Everolimus In Metastatic Breast Cancer Research Articles

The role of everolimus in metastatic breast cancer and possibilities of moving forward-a narrative review.

In hormone-receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer endocrine-based therapies are preferred over chemotherapy. One of the treatment options is the combination of everolimus with exemestane or other endocrine drug in later lines mainly based on progression-free survival (PFS) results of the phase 3 BOLERO-2 trial. Altogether, clinical trials did not prove an overall survival (OS) benefit and considerable side effects hampered its application in the day-by-day practice. In recent years CDK4/6-inhibitors became a first-choice combination partner to the endocrine treatment, everolimus still has a place within the treatment armamentarium. Although everolimus is a targeted drug, there is no accepted predictive biomarker and further patient selection is not possible. However, several directions can be defined how to optimally use everolimus. For update information on everolimus treatment in breast cancer I have performed a literature search. I used the keywords "breast cancer" and "everolimus" and extended the search in PubMed from 01/01/2014 to 10/02/2023. I considered all phase 3 trials, the phase 1-2 trials with not repetitive information, studies with biomarker results and I also checked review articles to identify potential relevant other clinical trial reports. I also have made a search in clinicaltrials.gov for recently completed and ongoing trials. I summarized the search results in this concise and brief report focusing on main trial results and ongoing research with everolimus. The most promising research directions seem to be further investigations for useable predictive biomarkers, for combinations with other targeted drugs (even in a triple combination) and for the feasibility of pharmacologically guided dosing method.

Real-world pharmacokinetics and pharmacodynamics of everolimus in metastatic breast cancer.

PurposeThis study investigated the relationship between the pharmacokinetics and pharmacodynamics of everolimus in patients with metastatic breast cancer (mBC) in real-world practice.MethodsTwenty-two patients with mBC treated with everolimus plus exemestane were enrolled. Blood everolimus concentrations were measured at outpatient visits. The inhibition of the mammalian target of rapamycin (mTOR) activity in peripheral blood mononuclear cells (PBMCs) was examined. The efficacy and safety endpoints were progression-free survival (PFS) and the cumulative incidence of dose-limiting toxicities (DLTs), respectively.ResultsBlood samples were obtained from 19 consenting patients. Everolimus did not completely inhibit mTOR activity in PBMCs at therapeutic concentrations (~ 56 % maximal inhibition). The most common adverse event was stomatitis (any grade 77 %). The trough concentration (Ctrough) was significantly higher in patients experiencing DLTs than in those without any DLTs (P = 0.030). The optimal Ctrough cutoff predicting DLT development was 17.3 ng/mL. The cumulative incidence of DLTs was significantly higher in patients with Ctrough ≥17.3 ng/mL than in other patients (sub-hazard ratio 4.87, 95 % confidence interval [CI] 1.53-15.5; P = 0.007). Furthermore, the median PFS was numerically longer in patients who maintained a steady-state Ctrough below the threshold than in those who did not (327 days [95 % CI 103-355 days] vs. 194 days [95 % CI 45 days-not estimable]; P = 0.35).ConclusionsThe suggested upper threshold for the therapeutic window of everolimus Ctrough was 17.3 ng/mL. Pharmacokinetically guided dosing may improve the efficacy and safety of everolimus for mBC, warranting further investigation in a larger study.Clinical trial registry: Not applicable.

Everolimus-Related Pneumonitis in Patients with Metastatic Breast Cancer: Incidence, Radiographic Patterns, and Relevance to Clinical Outcome.

This study investigated the incidence, radiographic patterns, and relevance to clinical outcome of everolimus-related pneumonitis (ERP) in patients with metastatic breast cancer (MBC). Data of patients with MBC treated with everolimus who had baseline and at least one follow-up chest computed tomography (CT) were obtained from a medical electronic database system. An independent review of the CT scans of these patients was conducted by two radiologists (NCT03730428). Log-rank and Cox proportional hazard regression analyses were used for time-to-event analyses. ERP was radiographically detected in 45 of 86 patients (52.3%). In more than 80% of these patients, ERP occurred during the first 4 months of everolimus treatment. Only 14 of the 45 patients with ERP were symptomatic (31.1%). Symptoms included cough, fever, and shortness of breath. Bilateral and lower distribution of the pneumonitis was most common. In most of the cases, ground-glass opacities and reticular opacities were noticed. Elderly patients were more likely to develop ERP. Patients with ERP had significantly longer progression-free survival (PFS; 6.8 vs. 4.1 months, p = .024) and overall survival (OS; 42.8 vs. 21.3 months, p = .016). ERP was a predictor of OS improvement confirmed by multivariate Cox analysis (hazard ratio, 0.49; 95% confidence interval, 0.25-0.97; p = .040). ERP was noted in half of the patients with MBC treated with everolimus. Our data suggested that ERP was associated with improved prognosis and may be used as a biomarker for the efficacy of everolimus in MBC. Close monitoring, prompt diagnosis, and proper treatment for ERP are essential to maintain the quality of life of patients and achieve maximum treatment benefits. Everolimus-related pneumonitis (ERP) is one of the most worrying drug adverse events, especially in Asian patients. However, little has been known about the clinical and radiographic details of ERP in patients with metastatic breast cancers (MBCs) treated with everolimus. The present study investigated the clinical characteristics, radiographic patterns, and its correlation with treatment outcome in patients with MBC. ERP was identified in more than half of patients with MBC during everolimus therapy and was associated with improved outcome. Close monitoring and prompt diagnosis and appropriate treatment for ERP are critical for the preservation of patients' quality of life and achievement of maximal treatment benefits.

Leukocytoclastic Vasculitis Associated with Exemestane/Everolimus Therapy in a Previously Irradiated Skin: Case Report

Background: Leukocytoclastic vasculitis may be secondary to medications, underlying infection, collagen-vascular disorders, or malignancy. We report the second case of leukocytoclastic vasculitis related to exemestane/ everolimus therapy in breast cancer and present our review of literature. Case presentation: A 68-year-old Caucasian woman, treated with exemestane and everolimus for metastatic breast cancer presented with skin necrosis and allodynia in the right mammary region. A biopsy disclosed leukocytoclastic vasculitis. The patient received radiation therapy to the right breast due to exulcerated breast cancer (20 × 2.5 Gy, total dose 50 Gy) two and a half years ago. Skin necrosis appeared after five days of treatment with everolimus and 22 days of exemestane. The treatment with exemestane was continued, but everolimus was discontinued. Allodynia disappeared in two weeks after everolimus discontinuation. The skin healed very slowly and an eschar persisted for several months. The prompt resolution of allodynia, evident healing of skin necrosis after everolimus discontinuation, and high score in the Naranjo Adverse Drug Reaction Probability Scale strongly suggest the causative role of everolimus in leukocytoclastic vasculitis. A review of literature revealed only one case of leukocytoclastic vasculitis caused by everolimus and one case of radiation recall dermatitis caused by exemestane/ everolimus. Even though it is a serious adverse effect, it is usually reversible by drug discontinuation and symptomatic treatment only. Conclusion: Everolimus-related skin recall presented as leukocytoclastic vasculitis is a very rare adverse drug reaction.

Osteonecrosis of the jaw associated with everolimus: A case report.

Everolimus, a mammalian target of rapamycin inhibitor, has recently been approved for the treatment of metastatic estrogen receptor-positive breast cancer, at a daily dose of 10 mg in combination with exemestane. Osteonecrosis of the jaw (ONJ) is a rare but severe condition, characterized by exposed necrotic bone, and is associated with various drugs that are often used to treat advanced malignancies. We herein report the case of a patient with breast cancer who developed ONJ during treatment with everolimus, which improved after discontinuation of the drug. To the best of our knowledge, this is the first reported case of everolimus-associated ONJ in a patient receiving everolimus for metastatic breast cancer. In 2014, an 80-year-old woman was started on treatment with everolimus and exemestane for stage IIB estrogen receptor-positive breast cancer. Within 2 months, the left side of her face became edematous, with localized heat and tenderness of the left mandibular region and a 3-mm round area of exposed bone. There was purulent discharge and the surrounding gingiva was edematous and erythematous. The left mandible exhibited a low signal intensity area on T1-weighted magnetic resonance imaging. Treatment was discontinued and ONJ showed improvement after 2 months. Therefore, when prescribing everolimus for metastatic breast cancer, oncologists should be aware of the possibility of ONJ as a complication.

Everolimus in Metastatic Breast Cancer: Clinical Experience as a Late Treatment Line

Background: Everolimus (Afinitor®) plus exemestane are indicated for hormone receptor-positive, HER2/neu-negative metastatic breast cancer (MBC), in menopausal women without symptomatic visceral disease after recurrence or progression following aromatase inhibitors. But everolimus efficacy as late treatment has not been explored. Methods: Sixty-three MBC patients progressing under hormonotherapy (HT; n = 30) or after chemotherapy (CT; n = 32) received everolimus plus HT (EHT) and were analyzed for safety, efficacy and overall survival (OS). This cohort was compared with our previous 530 MBC patients stratified by line (PMID 21852136). Results: The median duration of EHT was 27.8 weeks at 5-10 mg/day until clinical progression or toxicity. Median OS was not reached (median follow-up 18 months). Twelve-month survival was 100, 79 and 49% for patients treated with 0 (n = 13), 1-2 (n = 18) and >3 CT (n = 32), respectively. Median time-to-treatment failure was 6.4 months. In 62 EHT patients randomly matched 1:7 with 421 previous patients for age and number of CT, OS improved compared with patients receiving a new CT (p = 0.062). In patients pretreated with <2 CT, EHT gave a better OS than in those with a new CT (p = 0.026). Conclusions: These results may support the use of EHT whatever the number of previous lines.

Pneumocystis Jirovecii pneumonia (PJP) in metastatic breast cancer (MBC) patients (pts) treated with mTOR inhibitor everolimus (EVE) and exemestane (AI).

e11582 Background: The mTOR inhibitor EVE has been shown to augment the clinical activity of AI in MBC. Interstitial pneumonitis (IP) - presumed to be drug-induced - occurs in up to 20% of pts receiving EVE in MBC. The mTOR inhibitors as a class are immunosuppressive, and tacrolimus and EVE have been used to prevent rejection following organ transplants. PJP is a very rare complication of MBC therapy, usually seen only in pts receiving corticosteroids. A single case-report of PJP associated with EVE in MBC has been reported. We report the first series of PJP in pts treated with EVE/AI for MBC. Methods: We conducted a retrospective review of all MBC pts treated with EVE/AI at our institution and analyzed the cases who had a respiratory adverse event of any grade and a concomitant diagnosis of PJP. Results: Fifty-one pts received EVE/AI for MBC between September 2012 and December 2014. Five pts (9.8%) had a diagnosis of PJP while on EVE/AI. One non-EVE/AI MBC pt, who was receiving frequent steroids with wee...

Everolimus in metastatic breast cancer (MBC): Clinical experience as a late treatment line.

e11526 Background: Everolimus, in combination with exemestane, is indicated to treat hormone receptor-positive, HER2-negative metastatic breast cancer (MBC), in postmenopausal women without symptom...

Everolimus in the Treatment of Metastatic Breast Cancer.

The discovery of the mammalian target of rapamycin (mTOR) molecular pathway has brought insight into its vital role in breast cancer pathogenesis. Several clinical trials have shown that the mTOR inhibitor everolimus could improve patient outcomes in several subtypes of breast cancer, including hormone receptor–positive, human epidermal growth factor receptor–negative metastatic disease that has progressed after prior endocrine therapy. This review summarizes findings from clinical trials that have demonstrated the benefit of everolimus in metastatic breast cancer and highlights some new research directions utilizing everolimus.

Fatal hepatitis B reactivation due to everolimus in metastatic breast cancer: case report and review of literature

Hepatitis B reactivation can occur with cytotoxic chemotherapy in patients with hepatitis B and cancer. Reactivation can occur in a patient with chronic hepatitis, an inactive carrier, or one with resolved hepatitis. Clinical presentation may range from subclinical elevation of liver enzymes to fatal fulminant hepatic failure. Mammalian target of rapamycin inhibitors, which include everolimus, are a new generation of targeted agents that are currently approved for many cancers (since March 2009) including advanced hormone receptor positive, human epidermal growth factor receptor 2-negative breast cancer, in conjunction with exemestane (as of July 2012). We are therefore still learning the various adverse events that occur with this new class of agents. Here, we present an unfortunate case of fatal hepatitis B reactivation in a woman with metastatic breast cancer treated with everolimus and exemestane. We have detailed the controversies around hepatitis B screening prior to immunosuppressive therapy. Clinicians and patients should be aware of this rare but fatal complication prior to everolimus use, and a detailed history, screening for hepatitis B and prophylactic antiviral treatment should be considered.