role of OFS for women receiving tamoxifen, but those results are not expected until late 2014.
Study details
The joint analysis, simultaneously published online in the New England Journal of Medicine, included 4,690 premenopausal women with early hormone-sensitive breast cancer, who were randomly assigned to exemestane 25 mg daily or tamoxifen 20 mg daily for 5 years (2014 [doi:10.1056/NEJMoa1404037]).
Randomization occurred within 12 weeks of surgery for all women in TEXT and women in SOFT who did not receive chemotherapy. Women in SOFT who received prior (neo)adjuvant chemotherapy were randomized within 8 months of chemotherapy completion when premenopausal status was demonstrated.
OFS in both trials was achieved through monthly injections of the gonadotropin-releasing hormone agonist triptorelin pamoate (Trelstar Depot), bilateral oophorectomy, or ovarian radiation.
Routine use of bisphosphonates was not permitted, but adjuvant trastuzumab was allowed, if indicated.
Overall, 42% of women were lymph node–positive, 36% had tumors larger than 2 cm, and 12% had human epidermal growth factor receptor 2–positive breast cancer. Their median age was 43 years.
Outcomes
At 5 years, exemestane plus OFS significantly improved the primary endpoint of disease-free survival from 87.3% with tamoxifen plus OFS to 91.1% (hazard ratio, 0.72; P = .0002), Dr. Pagani said.
No striking heterogeneity of treatment effect was observed in prospectively planned subgroup analyses including the cohorts defined by trial, chemotherapy stratum, and node status.
"The relative and absolute differences at 5 years compare favorably with those reported in the practice-changing BIG 1-98 and ATAC [Arimidex, Tamoxifen, Alone or in Combination] trials of aromatase inhibitors vs. tamoxifen in postmenopausal women," she said.
At 5 years, 92.8% of women assigned to receive exemestane plus ovarian suppression were free from breast cancer vs. 88.8% of those given tamoxifen plus ovarian suppression (HR, 0.66; P less than .0001).
The rate of freedom from distant recurrence at 5 years was also superior in the exemestane group (93.8% vs. 92%; HR, 0.78; P = .02). In all, 60% of first events involved distant sites.
These benefits, however, have yet to translate into a significant overall survival benefit at 5 years for exemestane plus ovarian suppression, compared with tamoxifen plus ovarian suppression (95.9% vs. 96.9%; HR, 1.14; P = .37), said Dr. Pagani, who added that conclusions about long-term survival are premature at this early follow-up.
Where do we go from here?
ASCO immediate past-president Dr. Clifford Hudis said in a press briefing that the joint analysis provides long-awaited and actionable information on how best to treat premenopausal women with hormone-sensitive breast cancer who appear cured after surgery, but that data from the tamoxifen-alone arm in SOFT are needed to change practice for those unconvinced about the need for ovarian suppression.
Dr. Davidson said she’s left pondering how the results will be integrated into practice. Will clinicians use 10 years of tamoxifen, as supported by the ATLAS and aTTOM trials, or will they use an extended adjuvant approach of 5 years of tamoxifen followed by a switch to 5 years of AI for women who become postmenopausal during their tamoxifen, as supported by the MA 17 trial? It’s also possible some will follow the lead set by TEXT/SOFT and use 5 years of ovarian suppression and AI.
"If the benefits of OFS with AI hold up, we may want to revisit the role of oophorectomy in selected patients, who want to avoid injections and have a permanent menopause," she added. "We will need to make sure we maximize bisphosphonates for bone health, but I’m not prepared to use bisphosphonates as a routine form of adjuvant therapy in these women just yet."
Finally, Dr. Davidson said long-term follow-up of TEXT/SOFT is vital for both benefit and toxicity. Though overall compliance was good, she noted earlier in her talk that 16% of women on exemestane plus OFS prematurely stopped therapy vs. 11% on tamoxifen plus OFS. "Financial toxicity" is also an issue, with the wholesale acquisition cost at her institution for 1 year of exemestane 25 mg daily at $7,344 vs. $1,369 for tamoxifen, she said.
Dr. Pagani stressed during the press briefing that the results do not mean all premenopausal women should be given an AI plus ovarian suppression, but that the decision should be individualized with input from the physician and patient.
The research was supported in part by Pfizer, Ipsen, the International Breast Cancer Study Group, and the National Cancer Institute (NCI). Dr. Pagani reported research funding from Ipsen and Pfizer. Dr. Davidson reported research funding from the Breast Cancer Research Foundation and National Institutes of Health (NIH).
CHICAGO – Adjuvant exemestane is more effective at preventing recurrence than tamoxifen is when either is given with ovarian function suppression in premenopausal women with hormone-sensitive breast cancers, according to a joint analysis of the phase III TEXT and SOFT trials.
"Exemestane plus OFS [ovarian function suppression] significantly improves disease-free survival, breast cancer free–interval, and distant recurrence free–interval and is a new treatment option for premenopausal women with hormone receptor-positive early breast cancer," lead study author Dr. Olivia Pagani said during a plenary session at the annual meeting of the American Society of Clinical Oncology.
The results were consistent in TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial), and in women who did and did not receive chemotherapy, said Dr. Pagani, clinical director of the breast unit at the Oncology Institute of Southern Switzerland, Bellinzona.
Among the 43% of women who did not receive chemotherapy, 97.6% of these women in TEXT and 97.5% in SOFT who received the aromatase inhibitor exemestane (Aromasin) remained free from breast cancer at 5 years.
On average, these women had lower-risk features such as older age and smaller tumors, however, 21% of them in TEXT and 8% in SOFT had node-positive disease, she observed. After 5.7 years median follow-up, there were very few distant recurrences in this subgroup, only 1% in the exemestane group.
"These results suggest that some premenopausal women have an excellent prognosis with highly effective endocrine therapy without chemotherapy," Dr. Pagani said.
Invited discussant Dr. Nancy E. Davidson, director of the University of Pittsburgh Cancer Institute, said, "We should remember the power of endocrine therapy in properly selected patients of all ages. Not every premenopausal patient needs chemotherapy."
Dr. Davidson said the results show that the combination of ovarian suppression and an aromatase inhibitor (AI) is "an evidence-based approach and may provide support to use the combination in women who cannot take tamoxifen or perhaps in those at very high risk, especially if they don’t take chemotherapy."
She went on to say, however, that "For now, I’m waiting for the results of SOFT to finalize my approach."
Currently, the standard adjuvant endocrine therapy for premenopausal women is 5 years of tamoxifen, while aromatase inhibitors are primarily used in postmenopausal women, where they have been shown to improve outcomes over tamoxifen.
Physicians in some countries, typically outside the United States, however, recommend adding OFS to tamoxifen in high-risk younger women, but the benefit of this strategy is uncertain. SOFT included a third treatment arm of tamoxifen alone to address the role of OFS for women receiving tamoxifen, but those results are not expected until late 2014.
Study details
The joint analysis, simultaneously published online in the New England Journal of Medicine, included 4,690 premenopausal women with early hormone-sensitive breast cancer, who were randomly assigned to exemestane 25 mg daily or tamoxifen 20 mg daily for 5 years (2014 [doi:10.1056/NEJMoa1404037]).
Randomization occurred within 12 weeks of surgery for all women in TEXT and women in SOFT who did not receive chemotherapy. Women in SOFT who received prior (neo)adjuvant chemotherapy were randomized within 8 months of chemotherapy completion when premenopausal status was demonstrated.
OFS in both trials was achieved through monthly injections of the gonadotropin-releasing hormone agonist triptorelin pamoate (Trelstar Depot), bilateral oophorectomy, or ovarian radiation.
Routine use of bisphosphonates was not permitted, but adjuvant trastuzumab was allowed, if indicated.
Overall, 42% of women were lymph node–positive, 36% had tumors larger than 2 cm, and 12% had human epidermal growth factor receptor 2–positive breast cancer. Their median age was 43 years.
Outcomes
At 5 years, exemestane plus OFS significantly improved the primary endpoint of disease-free survival from 87.3% with tamoxifen plus OFS to 91.1% (hazard ratio, 0.72; P = .0002), Dr. Pagani said.
No striking heterogeneity of treatment effect was observed in prospectively planned subgroup analyses including the cohorts defined by trial, chemotherapy stratum, and node status.
"The relative and absolute differences at 5 years compare favorably with those reported in the practice-changing BIG 1-98 and ATAC [Arimidex, Tamoxifen, Alone or in Combination] trials of aromatase inhibitors vs. tamoxifen in postmenopausal women," she said.
At 5 years, 92.8% of women assigned to receive exemestane plus ovarian suppression were free from breast cancer vs. 88.8% of those given tamoxifen plus ovarian suppression (HR, 0.66; P less than .0001).
The rate of freedom from distant recurrence at 5 years was also superior in the exemestane group (93.8% vs. 92%; HR, 0.78; P = .02). In all, 60% of first events involved distant sites.
These benefits, however, have yet to translate into a significant overall survival benefit at 5 years for exemestane plus ovarian suppression, compared with tamoxifen plus ovarian suppression (95.9% vs. 96.9%; HR, 1.14; P = .37), said Dr. Pagani, who added that conclusions about long-term survival are premature at this early follow-up.
Where do we go from here?
ASCO immediate past-president Dr. Clifford Hudis said in a press briefing that the joint analysis provides long-awaited and actionable information on how best to treat premenopausal women with hormone-sensitive breast cancer who appear cured after surgery, but that data from the tamoxifen-alone arm in SOFT are needed to change practice for those unconvinced about the need for ovarian suppression.
Dr. Davidson said she’s left pondering how the results will be integrated into practice. Will clinicians use 10 years of tamoxifen, as supported by the ATLAS and aTTOM trials, or will they use an extended adjuvant approach of 5 years of tamoxifen followed by a switch to 5 years of AI for women who become postmenopausal during their tamoxifen, as supported by the MA 17 trial? It’s also possible some will follow the lead set by TEXT/SOFT and use 5 years of ovarian suppression and AI.
"If the benefits of OFS with AI hold up, we may want to revisit the role of oophorectomy in selected patients, who want to avoid injections and have a permanent menopause," she added. "We will need to make sure we maximize bisphosphonates for bone health, but I’m not prepared to use bisphosphonates as a routine form of adjuvant therapy in these women just yet."
Finally, Dr. Davidson said long-term follow-up of TEXT/SOFT is vital for both benefit and toxicity. Though overall compliance was good, she noted earlier in her talk that 16% of women on exemestane plus OFS prematurely stopped therapy vs. 11% on tamoxifen plus OFS. "Financial toxicity" is also an issue, with the wholesale acquisition cost at her institution for 1 year of exemestane 25 mg daily at $7,344 vs. $1,369 for tamoxifen, she said.
Dr. Pagani stressed during the press briefing that the results do not mean all premenopausal women should be given an AI plus ovarian suppression, but that the decision should be individualized with input from the physician and patient.
The research was supported in part by Pfizer, Ipsen, the International Breast Cancer Study Group, and the National Cancer Institute (NCI). Dr. Pagani reported research funding from Ipsen and Pfizer. Dr. Davidson reported research funding from the Breast Cancer Research Foundation and National Institutes of Health (NIH).
AT THE ASCO ANNUAL MEETING 2014
Key clinical point: Exemestane plus OFS is a new treatment option in the setting of premenopausal hormone-sensitive early breast cancer.
Major finding: Exemestane plus OFS significantly improved disease-free survival from 87.3% with tamoxifen plus OFS to 91.1% (HR, 0.72; P = .0002).
Data source: Joint analysis of two phase III studies in 4,690 premenopausal women with hormone receptor-positive, early breast cancer.
Disclosures: The research was supported in part by Pfizer, Ipsen, the International Breast Cancer Study Group, and the NCI. Dr. Pagani reported research funding from Ipsen and Pfizer. Dr. Davidson reported research funding from the Breast Cancer Research Foundation and the NIH.
