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Journal of Clinical Oncology : Official... Mar 2023JCO The combined analysis of SOFT-TEXT compared outcomes in 4,690 premenopausal women with estrogen/progesterone receptor-positive (ER/PgR+) early breast cancer... (Randomized Controlled Trial)
Randomized Controlled Trial
JCO The combined analysis of SOFT-TEXT compared outcomes in 4,690 premenopausal women with estrogen/progesterone receptor-positive (ER/PgR+) early breast cancer randomly assigned to 5 years of exemestane + ovarian function suppression (OFS) versus tamoxifen + OFS. After a median follow-up of 9 years, exemestane + OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI), but not overall survival, compared with tamoxifen + OFS. We now report DFS, DRFI, and overall survival after a median follow-up of 13 years. In the intention-to-treat (ITT) population, the 12-year DFS (4.6% absolute improvement, hazard ratio [HR], 0.79; 95% CI, 0.70 to 0.90; < .001) and DRFI (1.8% absolute improvement, HR, 0.83; 95% CI, 0.70 to 0.98; = .03), but not overall survival (90.1% 89.1%, HR, 0.93; 95% CI, 0.78 to 1.11), continued to be significantly improved for patients assigned exemestane + OFS over tamoxifen + OFS. Among patients with human epidermal growth factor receptor 2-negative tumors (86.0% of the ITT population), the absolute improvement in 12-year overall survival with exemestane + OFS was 2.0% (HR, 0.85; 95% CI, 0.70 to 1.04) and 3.3% in those who received chemotherapy (45.9% of the ITT population). Overall survival benefit was clinically significant in high-risk patients, eg, women age < 35 years (4.0%) and those with > 2 cm (4.5%) or grade 3 tumors (5.5%). These sustained reductions of the risk of recurrence with adjuvant exemestane + OFS, compared with tamoxifen + OFS, provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of OFS.[Media: see text].
Topics: Adult; Female; Humans; Adjuvants, Immunologic; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Follow-Up Studies; Premenopause; Tamoxifen
PubMed: 36521078
DOI: 10.1200/JCO.22.01064 -
Chirurgia (Bucharest, Romania : 1990) 2017Hormonal therapy is mandatory for all patients with hormonereceptor- positive breast neoplasms. It is active both in adjuvant and metastatic disease. The only active... (Review)
Review
Hormonal therapy is mandatory for all patients with hormonereceptor- positive breast neoplasms. It is active both in adjuvant and metastatic disease. The only active adjuvant hormonal therapy in pre- and postmenopause is Tamoxifen. The adjuvant treatment duration influences disease-free survival, the risk of a contralateral breast cancer apparition and overall survival. The aromatase inhibitors: Anastrozol, Letrozol, Exemestan are only used in postmenopause. Fulvestrant is used in recurrent disease after or during treatment with Tamoxifen. LHRH analogues are used in premenopausal patients in adjuvantcy and sometimes in case of recurrences. Around 50% of hormonereceptor- positive breast neoplasms are or become resistant to hormone therapy. Some molecules involved in some tumour cellular growth pathways reverse the resistance to hormone therapy (Palbociclib, Everolimus).
Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Estradiol; Female; Fulvestrant; Gonadotropin-Releasing Hormone; Humans; Postmenopause; Premenopause; Quality of Life; Tamoxifen; Treatment Outcome
PubMed: 28862117
DOI: 10.21614/chirurgia.112.4.413 -
The New England Journal of Medicine Jul 2018In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials.
METHODS
Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy.
RESULTS
In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group.
CONCLUSIONS
Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703 , respectively.).
Topics: Adult; Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Recurrence, Local; Premenopause; Receptor, ErbB-2; Tamoxifen; Young Adult
PubMed: 29863451
DOI: 10.1056/NEJMoa1803164 -
The New England Journal of Medicine Feb 2012Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity.
METHODS
In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed.
RESULTS
Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001).
CONCLUSIONS
Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).
Topics: Adult; Aged; Aged, 80 and over; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Bone Neoplasms; Breast Neoplasms; Disease-Free Survival; ErbB Receptors; Everolimus; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Postmenopause; Recurrence; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases
PubMed: 22149876
DOI: 10.1056/NEJMoa1109653 -
The New England Journal of Medicine Jul 2014Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer.
METHODS
In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials.
RESULTS
After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women.
CONCLUSIONS
In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).
Topics: Adult; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Estradiol; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Mastectomy; Middle Aged; Osteoporosis; Premenopause; Quality of Life; Tamoxifen; Triptorelin Pamoate
PubMed: 24881463
DOI: 10.1056/NEJMoa1404037 -
The New England Journal of Medicine Jan 2015Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain.
METHODS
We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal.
RESULTS
After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87).
CONCLUSIONS
Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression. (Funded by Pfizer and others; SOFT ClinicalTrials.gov number, NCT00066690.).
Topics: Adult; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Mastectomy; Middle Aged; Premenopause; Tamoxifen
PubMed: 25495490
DOI: 10.1056/NEJMoa1412379 -
Clinical Cancer Research : An Official... Aug 2021Standard-of-care treatment for metastatic hormone receptor-positive (HR), HER2-negative (HER2) breast cancer includes endocrine therapy (ET) combined with a...
PURPOSE
Standard-of-care treatment for metastatic hormone receptor-positive (HR), HER2-negative (HER2) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR, HER2 advanced breast cancer (ABC) after progression on a CDK4/6i.
PATIENTS AND METHODS
This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR/HER2 breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis.
RESULTS
Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1-28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1-51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported.
CONCLUSIONS
Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR/HER2 ABC after progression on a CDK4/6i.
Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Disease Progression; Everolimus; Female; Humans; Middle Aged; Purines; Receptor, ErbB-2
PubMed: 33722897
DOI: 10.1158/1078-0432.CCR-20-2114 -
Journal of Clinical Oncology : Official... Apr 2020The Tamoxifen and Exemestane Trial (TEXT)/Suppression of Ovarian Function Trial (SOFT) showed superior outcomes for premenopausal women with hormone receptor...
PURPOSE
The Tamoxifen and Exemestane Trial (TEXT)/Suppression of Ovarian Function Trial (SOFT) showed superior outcomes for premenopausal women with hormone receptor (HR)-positive breast cancer treated with adjuvant exemestane plus ovarian function suppression (OFS) or tamoxifen plus OFS versus tamoxifen alone. We previously reported the magnitude of absolute improvements in freedom from any recurrence across a continuous, composite measure of recurrence risk to tailor decision making. With longer follow-up, we now focus on distant recurrence.
METHODS
The TEXT/SOFT HR-positive/human epidermal growth factor receptor 2 (HER2)-negative analysis population included 4,891 women stratified by predetermined chemotherapy use. Kaplan-Meier estimates of 8-year freedom from distant recurrence were analyzed using subpopulation treatment effect pattern plot (STEPP) methodology across subpopulations defined by the continuous composite measure of recurrence risk. For each patient, the composite risk value was obtained from a Cox model that incorporated age; nodal status; tumor size; grade; and estrogen receptor, progesterone receptor, and Ki-67 labeling index expression levels.
RESULTS
The overall rate of 8-year freedom from distant recurrence was 91.1% and ranged from approximately 100% to 63% across lowest to highest composite risks. TEXT patients who received chemotherapy had an average absolute improvement with exemestane plus OFS versus tamoxifen plus OFS of 5.1%, and STEPP analysis showed improvements from less than 1% to more than 15% from lowest to highest composite risks. SOFT patients who remained premenopausal after chemotherapy had an average 5.2% absolute improvement with exemestane plus OFS versus tamoxifen and reached 10% across composite risks; for tamoxifen plus OFS versus tamoxifen, the maximum improvement was approximately 3.5%. Women who did not receive chemotherapy had a more than 97% rate of 8-year freedom from distant recurrence, and improvements with exemestane plus OFS ranged from 1% to 4%.
CONCLUSION
Premenopausal women with HR-positive/HER2-negative breast cancer and high recurrence risk, as defined by clinicopathologic characteristics, may experience a 10% to 15% absolute improvement in 8-year freedom from distant recurrence with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone. The potential benefit of escalating endocrine therapy versus tamoxifen alone is minimal for those at low recurrence risk.
Topics: Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Female; Humans; Neoplasm Recurrence, Local; Ovariectomy; Ovary; Premenopause; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Triptorelin Pamoate
PubMed: 31618131
DOI: 10.1200/JCO.18.01967