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.

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.

Towards clinical adherence monitoring of oral endocrine breast cancer therapies by LC-HRMS-method development, validation, comparison of four sample matrices, and proof of concept.

Oral endocrine therapies (OET) for breast cancer treatment need to be taken over a long period of time and are associated with considerable side effects. Therefore, adherence to OET is an important issue and of high clinical significance for breast cancer patients' caregivers. We hypothesized that a new bioanalytical strategy based on liquid chromatography and high-resolution mass spectrometry might be suitable for unbiased adherence monitoring (AM) of OET. Four different biomatrices (plasma, urine, finger prick blood by volumetric absorptive microsampling (VAMS), oral fluid (OF)) were evaluated regarding their suitability for AM of the OET abemaciclib, anastrozole, exemestane, letrozole, palbociclib, ribociclib, tamoxifen, and endoxifen. An analytical method was developed and validated according to international recommendations. The analytical procedures were successfully validated in all sample matrices for most analytes, even meeting requirements for therapeutic drug monitoring. Chromatographic separation of analytes was achieved in less than 10 min and limits of quantification ranged from 1 to 1000 ng/mL. The analysis of 25 matching patient samples showed that AM of OET is possible using all four matrices with the exception of, e.g., letrozole and exemestane in OF. We were able to show that unbiased bioanalytical AM of OET was possible using different biomatrices with distinct restrictions. Sample collection of VAMS was difficult in most cases due to circulatory restraints and peripheral neuropathy in fingers and OF sampling was hampered by dry mouth syndrome in some cases. Although parent compounds could be detected in most of the urine samples, metabolites should be included when analyzing urine or OF. Plasma is currently the most suitable matrix due to available reference concentrations.

Real-Life Analysis of Efficacy and Safety of Everolimus Plus Exemestane in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Metastatic Breast Cancer Patients: A Turkish Oncology Group (TOG) Study.

PURPOSE: This study evaluated the efficacy and safety of everolimus (EVE) plus exemestane (EXE) in hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer (MBC) patients in real-life settings. METHODS: Overall, 204 HR+, HER2- MBC patients treated with EVE + EXE after progressing following prior endocrine treatment were included. Overall survival (OS) and progression-free survival (PFS) and safety data were analyzed. RESULTS: The objective response rate, median PFS, and median OS were 33.4%, 8.9 months, and 23.4 months, respectively. Multivariate analysis revealed that negative progesterone receptor status was a significant determinant of poor treatment response (p = 0.035) and PFS (p = 0.024). The presence of bone-only metastasis was associated with better treatment response (p = 0.002), PFS (p < 0.001), and OS (p = 0.001). CONCLUSION: We confirmed the favorable efficacy and safety profile of EVE + EXE for HR+, HER - MBC patients.

E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group.

PURPOSE: Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. PATIENTS AND METHODS: E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. RESULTS: Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. CONCLUSION: The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.

Nasal Polyposis and Its Association with Cardiac Functions.

OBJECTIVE: The aim of the study was to ascertain the effect of nasal polyposis on cardiac functions. MATERIAL AND METHODS: A prospective randomized interventional open-label endpoint-controlled study was conducted in an academic tertiary care hospital. Thirty-one patients with chronic rhinosinusitis with nasal polyposis were enrolled and administered fluticasone furoate nasal spray for 3 weeks before randomly segregation into surgical or medical group. The treatment continued for 3 months in both groups. The SNOT-22 (Sino-Nasal Outcome Test-22) score, polyp grade, and right ventricular and pulmonary arterial functions were recorded in both groups before and after 3 months of the intervention. RESULTS: Both groups had significant improvement in SNOT-22 scores after 3 months of intervention. Both groups showed improvement in cardiac functions, but statistical significance was found only in subjects who underwent surgery. CONCLUSION: Nasal polyp affects cardiac functions, and this needs further evaluation and research through studies on large samples.

Mutation analysis using cell-free DNA for endocrine therapy in patients with HR+ metastatic breast cancer.

We prospectively evaluated the utility of ESR1 and PIK3CA mutation analysis with cell-free DNA (cfDNA) using droplet digital PCR (ddPCR) for the efficacy of endocrine therapy (ET) in hormone receptive positive (HR+) metastatic breast cancer (MBC) patients. CfDNA was analyzed just before the start of ET for MBC. E380Q, Y537N, Y537S, and D538G were assessed for ESR1 mutations and H1047R, E545K, and E542K were assessed for PIK3CA mutations. A total of 75 patients were enrolled. Of those, 31 (41.3%) received letrozole with palbociclib, and 28 (37.3%) received exemestane and everolimus (EverX). ESR1 mutations were found in 36 (48.0%) patients, of which 16 (21.3%) had more than one variant. Seventeen (23.6%) patients had one PIK3CA mutation and 8 (11.1%) had two. In the total population, time to progression of the first ET after enrollment (TTP1) decreased significantly as the number of ESR1 mutations increased (p < 0.001). PIK3CA mutations were also significantly associated with shorter TTP1 (median TTP1: 16.2 months vs. 10.9 months, p = 0.03). In contrast, PIK3CA mutations were significantly associated with longer TTP in patients receiving EverX treatment (median TTP of EverX: 15.9 months vs. 5.2 months, p = 0.01) and remained a significant factor in multivariable analysis for TTP of EverX in this subgroup (hazard ratio = 0.2, 95% CI = 0.1- 0.8, p = 0.03). ESR1 and PIK3CA mutations in cfDNA were associated with clinical efficacies of ET in HR+ MBC patients.

A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer.

BACKGROUND: Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). METHODS: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). RESULTS: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). CONCLUSIONS: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). TRIAL REGISTRATION: ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.

Dynamic changes of CTCs in patients with metastatic HR(+)/HER2(-) breast cancer receiving salvage treatment with everolimus/exemestane.

PURPOSE: Detection of CTCs represents a poor prognostic factor in patients with early and metastatic breast cancer (mBC) and treatment with everolimus-exemestane (E/E) is an established effective treatment in hormone receptor-positive/HER2-negative mBC patients. The effect of E/E on CTCs in mBC patients was prospectively investigated. METHODS: CTCs from 50 pre-treated patients with mBC receiving E/E were analyzed using the CellSearch (CS) platform and triple immunofluorescence (IF) staining for cytokeratin, M30 and Ki67 expression to assess their proliferative and apoptotic status. RESULTS: CTCs (by CS) were detected in 64% of patients before treatment and E/E administration resulted in their decreased prevalence [(n = 18; 36%, p = 0.004) and (n = 7; 19.4%, p = 0.019) post-1st and post-3rd treatment cycle, respectively] whereas it was significantly increased at disease progression (PD: 61%) compared to post-1st and post-3rd cycle (p = 0.049 and p = 0.021, respectively). Ki67-positive CTCs were detected in 60%, 60%, 17% and 50% of patients before treatment, post-1st, post-3rd cycle and at PD, respectively, while the opposite was observed for M30-positive CTCs (0% at baseline, 10% after the 1st cycle, 50% after the 3rd cycle and 0% at PD). The detection of even ≥ 1 CTC/5 ml after one cycle was associated with decreased PFS (3.3 vs 9.0 months, p = 0.025) whereas the detection of even ≥ 2 CTCs at PD was associated with decreased OS (32.4 vs 19.5 months; p = 0.009). CONCLUSIONS: The combination of E/E resulted in early elimination of proliferating CTCs in mBC patients and this effect was associated with a favorable clinical outcome.

Secondary endpoints analysis in patients with estrogen receptor-positive metastatic breast cancer treated with everolimus and exemestane enrolled in Oral Care-BC.

BACKGROUND: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE. METHODS: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months. RESULTS: There were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI <  25 mg/m2 and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial. CONCLUSIONS: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI <  25 mg/m2, and who did not receive BMA while receiving EVE and EXE may have better prognoses. TRIAL REGISTRATION: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov ( NCT02376985 ).

Lack of everolimus diffusion in pleural fluid during pleural progression of breast cancer: A case report.

BACKGROUND: We report here a case where no everolimus pleural diffusion was evidenced at the same time of pleural progression of a metastatic breast cancer treated with everolimus and exemestane. CASE DESCRIPTION: A 69-year-old woman was diagnosed in October 2006 with stage III invasive ductal breast adenocarcinoma. After nine months of everolimus and exemestane treatment, she presented with a pleural progression. Everolimus concentration was measured in blood and in pleural fluid. Residual blood concentration was at 9.1 ng/mL, while no everolimus was observed in the pleural fluid. MANAGEMENT AND OUTCOME: Due to inefficacy of everolimus in this patient, she was switched to palbociclib and fulvestrant. CONCLUSION: Everolimus seems to have a poor diffusion in the pleural fluid.

Galeterone sensitizes breast cancer to chemotherapy via targeting MNK/eIF4E and ß-catenin.

Aberrant activation of eIF4E signalling pathway is common in breast cancer and holds potential therapeutic options. In our work, galeterone as a chemical compound under clinical trials for the treatment of prostate cancer, was identified to be effective in targeting breast cancer cells via suppressing MNK-eIF4E and ß-catenin. In despite of varying IC50, galeterone at nanomolar concentrations significantly decreased viability, proliferation and migration of a panel of breast cancer cell lines regardless of clinical subtypes and genetic mutations, and to a higher extent than in normal breast cells. Galeterone significantly enhanced the effects of chemotherapeutic drugs in reducing proliferation and viability but not migration. The in vivo efficacy of galeterone as single drug alone and its ability in augmenting chemotherapy's efficacy were also shown in breast cancer xenograft mouse model. Mechanism analysis demonstrated that galeterone decreased MNK1/2 level and phosphorylation of eIF4E. In addition, galeterone decreased ß-catenin level via promoting GSK-3ß-mediated ß-catenin degradation, and furthermore that Akt but not CK1 was involved in ß-catenin degradation by galeterone. Rescue studies demonstrated that both MNK/eIF4E and ß-catenin were responsible for anti-breast cancer activity of galeterone. Our study provides pre-clinical evidence to initialize clinical trials for breast cancer using galeterone in combination with chemotherapy.

Efficacy of everolimus combined with endocrine therapy in HR-positive/HER-2-negativeadvanced breast cancer.

PURPOSE: To explore the efficacy and safety of everolimus combined with endocrine therapy in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER-2)-negative advanced breast cancer. METHODS: The clinical information of 108 patients with HR-positive/HER-2-negative advanced breast cancer, who were admitted to and treated in our hospital from June 2014 to June 2016, was retrospectively analyzed. Of them, 54 patients were treated with everolimus combined with endocrine drugs (Everolimus group), while the other 54 patients underwent endocrine monotherapy (Control group). The clinical response rate and incidence of adverse reactions were compared between the two groups of patients, and the patients were followed up to record survival. Besides, the possible influencing factors for progression-free survival (PFS) were analyzed. RESULTS: The objective response rate (ORR) was 22.2% and 14.8%, respectively, in everolimus group and the Control group, while the clinical benefit rate (CBR) was 66.7% and 37.0%, respectively, in the two groups. There were statistically significant differences in the CBRs of the first-line and second-line therapies. The majority of adverse reactions were in grade I and II, with lower incidence rates of grade III and IV adverse reactions. The median PFS of the two groups of patients was 7.3±5.6 months and 6.7±5.1 months, respectively. The log-rank test revealed that there was a statistically significant difference in the PFS between the two groups of patients. According to the multivariate regression analysis results, progesterone receptor (PR)+, absence of visceral metastases, and sensitivity to endocrine therapy were the protective prognostic factors for PFS. CONCLUSION: Everolimus combined with endocrine therapy has significant clinical efficacy in patients with HR-positive/HER-2-negative advanced breast cancer, and can effectively improve the survival of patients with tolerable adverse reactions. PR+, absence of visceral metastases and sensitivity to endocrine therapy are the protective prognostic factors for PFS.

Effect of once-daily fluticasone furoate/vilanterol versus vilanterol alone on bone mineral density in patients with COPD: a randomized, controlled trial.

BACKGROUND: The relationship between inhaled corticosteroids and bone mineral density (BMD) remains uncertain despite extensive research. METHODS: This was an international, multicenter, randomized, double-blind, parallel-group, 3-year noninferiority study. Patients with chronic obstructive pulmonary disease (COPD) (⩾40 years of age; smoking history ⩾10 pack years) and at least one native hip evaluable for BMD were enrolled and randomized 1:1, stratified by sex, to treatment with vilanterol (VI) 25 µg or fluticasone furoate/vilanterol (FF/VI) 100 µg/25 µg. BMD measurements were taken via dual-energy X-ray absorptiometry every 6 months. The primary endpoint was assessment of the noninferiority of change from baseline in total hip BMD per year at the -1% noninferiority level. Change from baseline in BMD at the lumbar spine and BMD measurements by sex were secondary endpoints. Incidences of COPD exacerbations and bone fractures throughout the study were also recorded. RESULTS: Of 283 randomized patients, 170 (60%) completed the study. Noninferiority was demonstrated for FF/VI versus VI with regards to change from baseline in total hip BMD per year, with changes of -0.27% and 0.18%, respectively, and a treatment difference of -0.46% per year [95% confidence interval (CI) -0.97 to 0.06]. The treatment difference for FF/VI versus VI regarding lumbar spine BMD was -0.51% per year (95% CI -1.11 to 0.10). COPD exacerbations and bone fracture rates were similar between treatment groups. CONCLUSION: FF/VI showed noninferiority to VI for change from baseline in total hip BMD per year, when assessed at the -1% noninferiority margin in a combined sample of men and women with COPD.The reviews of this paper are available via the supplemental material section.

Phase Ib Dose-escalation/Expansion Trial of Ribociclib in Combination With Everolimus and Exemestane in Postmenopausal Women with HR+, HER2- Advanced Breast Cancer.

PURPOSE: Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane). PATIENTS AND METHODS: Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy. RESULTS: Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug-drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response. CONCLUSIONS: Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2- ABC.

A Prognostic Model Based on PAM50 and Clinical Variables (PAM50MET) for Metastatic Hormone Receptor-positive HER2-negative Breast Cancer.

PURPOSE: Predicting prognosis in HR+/HER2- metastatic breast cancer (MBC) might be clinically useful; however, no validated prognostic biomarkers exist in this setting to date. PATIENTS AND METHODS: In phase III, EGF30008 trial, 484 patients with HER2- MBC who received letrozole and placebo or lapatinib were selected. PAM50 data, ECOG performance status, visceral disease, number of metastasis, biopsy type, and age were evaluated. A progression-free survival (PFS) Cox model was evaluated. The final model (PAM50MET) with a prespecified cutoff was validated in patients (n = 261) with HR+/HER2- advanced breast cancer (aBC) from BOLERO-2 (phase III trial that evaluated exemestane and placebo or everolimus). RESULTS: In EGF30008, prognostic models with PAM50 plus clinical variables yielded higher C-index values versus models with only PAM50 or clinical variables. The PAM50MET model combined 21 variables: 2 PAM50 subtypes, basal signature, 14 genes, and 4 clinical variables. In EGF30008, the optimized cutoff was associated with PFS [HR = 0.37; 95% confidence interval (CI), 0.29-0.47; P < 0.0001] and overall survival (OS; HR = 0.37; 95% CI, 0.27-0.51; P < 0.0001). The median (months; 95% CI) PFS and OS were 22.24 (19.0-24.9) and not reached in PAM50MET-low versus 9.13 (8.15-11.0) and 33.0 (28.0-40.0) in PAM50MET-high groups, respectively. In BOLERO-2, the PAM50MET-low was associated with better PFS (HR = 0.72; 95% CI, 0.53-0.96; P = 0.028) and OS (HR = 0.51; 95% CI, 0.35-0.69; P < 0.0001). The median (months) (95% CI) PFS and OS were 6.93 (5.57-11.0) and 36.9 (33.4-NA) in PAM50MET-low versus 5.23 (4.2-6.8) and 23.5 (20.2-28.3) in PAM50MET-high groups, respectively. CONCLUSIONS: PAM50MET is prognostic in HR+/HER2- MBC, and further evaluation might help identify candidates for endocrine therapy only or novel therapies.

A Randomized Placebo Controlled Phase II Trial Evaluating Exemestane with or without Enzalutamide in Patients with Hormone Receptor-Positive Breast Cancer.

PURPOSE: To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor-positive (HR+) breast cancer. PATIENTS AND METHODS: In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis. RESULTS: Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54-1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66-1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (P interaction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10-0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. CONCLUSIONS: Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.

Case report: 5-year progression free survival and complete liver response in a patient with metastatic breast cancer treated with everolimus plus exemestane.

RATIONALE: Within a rapidly expanding therapeutic armamentarium, the combination of everolimus (Eve) plus exemestane (Exe) utility needs to be reinstated in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). PATIENT CONCERNS: We herein report on a patient affected by HR+ HER2- MBC treated with radical surgery after neoadjuvant chemotherapy, who relapsed early on adjuvant tamoxifen, progressed rapidly on first line anastrozole, and failed treatment with third line capecitabine. DIAGNOSES: Metastatic luminal breast cancer progressed under standard endocrine therapy and chemotherapy. INTERVENTIONS: Third line with Eve plus Exe was given after chemotherapy. OUTCOMES: Patient experienced a 5-year progression free interval. LESSONS: Eve plus Exe remains a valid option in HR+HER2- MBC.

PEGylated Nanoliposomes Potentiated Oral Combination Therapy for Effective Cancer Treatment.

The conventional treatment regimen for cancer with a single chemotherapeutic agent is far behind the clinical expectations due to the complexity of cancer biology and is also associated with poor Quality of Life (QOL) due to off-site toxicity and multidrug resistance. In recent years, nanopotentiated combination therapy has shown significant improvement in cancer treatment via a synergistic approach. However, being synthetic in nature, nanocarriers have been associated with the activation of the Complement (C) activation system resulting in serious hypersensitivity reactions known as CActivation Related Pseudoallergy (CARPA) effect once given via intravenous injection. On the other hand, nanopotentiated oral drug delivery offers several advantages for the effective and safe delivery of the drug to the target site. This hypothesis aims to put forward wherein Exemestane (chemotherapeutic agent) and lycopene (herbal bioactive) co-laden into PEGylated liposomes and delivered to the breast cancer via the oral route. PEGylation of the liposomes would prevent both molecules from the harsh microenvironment of the Gastrointestinal Tract (GIT) and would eventually promote their intestinal absorption via the lymphatic pathway to the systemic circulation. Lycopene being a potent antioxidant and anti-cancer herbal bioactive would promote the therapeutic efficacy of the Exemestane via a synergistic approach. This nanopotentiated oral combination therapy would pave the path for the safe and effective treatment of cancer.

Overestimation of Late Distant Recurrences in High-Risk Patients With ER-Positive Breast Cancer: Validity and Accuracy of the CTS5 Risk Score in the TEAM and IDEAL Trials.

PURPOSE: Most distant recurrences (DRs) in women with hormone receptor-positive breast cancer occur after 5 years from diagnosis. The Clinical Treatment Score post-5 years (CTS5) estimates DRs after 5 years of adjuvant endocrine therapy (AET). The aim of this study was to externally validate the CTS5 as a prognostic/predictive tool. METHODS: The CTS5 categorizes patients who have been disease free for 5 years into low, intermediate, and high risk and calculates an absolute risk for developing DRs between 5 and 10 years. Discrimination and calibration were assessed using data from the TEAM and IDEAL trials. The predictive value of the CTS5 was tested with data from the IDEAL trial. RESULTS: A total of 5,895 patients from the TEAM trial and 1,591 patients from the IDEAL trial were included. When assessing the CTS5 discrimination, significantly more DRs were found at 10 years after diagnosis in the CTS5 high- and intermediate-risk groups than in the low-risk group (hazard ratio, 5.7 [95% CI, 3.6 to 8.8] and 2.8 [95% CI, 1.7 to 4.4], respectively). In low- and intermediate-risk patients, the CTS5-predicted DR rates were higher, although not statistically significantly so, than observed rates. However, in high-risk patients, the CTS5-predicted DR rates were significantly higher than observed rates (29% v 19%, respectively; P < .001). The CTS5 was not predictive for extended AET duration. CONCLUSION: The CTS5 score as applied to patients treated in the TEAM and IDEAL cohorts discriminates between risk categories but overestimates the risk of late DRs in high-risk patients. Therefore, the numerical risk assessment from the CTS5 calculator in its current form should be interpreted with caution when used in daily clinical practice, particularly in high-risk patients.

Pyrotinib with trastuzumab and aromatase inhibitors as first-line treatment for HER2 positive and hormone receptor positive metastatic or locally advanced breast cancer: study protocol of a randomized controlled trial.

BACKGROUND: HER2 dual-blockade combined with aromatase inhibitors (AI) is a promising strategy to improve progression-free survival (PFS) in hormone receptor (HR) positive, metastatic breast cancer (MBC). Pyrotinib is a novel irreversible epidermal growth factor receptor/HER2 dual tyrosine kinase inhibitor. However, there is scarcity of data on the effectiveness and safety of pyrotinib combined with trastuzumab and AI as first-line treatment in a metastatic setting. METHODS/DESIGN: The present study is a prospective, randomized, open-label trial. 198 patients with HER2+/HR+ MBC will be recruited. Eligible patients will be allocated (2:1) to either an experimental group (pyrotinib + trastuzumab + AI) or a control group (trastuzumab + AI). Allocation will be stratified by 1) time since adjuvant hormone therapy (≤ 12 months/> 12 months/no prior hormone therapy); 2) lesion sites (visceral / non-visceral). The primary endpoint is PFS. DISCUSSION: To our knowledge, this is the first prospective randomized controlled trial to assess dual HER2-blockade with pyrotinib in the metastatic setting. This study will provide valuable evidence regarding the efficacy and safety of pyrotinib when combined with trastuzumab and an AI as first-line treatment for MBC. Moreover, it will also evaluate the feasibility of endocrine therapy as an alternative to chemotherapy in providing de-escalation therapy with less toxicity for advanced HR+/HER2+ patients. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03910712 . Registered on 10 Apr. 2019.