Impact of Premenopausal Status at Breast Cancer Diagnosis
Impact of Premenopausal Status at Breast Cancer Diagnosis
Background: MA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen.
Patients and methods: Exploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and quality of life (QOL) in MA17 were performed based on menopausal status at breast cancer diagnosis.
Results: At diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13–0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51–0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03–0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22–0.94; P = 0.03).
Conclusions: Extended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen.
Ovarian function suppression, tamoxifen, and aromatase inhibitors (AI) antagonize estrogen in hormone-dependent breast cancer. Adjuvant therapy for women postmenopausal at diagnosis with ER+ tumors includes 5 years of tamoxifen or AI, or tamoxifen for 2–3 years followed by 2–3 years of AI, or 5 years of tamoxifen followed by 5 years of AI. In women premenopausal at diagnosis, standard adjuvant therapy is 5 years of tamoxifen which decreases the risk of recurrence and improves survival. Longer durations afford no additional benefit.
MA17 is one of few adjuvant AI trials that included women who were premenopausal at initial diagnosis. The NCIC Clinical Trials Group (NCIC CTG) MA17 trial randomized 5187 women who were within 3 months of completing 4.5–6 years of tamoxifen and postmenopausal after tamoxifen, to receive letrozole (LET) or placebo (PLAC). At median follow-up of 2.5 years on extended LET, disease-free survival (DFS) was improved [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.45–0.76); P < 0.001] as was survival in node-positive patients (N = 2594) in the initial analysis (HR 0.61, 95% CI 0.38–0.98; P = 0.04), and a more recent analysis showed OS advantage in the overall study population. Analysis after unblinding and allowing late cross-over from PLAC to LET improved DFS (adjusted HR 0.37; 95% CI 0.23–0.61; P < 0.0001) and distant DFS (DDFS; HR 0.39; 95% CI 0.20–0.74; P = 0.004) at median follow-up of 5.3 years from randomization on MA17. Despite 66% cross-over to LET after unblinding, an intent-to-treat analysis of women originally assigned to LET in MA17 showed improvement in DFS (HR 0.68, 95% CI 0.55–0.83, P = 0.0001) in both node-positive and -negative patients, as well in the risk of contralateral breast cancer (CLBC; HR 0.61, 95% CI 0.39–0.97, P = 0.033).
All women on MA17 were postmenopausal at randomization after completing tamoxifen, and although the majority had also been postmenopausal at the time of primary diagnosis, a minority had been premenopausal. In light of known benefit of adjuvant ovarian function suppression in premenopausal endocrine receptor-positive disease, we hypothesized differences in outcomes between women on MA17 who were premenopausal at original diagnosis and became postmenopausal by the time they completed 5 years of tamoxifen, versus those who had been postmenopausal from the beginning. Here, we report analyses from the MA17 trial based on menopausal status at the time of first diagnosis. In addition to our primary analysis, we report outcomes among women who at unblinding (at times 2–7 years after tamoxifen) were found to be on placebo and were offered the choice of taking letrozole or remaining on observation.
Abstract and Introduction
Abstract
Background: MA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen.
Patients and methods: Exploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and quality of life (QOL) in MA17 were performed based on menopausal status at breast cancer diagnosis.
Results: At diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13–0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51–0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03–0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22–0.94; P = 0.03).
Conclusions: Extended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen.
Introduction
Ovarian function suppression, tamoxifen, and aromatase inhibitors (AI) antagonize estrogen in hormone-dependent breast cancer. Adjuvant therapy for women postmenopausal at diagnosis with ER+ tumors includes 5 years of tamoxifen or AI, or tamoxifen for 2–3 years followed by 2–3 years of AI, or 5 years of tamoxifen followed by 5 years of AI. In women premenopausal at diagnosis, standard adjuvant therapy is 5 years of tamoxifen which decreases the risk of recurrence and improves survival. Longer durations afford no additional benefit.
MA17 is one of few adjuvant AI trials that included women who were premenopausal at initial diagnosis. The NCIC Clinical Trials Group (NCIC CTG) MA17 trial randomized 5187 women who were within 3 months of completing 4.5–6 years of tamoxifen and postmenopausal after tamoxifen, to receive letrozole (LET) or placebo (PLAC). At median follow-up of 2.5 years on extended LET, disease-free survival (DFS) was improved [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.45–0.76); P < 0.001] as was survival in node-positive patients (N = 2594) in the initial analysis (HR 0.61, 95% CI 0.38–0.98; P = 0.04), and a more recent analysis showed OS advantage in the overall study population. Analysis after unblinding and allowing late cross-over from PLAC to LET improved DFS (adjusted HR 0.37; 95% CI 0.23–0.61; P < 0.0001) and distant DFS (DDFS; HR 0.39; 95% CI 0.20–0.74; P = 0.004) at median follow-up of 5.3 years from randomization on MA17. Despite 66% cross-over to LET after unblinding, an intent-to-treat analysis of women originally assigned to LET in MA17 showed improvement in DFS (HR 0.68, 95% CI 0.55–0.83, P = 0.0001) in both node-positive and -negative patients, as well in the risk of contralateral breast cancer (CLBC; HR 0.61, 95% CI 0.39–0.97, P = 0.033).
All women on MA17 were postmenopausal at randomization after completing tamoxifen, and although the majority had also been postmenopausal at the time of primary diagnosis, a minority had been premenopausal. In light of known benefit of adjuvant ovarian function suppression in premenopausal endocrine receptor-positive disease, we hypothesized differences in outcomes between women on MA17 who were premenopausal at original diagnosis and became postmenopausal by the time they completed 5 years of tamoxifen, versus those who had been postmenopausal from the beginning. Here, we report analyses from the MA17 trial based on menopausal status at the time of first diagnosis. In addition to our primary analysis, we report outcomes among women who at unblinding (at times 2–7 years after tamoxifen) were found to be on placebo and were offered the choice of taking letrozole or remaining on observation.
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