Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

By J. Baselga, Mario Campone, M. Piccart, H. Burris, H. Rugo, T. Sahmoud, S. Noguchi, M. Gnant, K. Pritchard, F. Lebrun and 11 more. New England Journal of Medicine, 2011

2,734 citations recorded by the source corpus.

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.)

Subfields: Molecular Biology, Public Health, Environmental and Occupational Health, Pulmonary and Respiratory Medicine

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Citations in the corpus

A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). (2015, background): “54) NS No improvement 2 [99] by gest on M ay 0, 2015 http://annofordjournals.”
Clinical Translation of Nanomedicine (2015, neutral): “approved by the FDA (1996). A phase I study of ABCD in”
The PI3K pathway in human disease (2017, neutral): “The BOLERO-2 trial established the efﬁcacy of everolimus plus exemestane in ER + /HER2 – breast cancer (Baselga et al., 2012).”
Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor positive breast cancer (2014, methodology): “3%of the primary tumors from the BOLERO2 study, where patients with ERþ metastatic breast cancer that had progressed in the metastatic setting were randomized to exemestane the TORC1 inhibitor everolimus (32, 36).”
The PI3K/AKT Pathway as a Target for Cancer Treatment. (2016, neutral): “Treatment with the combination resulted in significantly higher PFS than was seen in the exemestane arm (64).”
ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. (2021, background): “34 In patients who relapsed on adjuvant AI therapy, or within 12 months of stopping adjuvant AI, a CDK4/6 inhibitor in combination with fulvestrant is advised [ESMO-MCBS v1.”
Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. (2017, neutral): “Consistent with emerging clinical data, the luminal subtype also showed dependence on components of the PIK3CA/mTOR andCDK4 pathways (Baselga et al., 2012; Hortobagyi et al., 2016).”