Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: Subgroup analysis from the BOLERO-2 study

AbstractBackgroundEverolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2–) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraL EveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2months, respectively) and independent (11.0 versus 4.1months, respectively) central assessment in postmenopausal women with HR+, HER2– ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%).MethodsPrespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases.FindingsAt a median follow-up of 18months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8months) and in those without visceral metastases (N=318; 9.9 versus 4.2months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8months with EVE+EXE versus 2.8months with PBO+EXE. Among patients with visceral metastases and ECOG PS ⩾1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5months).InterpretationAdding EVE to EXE markedly extended PFS by ⩾4months among patients with HR+ HER2– ABC regardless of the presence of visceral metastases.FundingNovartis

How could the herbicidal effects of selected essential oil compounds be related to their membrane activity ?

The European legislation on plant protection products (PPP) is about to undergo important changes in the coming years. The chemical PPP destined to be removed from the European market are responsible for the appearance of resistance phenomena to plants pests. It is therefore necessary to explore new alternatives, one of them being the search for natural herbicides. Essential oils (EO) could provide a welcome alternative due to their proven activity as PPP. Even if these compounds seem to have a bright future as PPP, their activity is mainly approached through empirical observations. EO are also a complex mix of of different molecules that could act individually or in synergy. Particularly, very little is known when it comes to molecular mechanisms of action and the relations between structure and activity of the active compounds. This study aims to investigate the structure/activity relationships of some EO molecules, among which cinnamaldehyde (CIN) from cinnamon and citronellal and citronellol from lemongrass. Due to their lipophilic properties, EO tend to interact with one or more of the layers found in the outer plant tissues, among which the cell membranes. For cinnalmaldehyde (and other EO compounds), it has been shown that they are able to interact with bacterial phospholipids and induce change in lipid organization (fluidity, packing,..) on model lipid monolayers (Nowotarska et al, 2014). Citronnellol was notably shown to displace cholesterol from its phospholipid complexes (Lange, Y et al, 2009). However, nothing is known about any interaction with lipids specific to plant plasma membrane (PPM). In this study, we analyzed the effects of the above three EO compounds on model PPM by complementary in vitro and in silico biophysical approaches. We showed that the three compounds have differential effects on plant lipids and different herbicidal properties on plantae. While part of the herbicidal activity could be related to membrane perturbation, some clues remain to be elucidated. Future studies at a molecular point of view would help to better decipher the herbicidal action involving the membrane, other outer plant tissues such as the cuticule and/or and a potential effect on EO compounds on proteins or genomic DNA, as it was shown for CIN on E. Coli (He, TF et al, 2018)

Immediate Administration of Zoledronic Acid Reduces Aromatase Inhibitor-Associated Bone Loss in Postmenopausal Women With Early Breast Cancer: 12-month analysis of the E-ZO-FAST trial.

BACKGROUND: Letrozole is a proven and effective adjuvant therapy in postmenopausal women with hormone receptor-positive (HR(+)) early breast cancer (EBC). As with other aromatase inhibitors (AIs), long-term letrozole administration is associated with decreased bone mineral density (BMD) and increased fracture risk. This study compared potential bone-protecting effects of immediate vs. delayed administration of zoledronic acid (ZOL) in patients with EBC receiving adjuvant letrozole. PATIENTS AND METHODS: Patients with HR(+) EBC in whom adjuvant letrozole treatment was initiated (2.5 mg/day for 5 years) were randomized to immediate ZOL treatment (immediate ZOL) or delayed ZOL treatment (delayed ZOL) (both at 4 mg every 6 months). Patients in the delayed ZOL group received ZOL only for a BMD T-score that decreased to < -2.0 (lumbar spine [LS] or total hip [TH]) or for fracture. The primary endpoint was percentage change in the LS BMD at month 12. Patients were stratified by established or recent postmenopausal status, baseline T-scores, and adjuvant chemotherapy history. RESULTS: At 12 months, the LS BMD increased in the immediate ZOL group (+2.72%) but decreased in the delayed ZOL group (-2.71%); the absolute difference between groups was significant (5.43%; P < .0001). Across all subgroups, patients receiving immediate ZOL had significantly increased LS and TH BMD vs. those who received delayed ZOL (P < .0001). Differences in fracture incidence or disease recurrence could not be ascertained because of early data cutoff and low incidence of events. Adverse events were generally mild, transient, and consistent with the known safety profiles of both agents. CONCLUSION: Immediate ZOL administration effectively prevented BMD loss and increased BMD in postmenopausal women with HR(+) EBC receiving adjuvant letrozole, regardless of BMD status at baseline

Everolimus plus exemestane as first-line therapy in HR⁺, HER2⁻ advanced breast cancer in BOLERO-2.

The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25-0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18-0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR(+), HER2(-) advanced breast cancer in postmenopausal patients

Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†.

The BOLERO-2 study previously demonstrated that adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) by more than twofold in patients with hormone-receptor-positive (HR(+)), HER2-negative advanced breast cancer that recurred or progressed during/after treatment with nonsteroidal aromatase inhibitors (NSAIs). The overall survival (OS) analysis is presented here.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Everolimus plus exemestane as first-line therapy in HR+, HER2- advanced breast cancer in BOLERO-2

The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2 -) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25-0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18-0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR+, HER2- advanced breast cancer in postmenopausal patients. © 2013 The Author(s).SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer: Results From BOLERO-2

Purpose To explore the genetic landscape of tumors from patients enrolled in the BOLERO-2 trial to identify potential correlations between genetic alterations and efficacy of everolimus treatment. The BOLERO-2 trial has previously demonstrated that adding everolimus to exemestane prolonged progression-free survival (PFS) by greater than twofold in patients with hormone receptor-positive, human epidermal growth factor receptor-2–negative advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. Methods Next-generation sequencing was used to analyze genetic status of cancer-related genes in 302 archival tumor specimens from patients representative of the BOLERO-2 study population. Correlations between the most common somatic alterations and degree of chromosomal instability, and treatment effect of everolimus were investigated. Results Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, CCND1, and TP53 genes or the pathways of which they are components. However, quantitative differences in everolimus benefit were observed between patient subgroups defined by the mutation locations in PIK3CA (exon 20 and other exons). In addition, the degree of chromosomal instability correlated with treatment efficacy in the everolimus arm. Conclusion The data suggest that adding everolimus to exemestane results in marked prolongation of PFS in postmenopausal women with hormone receptor-positive breast cancer whose tumors have limited chromosomal instabilities and abnormalities in potentially compensatory signaling pathways controlling growth/survival, cell-cycle progression, or DNA damage/repair. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.