Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2−) advanced breast cancer patients: New insights beyond clinical trials. The EVA study

Cazzaniga, M.; Airoldi, Mario; Arcangeli, Valentina; Artale, Salvatore; Atzori, Francesco; Ballerio, A; Bianchi, Giulia; Blasi, Livio; Campidoglio, Serena; Ciccarese, Mariangela; Cursano, Maria Concetta; Piezzo, Michela; Fabi, Alessandra; Ferrari, Lucia; Ferzi, A.; Ficorella, Corrado; Frassoldati, Antonio; Fumagalli, Alberto; Garrone, Ornella; Gebbia, Vittorio; Generali, Daniele; Verde, Nicla La; Maur, M; Michelotti, Andrea; Moretti, G; Musolino, Antonino; Palumbo, R.; Pistelli, Mirco; Porpiglia, M; Sartori, Donata; Scavelli, Claudio; Schirone, Alessio; Turletti, Anna; Valerio, Maria Rosaria; Vici, Patrizia; Zambelli, Alberto; Clivio, Luca; Torri, Valter

doi:10.1016/j.breast.2017.06.043

Cited by 22 publications

(16 citation statements)

References 10 publications

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“…Altogether these data provide a unique opportunity to determine the efficacy and safety of EVE in combination with EXE in these underserved elderly subsets. In addition to these previous trials, the EVA study provides the same opportunity with data coming from the real-life evidence [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…On the contrary, proactive management of AE risk in the context of comorbidities common to the elderly population remains a key issue for patients’ selection, as well as a careful monitoring of AEs during treatment is strongly recommended, in order to facilitate early diagnosis and appropriate management [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…Physicians were asked to identify all consecutive patients who fitted the pre-specified criteria of the study and to collect patients’ data from the clinical records in an electronic case-report-form (CRF) dedicated to the study. As described in the main paper [ 9 ], the effective Dose-Intensity (DI) of EVE therapy per patient was calculated adding the number of days at 10 mg plus those at 5 mg plus the number of days without any dose (0 mg), the sum was then divided per the total administered dose for the effective number of treatment days, including the interruption periods. We subsequently identified three groups of patients according to the following DIs: A) ≤ 5mg/day; B) 5.1 – 7.5 mg/day and C) > 7.5 mg/day.…”

Section: Methodsmentioning

confidence: 99%

“…The EVA study is a multicentre, longitudinal, retrospective study which reported the outcome of ABC patients treated with the combination of EVE and Exemestane (EXE) in a real-life setting [ 9 ]. The improved safety and efficacy profile for EVE-EXE combination compared with EXE alone suggests that this strategy could be a valid option of treatment after a first-line therapy with Overall Response Rate (ORR)[ 4 ] [ 9 ], as well as in patients previously treated with high-dose(HD) Fulvestrant, as demonstrated by our previously reported results.…”

Section: Introductionmentioning

confidence: 99%

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Everolimus (EVE) and exemestane (EXE) in patients with advanced breast cancer aged ≥ 65 years: new lessons for clinical practice from the EVA study

et al. 2018

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BACKGROUNDThe present analysis focuses on real-world data of Everolimus-Exemestane in advanced HR+ve, HER2-ve elderly breast cancer patients (aged 65 years) included in the EVA study, with unique findings in those aged 70 years.METHODSData are collected from clinical records and analysed according to age cut-off (< 65 years; 65 - 69 years and {greater than or equal to} 70 years). Relationship of analyzed variables with response were tested by mean of a Mantel-Haenszel chi square test. Time to event analysis was described by Kaplan Meier approach and association with baseline characteristics was analysed by stratified log-rank test and proportional hazard model.RESULTSFrom July 2013 to December 2015, the EVA study enrolled overall 404 pts. 154 patients out of 404 (38,1%) were aged {greater than or equal to} 65 years, of whom 87 were {greater than or equal to} 70 years. Median duration of EVE treatment was 28.5 weeks (95% CI 19.0 - 33.8) in patients aged 65-69 years and 24,4 weeks (95% CI 19,2 - 33,2) in those aged {greater than or equal to} 70 years. Fewer patients aged 65 years received the highest EVE Dose-Intensity (>7.5 mg/day) in comparison to younger patients (49,6% vs. 66,8%). Grade 3–4 toxicities occurred to 55 patients (35,7%), mainly stomatitis (10,9%), rash (5,8%) and non-infectious pneumonitis (NIP) (3,6%). Some toxicities, such as weight loss and anaemia were peculiarly observed in patients aged {greater than or equal to} 70 years. Five treatment-related deaths were collected (3,2%).CONCLUSIONSEVE-EXE combination remains one of the potential treatments in HR+ patients also for elderly ones.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Everolimus (EVE) and exemestane (EXE) in patients with advanced breast cancer aged ≥ 65 years: new lessons for clinical practice from the EVA study

et al. 2018

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“…Finally, the effects of PI3K/mTOR or cSRC inhibition on the metastatic properties of the CMT‐U27 cell line were investigated in a zebrafish embryo xenograft model that was previously validated in our laboratory and used in this study because of the 3R principle (reduction, refinement and replacement) of animal use in biomedical research . Because the PI3K/mTOR inhibitor everolimus and the cSRC inhibitor dasatinib are used in clinical trials for humans with advanced breast cancer, they were used in this study.…”

Section: Resultsmentioning

confidence: 99%

Dasatinib inhibition of cSRC prevents the migration and metastasis of canine mammary cancer cells with enhanced Wnt and HER signalling

Timmermans-Sprang

Mestemaker

Steenlage

et al. 2019

Vet Comparative Oncology

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Human epidermal growth factor 2 (HER2) overexpression leads to aggressive mammary tumour growth. Although the prognosis of HER2+ tumours in humans is greatly improved using biologicals, therapy resistance, which may be caused by increased phosphatidyl‐3‐kinase (PI3K), rous sarcoma proto‐oncogene (cSRC) or wingless‐type MMTV integration site family (Wnt) activity, is a major concern. A recent analysis of 12 canine mammary cell lines showed an association between HER2/3 overexpression and phosphatase and tensin homologue (PTEN) deletion with elevated Wnt‐signalling. Wnt‐activity appeared to be insensitive to phosphatidyl‐3‐kinase (PI3K) inhibitors but sensitive to Src‐I1. We hypothesized that Wnt activation, was caused by HER2/3‐activated cSRC activation. The role of HER2/3 on Wnt signalling was investigated by silencing HER2/3 expression using specific small interfering RNA (siRNAs). Next, the effect of an epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor on Wnt activity and migration was investigated and compared to other tyrosine kinase inhibitors (TKIs) of related signalling pathways. Finally, two TKIs, a cSRC and a PI3K inhibitor, were investigated in a zebrafish xenograft model. Silencing of HER1‐3 did not inhibit the intrinsic high Wnt activity, whereas the HER kinase inhibitor afatinib showed enhanced Wnt activity. The strongest inhibition of Wnt activity and cell viability and migration was shown by cSRC inhibitors, which also showed strong inhibition of cell viability and metastasis in a zebrafish xenograft model. HER2/3 overexpression or HER2/3‐induced cSRC activation is not the cause of enhanced Wnt activity. However, inhibition of cSRC resulted in a strong inhibition of Wnt activity and cell migration and metastasis. Further studies are needed to unravel the mechanism of cSRC activation and cSRC inhibition to restore sensitivity to HER‐inhibitors in HER2/3‐positive breast cancer.

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Efficacy and safety of everolimus plus exemestane in patients with hormone receptor‐positive, HER‐2‐negative advanced breast cancer: Results from the open‐label, multicentre, non‐interventional BRAWO study

Lüftner,

Schuetz,

Schneeweiss

et al. 2024

Intl Journal of Cancer

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BRAWO, a real‐world study, assessed the efficacy, quality of life (QoL) and safety of EVE + EXE in postmenopausal women with HR+/HER2– advanced breast cancer (ABC) in routine clinical practice. Postmenopausal women with HR+/HER2‐ABC with recurrence or progression after a NSAI were included. Primary Observation parameters included the evaluation of the effectiveness of EVE + EXE. A multivariate‐analysis using Cox proportional hazard model was built to identify predictors of progression. Overall, 2100 patients were enrolled (August 2012–December 2017); 2074 were evaluable for efficacy and safety analyses. Majority of patients (60.6%) received EVE + EXE as first (28.7%) or second‐line (31.9%) therapy. Visceral metastases were present in 54.1% patients. Median progression‐free survival (mPFS) reported as 6.6 months (95%CI: 6.3–7.0). Multivariate‐analysis in a subset of patients (n = 1837) found higher body mass index (BMI) and non‐visceral metastases to be independent predictors of favorable PFS. Patients with a BMI of 20 to <25 had a mPFS of 6.0 (95%CI: 5.4–6.4) and those with a BMI ≥30 had mPFS of 8.5 (95%CI: 6.9–9.9). 41.2% patients achieved stable disease and 7.3% partial response. No major changes were observed QoL; 86.4% patients received stomatitis prophylaxis and 41.4% experienced EVE related AEs of stomatitis, mainly low grade. AEs occurred in 91.2% of patients, of which stomatitis (42.6%) and fatigue (19.8%) were most frequent. The BRAWO study provides real‐world evidence of efficacy and safety of EVE + EXE in patients with HR+, HER2− ABC. A high BMI and the absence of visceral metastases were independent predictors of PFS in this cohort of patients.

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Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2−) advanced breast cancer patients: New insights beyond clinical trials. The EVA study

Cited by 22 publications

References 10 publications

Everolimus (EVE) and exemestane (EXE) in patients with advanced breast cancer aged ≥ 65 years: new lessons for clinical practice from the EVA study

Everolimus (EVE) and exemestane (EXE) in patients with advanced breast cancer aged ≥ 65 years: new lessons for clinical practice from the EVA study

Dasatinib inhibition of cSRC prevents the migration and metastasis of canine mammary cancer cells with enhanced Wnt and HER signalling

Efficacy and safety of everolimus plus exemestane in patients with hormone receptor‐positive, HER‐2‐negative advanced breast cancer: Results from the open‐label, multicentre, non‐interventional BRAWO study

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