Efficacy and tolerance of everolimus in 123 consecutive advanced ER positive, HER2 negative breast cancer patients. A two center retrospective study

Chocteau-Bouju, Dorothée; Chakiba, Camille; Mignot, L.; Madranges, Nicolas; Pierga, Jean‐Yves; Beuzeboc, Philippe; Quénel-Tueux, Nathalie; Dièras, Véronique; Bonnefoi, Hervé; Debled, Marc; Cottu, Paul

doi:10.1016/j.breast.2015.09.002

Cited by 9 publications

(13 citation statements)

References 14 publications

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“…The mTOR inhibitor everolimus has been recently approved for the treatment of advanced ER+ breast cancer in a context of endocrine resistance [ 6 ]. Although everolimus combined with an aromatase inhibitor improved progression-free survival, not all patients respond to everolimus and even those who respond eventually develop resistance [ 10 ]. Patient stratification and predictive biomarker are still lacking [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mTOR downregulates expression of DNA repair proteins and is highly efficient against BRCA2-mutated breast cancer in combination to PARP inhibition

et al. 2018

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Breast cancer is a complex disease in which each patient could present several genetic alterations that are therapeutically relevant in cancers. Here we explored the therapeutic benefit of combining PARP and mTOR inhibitors in a context of DNA repair deficiency and PI3K pathway activation.The combination of everolimus and olaparib was tested in BRCA2-mutated patient-derived xenografts (PDX) carrying alterations in the PI3K/AKT/mTOR pathway. An RPPA analysis of different signalling pathways was performed in untreated and treated xenografts.Everolimus and olaparib showed marked anti-tumor activities in the monotherapy setting and high efficacy when given in combination with 100% of mice showing tumor regressions. The fraction of P-H2AX positive cells was increased in both monotherapy arms and strongly increased in the combination setting. Everolimus given as monotherapy resulted in downregulation of different proteins involved in DNA damage repair, including FANCD2, RAD50 and SUV39H1. In the combination setting, expression of these proteins was almost completely abolished, suggesting convergence of PARP and mTOR in downregulation of DNA damage repair components.In conclusion, our results suggest that combining mTOR and DNA repair inhibition could be a successful strategy to treat a subset of breast cancer with BRCA2 mutation and alterations in the PI3K/AKT/mTOR pathway.

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Section: Introductionmentioning

confidence: 99%

Inhibition of mTOR downregulates expression of DNA repair proteins and is highly efficient against BRCA2-mutated breast cancer in combination to PARP inhibition

et al. 2018

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“…In this study, the median TTF in unelected patients was 5.2 months, which is similar to that reported in previous real-world cohort studies (4.0-5.7 months). 13–15 The shorter treatment duration compared to that in the BOLERO-2 trial can be attributed to the high proportion of heavily treated patients in our study (ie, 14.2% of patients had PS 2 or 3 and 53.7% of patients had more than 4 previous treatments of EVE). The reason why EVE was administered to more than half of the patients with the later treatment line was that EVE was used immediately after being approved to the later line patients who had been waiting for this drug in this cohort.…”

Section: Discussionmentioning

confidence: 76%

Clinical Predictive Factors for the Efficacy of Everolimus in Patients With Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer: A Multicenter Retrospective Cohort Study in Japan

Kikawa

Kotake

Kajiwara

et al. 2019

Breast Cancer�(Auckl)

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Purpose:To investigate the clinical predictive factors for the efficacy of everolimus (EVE) for advanced/metastatic breast cancer (AMBC).Methods:Routine practice data of consecutive patients with AMBC who received EVE at 5 institutions in western Japan were retrospectively analyzed in this cohort study (study registration no.: UMIN 000032569). The correlation among time to treatment failure (TTF), overall survival (OS), and clinical background was investigated via univariate and multivariate analyses using Cox hazards model for the clinically important variables.Results:A total of 134 patients were included in the analysis. The median TTF and OS were 5.2 months (95% confidence interval [CI]: 4.1-6.4) and 27.3 months (95% CI: 23.7-30.9), respectively. Multivariate analysis showed that dose reduction of EVE from any initial dose was associated with a longer TTF (hazard ratio [HR]: 0.52; 95% CI: 0.32-0.84, P = .007). Meanwhile, very low hormone sensitivity (ie, relapse within the first 2 years during adjuvant endocrine therapy or progression within 3 months of endocrine therapy immediately before EVE) was associated with a shorter TTF (HR: 2.48; 95% CI: 1.49-4.10, P < .001). In the analysis of stratified treatment outcomes, TTF was longer in the group with <3 liver metastases and in groups other than the very low hormone sensitivity group, regardless of the treatment line of EVE.Conclusions:Low hormone sensitivity and ⩾3 liver metastases were important prognostic factors for the efficacy of EVE. EVE may be less effective in patients with AMBC with these factors, and as such, chemotherapy should be administered instead.

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“…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.…”

Section: Introductionmentioning

confidence: 75%

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

Salaün,

Djerroudi,

Haik

et al. 2024

The Journal of Pathology CR

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Everolimus is widely used in patients with advanced ER‐positive, HER2‐negative breast cancer. We looked at alterations in the PIK3CA/AKT/mTOR pathway in a multicenter cohort as potential biomarkers of efficacy. Patients with advanced ER‐positive, HER2‐negative breast cancer treated with everolimus and endocrine therapy between 2012 and 2014 in two cancer centers were included. Targeted sequencing examined mutations in PIK3CA, ESR1, and AKT1 genes. An immunochemical analysis was conducted to evaluate expression of PTEN, INPP4B, STK11, p4EBP1, and pS6. We analyzed 71 patients (44 primary tumors; 27 metastatic tissues). Median age was 63 years [58–69]. All patients had heavily pretreated advanced disease. A mutation in the PIK3CA pathway was observed in 32 samples (PIK3CA exons 10 and 21 and AKT1 exon 4 in 15.5%, 24.0%, and 5.6% of samples), and in ESR1 in 5 samples (7.0%), respectively. Most samples showed cytoplasmic expression of the PIK3CA pathway proteins. Progression‐free survival was longer in patients with a pS6 or p4EBP1 histoscore ≥ median value (6.6 versus 3.7 months, p = 0.037), and in patients with a PTEN histoscore ≤ median value (7.1 versus 5.3 months, p = 0.02). Overall survival was longer in patients with pS6 ≥ 3rd quartile (27.6 versus 19.3 months, p = 0.038) and in patients with any mutation in the PIK3CA/AKT/mTOR pathway (27.6 versus 19.3 months, p = 0.011). The prognosis of patients treated with everolimus for advanced ER‐positive, HER2‐negative breast cancer appears primarily driven by molecular features associated with the activation of the PIK3CA/AKT/mTOR pathway.

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Efficacy and tolerance of everolimus in 123 consecutive advanced ER positive, HER2 negative breast cancer patients. A two center retrospective study

Cited by 9 publications

References 14 publications

Inhibition of mTOR downregulates expression of DNA repair proteins and is highly efficient against BRCA2-mutated breast cancer in combination to PARP inhibition

Inhibition of mTOR downregulates expression of DNA repair proteins and is highly efficient against BRCA2-mutated breast cancer in combination to PARP inhibition

Clinical Predictive Factors for the Efficacy of Everolimus in Patients With Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer: A Multicenter Retrospective Cohort Study in Japan

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

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