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BACKGROUND: Abnormalities of the PI3kinase/AKT/mTOR signaling network are common in breast cancer (BC) and are associated with endocrine resistance. Everolimus, an mTOR-inhibitor increased PFS when combined with endocrine therapy (ET) in the metastatic setting and is thought to revert endocrine resistance. S1207 is a phase III randomized, placebo-controlled trial evaluating the role of everolimus in combination with ET in the adjuvant setting among patients with high-risk hormone receptor-positive, HER2-negative BC (NCT01674140). METHODS: Eligible patients were >18 years of age with histologically confirmed invasive hormone receptor-positive and HER2-negative high-risk BC. Four risk groups were defined as: 1) > 2cm node-negative disease (or pN1mi), and either an Oncotype DX® Recurrence Score (RS) > 25 or MammaPrint® high-risk category (MP high); 2) 1-3 positive nodes and either RS >25, MP high or a pathological grade 3 tumor; 3) >4 positive lymph nodes. Patients treated with neoadjuvant chemotherapy were eligible if: 4) after surgery had >1 lymph node involvement. Patients were randomized 1:1 to physician’s choice adjuvant ET in combination with one year of everolimus (10 mg PO daily) or ET plus placebo stratified by risk group. The primary endpoint was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test. Secondary endpoints included overall survival (OS) and safety. The hazard ratio (HR) for treatment efficacy was estimated using Cox regression with stratification by risk groups. Subset analyses included preplanned evaluation within risk group and exploratory analyses of menopausal status and age. RESULTS: 1,939 patients were randomized between September 2013 and May 2019, of them 1,792 were eligible and included in the analysis (896 per arm). Primary reason for ineligibility was timing after chemotherapy/radiation or not high risk. Median age was 54 years (22-85) and 32% were premenopausal. With a median follow-up of 50.5 months, there were 389 IDFS events as of May 2022 (data cutoff). 5-year IDFS was 74.8% among patients treated with everolimus and 73.9% among patients treated with placebo, HR=0.93 (95% CI 0.76-1.14). However, the proportional hazards assumption was violated (p=0.02) suggesting differential treatment effect over time. The HR during the one year of treatment was 0.72 (95% CI 0.47-1.10) while after one year it was 1.00 (95% CI 0.80-1.26). The 5-year OS was 87.6% in the everolimus arm and 85.5% in the placebo arm, HR=0.98 (95% CI 0.75-1.28). Analysis by risk group did not show higher everolimus benefit as risk increased. No difference in IDFS or OS was seen among postmenopausal patients (IDFS HR=1.08 [95% CI 0.85-1.36], OS HR=1.19 [95% CI 0.87-1.61]). Among premenopausal patients, everolimus was associated with improved IDFS (HR=0.63 [95% CI 0.43-0.93]) and OS (HR=0.48 [95% CI 0.26-0.88]). Treatment completion of randomized therapy was lower in the everolimus arm compared to placebo (47.9% v 72.7%). Grade 3 and 4 toxicities were noted in 6.5% and 0.5% of patients in the placebo arm and in 31.2% and 3.7% in the everolimus arm respectively. CONCLUSIONS: Addition of one year of adjuvant everolimus to standard adjuvant ET did not improve IDFS or OS and was associated with low completion rate and increased AEs. Among premenopausal patients there was a benefit in IDFS and OS that is hypothesis generating. Future translational studies will evaluate potential predictors of everolimus benefit and drug toxicity. Citation Format: Marianna Chavez, Jieling Miao, Lajos Pusztai, Matthew P. Goetz, Priya Rastogi, Patricia A. Ganz, Eleftherios (Terry) Mamounas, Soonmyung Paik, Hanna Bandos, Wajeeha Razaq, Anne O’Dea, Virginia Kaklamani, Andrea L.M. Silber, Lisa E. Flaum, Eleni Andreopolu, Joseph Baar, Albert G. Wendt, Jennifer F. Carney, Priyanka Sharma, Julie R. Gralow, Danika L. Lew, William E. Barlow, Gabriel N. Hortobagyi. Results from a phase III randomized, placebo-controlled clinical trial evaluating adjuvant endocrine therapy +/- 1 year of everolimus in patients with high-risk hormone receptor-positive, HER2-negative breast cancer: SWOG S1207 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-07. |
