Long-Term Results with Everolimus in Advanced Hormone Receptor Positive Breast Cancer in a Multicenter National Real-World Observational Study

Abstract

Everolimus is the first oral targeted therapy widely used in advanced HR + / HER2− breast cancer. We sought to evaluate the impact of everolimus-based therapy on overall survival in the ESME-MBC database, a national metastatic breast cancer cohort that collects retrospective data using clinical trial-like methodology including quality assessments. We compared 1693 patients having received everolimus to 5928 patients not exposed to everolimus in the same period. Overall survival was evaluated according to treatment line, and a propensity score with the inverse probability of treatment weighting method was built to adjust for differences between groups. Crude and landmark overall survival analyses were all compatible with a benefit from everolimus-based therapy. Adjusted hazard ratios for overall survival were 0.34 (95% CI: 0.16–0.72, p = 0.0054), 0.34 (95% CI: 0.22–0.52, p < 0.0001), and 0.23 (95% CI: 0.14–0.36, p < 0.0001) for patients treated with everolimus in line 1, 2, and 3 and beyond, respectively. No clinically relevant benefit on progression-free survival was observed. Causes for everolimus discontinuation were progressive disease (56.2%), adverse events (27.7%), and other miscellaneous reasons. Despite the limitations inherent to such retrospective studies, these results suggest that adding everolimus-based therapy to the therapeutic sequences in patients with advanced HR+/HER2− breast cancer may favorably affect overall survival.

The prognosis of patients treated with everolimus for advanced ER‐positive, HER2‐negative breast cancer is driven by molecular features

“…In the present report, we propose a translational analysis of our previously reported cohort which demonstrated efficacy of everolimus including in heavily pre-treated patients, in line with the more recent ESME report [3,5]. We comprehensively evaluated the longterm prognostic value of the activation of the PIK3CA/ AKT/mTOR pathway in primary and metastatic samples of a subset of our series.…”

“…Advanced luminal breast cancer remains a noncurable disease despite recent clinically meaningful improvements with the introduction of CDK4/6 inhibitors in the therapeutic armamentarium [ 6 ]. Before the CDK4/6 inhibitor era, everolimus combined with alternative endocrine therapies had proven efficacy in the BOLERO‐2 pivotal trial [ 1 ], as well as in large multicenter real‐world studies [ 5 , 9 ]. Even if its use has been hampered by several nonhematological but clinically limiting adverse events leading to the development of alternative dosing schedules [ 10 ], everolimus is one of the recommended therapeutic options in patients developing resistance to endocrine therapy combined with CDK4/6 inhibitors ( https://www.esmo.org/living-guidelines/esmo-metastatic-breast-cancer-living-guideline and Reference [ 11 ]).…”

“…Several studies have repeatedly confirmed the efficacy of everolimus in the real‐world setting, including in very advanced disease [ 3 , 4 ]. Recently, the French epidemiological study and medico‐economic (ESME) program, a nation‐wide real‐world study of patients with advanced breast cancer, suggested that adding everolimus to the treatments sequences had a favorable impact on survival [ 5 ]. However, the use of everolimus in the daily practice has been limited by cumbersome adverse events, such as mucositis, weight loss, or hyperglycemia [ 1 , 3 ].…”

Molecular mechanisms and therapeutic applications of huaier in breast cancer treatment

“…Clinical studies have confirmed that pyrotinib-targeted therapy for breast cancer combined with Huaier granules significantly improves immune function and reduces the expression level of drugresistant genes, improving patient quality of life (Zhao and Yao, 2020). Everolimus, the first oral targeted therapy drug available for advanced HR+/HER2-breast cancer is everolimus, is an inhibitor of the target of rapamycin (mTOR) protein (Ma et al, 2023), and current clinical trials have demonstrated its efficacy in breast cancer-based endocrine therapy (François-Martin et al, 2023). Another commonly used agent is alpelisib, a specific PI3K inhibitor (Bello Roufai et al, 2023;Cerma et al, 2023).…”

High EIF4EBP1 expression reflects mTOR pathway activity and cancer cell proliferation and is a biomarker for poor breast cancer prognosis

“…Specific to breast cancer treatment resistance, PI3K pathway hyperactivation, typically via activating mutations in PI3KCA, the gene encoding the p1110 alpha subunit, will promote escape from hormone dependence in estrogen receptor (ER) positive breast cancer [10] and trastuzumab resistance in human epidermal growth factor (HER2) positive breast cancer [11], regardless of tumor stage [12,13]. As such, the mTOR inhibitor everolimus was the first oral targeted therapy widely used in advanced hormone positive breast cancer [14,15], and is additionally known to extend progression-free survival in patients with trastuzumab-resistant HER2-postive advanced breast cancer [16].…”