Fulvestrant plus vandetanib versus placebo for the treatment of patients with metastatic breast cancer resistant to aromatase inhibitor therapy (FURVA): a multicentre, Phase 2, randomised controlled trial

Background: FURVA, a randomised, double-blind Phase II trial, investigated whether the addition of vandetanib to fulvestrant improved progression-free survival (PFS) in patients with an aromatase inhibitor(AI)-resistant advanced breast cancer. Methods: Postmenopausal women with oestrogen receptor-positive (ER+ve)/HER2-negative advanced breast cancer, who experienced disease progression on an AI, were randomised (1:1) to fulvestrant 500 mg (Q28) with vandetanib 300 mg od (f + v) or placebo (f + p) until disease progression or discontinuation. The primary endpoint was PFS; secondary endpoints included overall survival (OS) and the influence of REarranged during Transfection (RET) signalling on outcomes. Results: In total, 165 participants were randomised to f + v (n = 80) or f + p (n = 85). Median PFS was 5.5 months (m) for f + v compared to 5.5 m for f + p (hazard ratio (HR) 0.88; 95% CI: 0.62–1.23; P = 0.22). Unexpectedly, high total RET expression was associated with a PFS advantage of 8.87 m vs 3.94 with low RET (HR 0.493: 95% CI 0.32–0.77; P = 0.002) independent of the treatment arm, supported by an OS advantage 21.95 m vs 18.04 (HR 0.584; 95% CI 0.34–1.00; P = 0.051) in the high-RET group. Conclusion: The addition of vandetanib to fulvestrant does not improve PFS. However, high total RET expression was associated with improved PFS, suggesting RET may have a prognostic role in patients treated with fulvestrant. Clinical trial registration: ClinicalTrials.gov, NCT02530411

Usual interstitial pneumonia in asbestos-exposed cohorts - concurrent idiopathic pulmonary fibrosis or atypical asbestosis?

Aims: To determine if usual interstitial pneumonia pattern fibrosis is seen in asbestosis METHODS AND RESULTS: The occurrence of usual interstitial pneumonia pattern fibrosis was studied in 4 asbestos cohorts systematically referred following post mortem to the U.K. Pneumoconiosis Unit, Cardiff. The combined exposed workforce was over 25,000 persons. Over the 17 year period 233 subjects were identified, 210 had degrees of interstitial fibrosis with a fibrotic non-specific interstitial pneumonia pattern and sub-pleural accentuation and 3 cases showed usual interstitial pneumonia pattern fibrosis. All 3 cases showed grade 4 fibrosis (honeycombing) with no asbestos fibre dose-response correlation. Poisson distribution of probability analysis indicated that the observed cases of usual interstitial pneumonia in this workforce could be wholly accounted for by the prevalence of idiopathic pulmonary fibrosis in the population CONCLUSIONS: Usual interstitial pneumonia pattern fibrosis is rarely observed in asbestos exposed subjects, shows no dose-response correlation with asbestos fibres on mineral analysis and this points to the alternate disease such as idiopathic pulmonary fibrosis. The results indicate that usual interstitial pneumonia pattern fibrosis should not be regarded as bonafide asbestosis, irrespective of the status of asbestos biomarkers and this impacts upon the post mortem handling of asbestos related deaths. This article is protected by copyright. All rights reserved

Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed

Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION):a multicentre, randomised, controlled, phase 2 trial

BackgroundCapivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer.MethodsIn this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0–2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0·20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952.FindingsBetween March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4·9 months (IQR 1·6–11·6). At the time of primary analysis for progression-free survival (Jan 30, 2019), 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Median progression-free survival was 10·3 months (95% CI 5·0–13·2) in the capivasertib group versus 4·8 months (3·1–7·7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0·58 (95% CI 0·39–0·84) in favour of the capivasertib group (two-sided p=0·0044; one-sided log rank test p=0·0018). The most common grade 3–4 adverse events were hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] of 71 in the placebo group), diarrhoea (ten [14%] vs three [4%]), rash (14 [20%] vs 0), infection (four [6%] vs two [3%]), and fatigue (one [1%] vs three [4%]). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related.InterpretationProgression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials

Synergistic targeting of breast cancer stem-like cells by human γδ T cells and CD8+ T cells

International audienceThe inherent resistance of cancer stem cells (CSCs) to existing therapies has largely hampered the development of effective treatments for advanced malignancy. To help develop novel immunotherapy approaches that efficiently target CSCs, an experimental model allowing reliable distinction of CSCs and non-CSCs was set up to study their interaction with non-MHC-restricted γδ T cells and antigen-specific CD8 + T cells. Stable lines with characteristics of breast CSC-like cells were generated from ras-transformed human mammary epithelial (HMLER) cells as confirmed by their CD44 hi CD24 lo GD2 + phenotype, their mesenchymal morphology in culture and their capacity to form mammospheres under non-adherent conditions, as well as their potent tumorigenicity, self-renewal and differentiation in xenografted mice. The resistance of CSC-like cells to γδ T cells could be overcome by inhibition of farnesyl pyrophosphate synthase (FPPS) through pretreatment with zoledronate or with FPPS-targeting short hairpin RNA. γδ T cells induced upregulation of MHC class I and CD54/ICAM-1 on CSC-like cells and thereby increased the susceptibility to antigen-specific killing by CD8 + T cells. Alternatively, γδ T-cell responses could be specifically directed against CSC-like cells using the humanised anti-GD2 monoclonal antibody hu14.18K322A. Our findings identify a powerful synergism between MHC-restricted and non-MHC-restricted T cells in the eradication of cancer cells including breast CSCs. Our research suggests that novel immunotherapies may benefit from a two-pronged approach combining γδ T-cell and CD8 + T-cell targeting strategies that triggers effective innate-like and tumour-specific adaptive responses

Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

Purpose One-third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here we identify a specific post-translational modification that occurs during endocrine resistance and which results in tumour susceptibility to the apoptosis inducer TNF-Related Apoptosis-Inducing Ligand (TRAIL). This potentially offers a novel stratified approach to targeting endocrine resistant breast cancer. Experimental Design Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumour viability, cancer stem cell (CSC) viability (tumourspheres), tumour growth kinetics and metastatic burden were assessed. Western blots for the TRAILpathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumours. Results Results Breast cancer cell lines with acquired resistance to tamoxifen-(TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSClike activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve tumours, while systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumour growth, CSC-like activity and metastases. Acquired TRAIL sensitivity correlated with a reduction in intra-cellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP. Conclusions These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine resistant breast cancers, which has both therapeutic and prognostic potential