Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer

Prudence A Francis, Olivia Pagani, Gini F Fleming, Barbara A Walley, Marco Colleoni, István Láng, Henry L Gómez, Carlo Tondini, Eva Ciruelos, Harold J Burstein, Hervé R Bonnefoi, Meritxell Bellet, Silvana Martino, Charles E Geyer Jr, Matthew P Goetz, Vered Stearns, Graziella Pinotti, Fabio Puglisi, Simon Spazzapan, Miguel A Climent, Lorenzo Pavesi, Thomas Ruhstaller, Nancy E Davidson, Robert Coleman, Marc Debled, Stefan Buchholz, James N Ingle, Eric P Winer, Rudolf Maibach, Manuela Rabaglio-Poretti, Barbara Ruepp, Angelo Di Leo, Alan S Coates, Richard D Gelber, Aron Goldhirsch, Meredith M Regan, SOFT and TEXT Investigators and the International Breast Cancer Study Group

Abstract

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.).

Figures

Figure 1.. Randomization and Analyses in SOFT…
Figure 1.. Randomization and Analyses in SOFT and TEXT.
SOFT denotes Suppression of Ovarian Function Trial, and TEXT Tamoxifen and Exemestane Trial.
Figure 2 (facing page).. Kaplan–Meier Estimates of…
Figure 2 (facing page).. Kaplan–Meier Estimates of Disease-free Survival after a Median Follow-up of 8 Years in SOFT.
Shown are Kaplan–Meier estimates of the rates of disease-free survival in SOFT according to treatment assignment — tamoxifen alone (T), tamoxifen plus ovarian suppression (T–OS), or exemestane plus ovarian suppression (E–OS) — among all the patients in the trial (Panel A) and according to chemotherapy status (Panels B and C). In Panel A, tamoxifen plus ovarian suppression resulted in a 24% lower relative risk of recurrence, a second invasive cancer, or death than tamoxifen alone (P = 0.009). In each panel, the 8-year data are highlighted by a black vertical line. The hazard ratios are for disease recurrence, a second invasive cancer, or death.
Figure 3.. Disease-free Survival among All Patients…
Figure 3.. Disease-free Survival among All Patients and According to HER2 and Chemotherapy Status in SOFT.
Shown are hazard ratios and estimates of 8-year disease-free survival in SOFT comparing patients who received tamoxifen alone with those who received tamoxifen plus ovarian suppression (Panel A) and those who received exemestane plus ovarian suppression (Panel B), according to status with respect to HER2 (human epidermal growth factor receptor 2) and receipt of chemotherapy. The hazard ratios are for disease recurrence, a second invasive cancer, or death. In the comparison involving patients receiving tamoxifen plus ovarian suppression, there was significant interaction according to HER2 status (P = 0.04), but the interaction was not significant in the comparison involving those receiving exemestane plus ovarian suppression (P = 0.44). The 8-year values for disease-free survival are based on Kaplan–Meier estimates. The solid vertical lines at 0.76 in Panel A and at 0.65 in Panel B indicate the overall hazard-ratio estimates for the two comparisons. The comparisons for patients with HER2-positive disease are not presented according to receipt or nonreceipt of chemotherapy because the majority of these patients (86%) had received chemotherapy. Among the patients with HER2-negative disease, testing was not performed for interaction with chemotherapy status. Data are not shown for 95 patients with unknown HER2 status. The x axis is scaled according to the natural logarithm of the hazard ratio. The size of the squares is inversely proportional to the standard error of the hazard ratio.
Figure 4.. Kaplan–Meier Estimates of Freedom from…
Figure 4.. Kaplan–Meier Estimates of Freedom from Distant Recurrence and of Overall Survival in SOFT.
Shown are estimates of rates of freedom from distant recurrence and of overall survival after a median follow-up of 8 years in SOFT among all the patients in the trial (Panels A and B, respectively) and among those who had received chemotherapy before randomization (Panels C and D, respectively). The addition of ovarian suppression to tamoxifen did not result in a significantly lower rate of distant recurrence than that with tamoxifen alone (P = 0.28), but the rate of overall survival was significantly higher (P = 0.01). In Panels A and C, the hazard ratios are for recurrence of breast cancer at a distant site; the hazard ratios in Panels B and D are for death. The 8-year values are based on Kaplan–Meier estimates of the time to an event. The estimates for patients who did not receive chemotherapy are provided in Figure S3B in the Supplementary Appendix; the rates were more than 97% in each treatment group for both end points.
Figure 5.. Kaplan–Meier Estimates of Disease-free Survival,…
Figure 5.. Kaplan–Meier Estimates of Disease-free Survival, Freedom from Distant Recurrence, and Overall Survival in the Combined SOFT and TEXT Population.
Shown are estimates of disease-free survival (Panel A), freedom from distant recurrence (Panel B), and overall survival (Panel C) among patients who received tamoxifen plus ovarian suppression (T–OS) and those who received exemestane plus ovarian suppression (E–OS) after a median follow-up of 9 years in the combined population. In each panel, the 8-year data are highlighted by a black vertical line. The hazard ratio in Panel A is for disease recurrence, a second invasive cancer, or death. In Panels B and C, the hazard ratios are for distant recurrence of breast cancer and for death, respectively. The 8-year values are based on Kaplan–Meier estimates of the time to an event.
Figure 6.. Estimates of Disease-free Survival, Freedom…
Figure 6.. Estimates of Disease-free Survival, Freedom from Distant Recurrence, and Overall Survival among Patients with HER2-Negative Disease in the Combined SOFT and TEXT Population.
Shown are hazard ratios and estimates of disease-free survival, freedom from distant recurrence, and overall survival among patients with HER2-negative breast cancer who received tamoxifen plus ovarian suppression (OS) and those who received exemestane plus ovarian suppression in the combined SOFT and TEXT population, according to receipt or nonreceipt of chemotherapy. The solid vertical lines at 0.70, 0.69, and 0.86 indicate the overall hazard-ratio estimates for disease-free survival (hazard ratio for disease recurrence, a second invasive cancer, or death), freedom from distant recurrence (hazard ratio for recurrence), and overall survival (hazard ratio for death), respectively, as calculated by means of Cox proportional-hazards models. In the HER2-negative population, inference from the treatment comparisons should be viewed as preliminary, since no testing was performed for heterogeneity of the treatment effects across cohorts. The 8-year values are based on Kaplan–Meier estimates of the time to an event. The size of the squares is inversely proportional to the standard error of the hazard ratio. The median follow-up was 9 years in the combined SOFT and TEXT population. The r esults for patients with HER2-positive disease are provided in Figure S10 in the Supplementary Appendix.

References

    1. Early Breast Cancer Trialists’ Collaborative Group. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patientlevel meta-analysis of randomised trials. Lancet 2011; 378:7 71–84.
    1. Davies C, Pan H, Godwin J, et 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.
    1. LHRH-agonists in Early Breast Cancer Overview Goup. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 2007; 369: 1711–23.
    1. Aebi S, Gelber S, Castiglione-Gertsch M, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 2000; 355: 1869–74.
    1. Goldhirsch A, Gelber RD, Yothers G, et al. Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr 2001; 30:4 4–51.
    1. Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 2015;3 72: 436–46.
    1. Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014; 371: 107–18.
    1. Regan MM, Pagani O, Fleming GF, et al. Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: design of the TEXT and SOFT trials. Breast 2013; 22: 1094–100.
    1. Cancer Therapy Evaluation Program. Common terminology criteria for adverse events v.3.0. August 9, 2006. ().
    1. Early Breast Cancer Trialists’ Collaborative Group. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 2015;3 86: 1341–52.
    1. Sorensen SV, Goh JW, Pan F, et al. Incidence-based cost-of-illness model for metastatic breast cancer in the United States. Int J Technol Assess Health Care 2012; 28: 12–21.
    1. Bartlett JMS, Ahmed I, Regan MM,et al. HER2 status predicts for upfront AI benefit: a TRANS-AIOG meta-analysis of 12,129 patients from ATAC, BIG 1–98 and TEAM with centrally determined HER2. Eur J Cancer 2017; 79: 129–38.
    1. Gnant M, Mlineritsch B, Stoeger H,et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol 2015;2 6: 313–20.
    1. Colleoni M, Rotmensz N, Peruzzotti G, et al. Role of endocrine responsiveness and adjuvant therapy in very young women (below 35 years) with operable breast cancer and node negative disease. Ann Oncol 2006; 17: 1497–503.
    1. Saha P, Regan MM, Pagani O, et al. Treatment efficacy, adherence, and quality of life among women younger than 35 years in the International Breast Cancer Study Group TEXT and SOFT adjuvant endocrine therapy trials. J Clin Oncol 2017; 35:3113–22.
    1. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J Clin Oncol 2016; 34:1689–701.
    1. Coates AS, Winer EP, Goldhirsch A,et al. Tailoring therapies — improving the management of early breast cancer: St. Gallen international expert consensus on the primary therapy of early breast cancer 2015. Ann Oncol 2015; 26: 1533–46.
    1. Paluch-Shimon S, Pagani O, Partridge AH, et al. ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3). Breast 2017; 35:203–17.
    1. Ribi K, Luo W, Bernhard J, et al. Adjuvant tamoxifen plus ovarian function suppression versus tamoxifen alone in premenopausal women with early breast cancer: patient-reported outcomes in the Suppression of Ovarian Function Trial. J Clin Oncol 2016; 34: 1601–10.
    1. Bernhard J, Luo W, Ribi K, et al. Patientreported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol 2015; 16: 848–58.
    1. Rocca WA, Gazzuola-Rocca L, Smith CY, et al. Accelerated accumulation of multimorbidity after bilateral oophorectomy: a population based cohort study. Mayo Clin Proc 2016; 91: 1577–89.
    1. Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ III. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 2006; 7: 821–8.
    1. Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol 2013; 121:709–16.
    1. Regan MM, Francis PA, Pagani O, et al. Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: TEXT and SOFT trials. J Clin Oncol 2016; 34: 2221–31.
    1. International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13–93. J Clin Oncol 2006; 24: 1332–41.
    1. Pan H, Gray R, Braybrooke J, et al. 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med 2017; 377: 1836–46.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe