Background Capivasertib (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 progressionfree survival in patients with aromatase inhibitor-resistant advanced breast cancer.Methods In 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.

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.

The 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 CD44hi CD24lo 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.

1005 Background: The PI3K/AKT signalling pathway is frequently activated in patients (pts) with estrogen receptor (ER) positive breast cancer (ER+BC) and has been implicated in endocrine therapy resistance. Capivasertib (AZD5363) is a highly-selective, oral, small molecule AKT inhibitor. The FAKTION trial investigated the addition of capivasertib to fulvestrant for postmenopausal women with ER+ and HER2 negative BC after relapse or disease progression on an aromatase inhibitor (AI). Methods: FAKTION is an investigator-led, double-blind, placebo-controlled, randomised phase II trial. Patients were recruited from 21 UK sites and randomly assigned (1:1) to fulvestrant 500mg (day 1 and 15 of cycle 1 and day 1 only of subsequent 28 day cycles) with either capivasertib 400mg bd or placebo (4 days on/3 days off starting C1D15) until disease progression, unacceptable toxicity or withdrawal of consent. Allocation was balanced by minimisation according to PIK3CA mutation and PTEN expression status, measurable/non-measurable disease, and primary/secondary endocrine resistance. The primary endpoint was progression-free survival (PFS). The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints included overall survival (OS), objective response and clinical benefit rates, safety and the effect of PI3K/Akt pathway activation on PFS. Results: Between Mar 2015 and Mar 2018, 140 pts were randomised to fulvestrant + capivasertib (n = 69) or fulvestrant + placebo (n = 71). In the Intention-to-treat analysis, after 112 events, median PFS was 10.3 months (m) for capivasertib compared to 4.8m for placebo (Hazard Ratio (HR) 0.57; 95% CI: 0.39 to 0.84; one-sided p = 0.0017; two-sided 0.0035). Fifty-two deaths were reported. Median OS was 26.0m for capivasertib compared to 20.0m for placebo, with a survival difference starting to emerge after 12m (HR = 0.59; 95% CI: 0.34 to 1.05; two-sided p = 0.071). Toxicity data and subgroup analyses including relative capivasertib benefit by PI3K/Akt pathway alteration will be presented at the conference. Conclusions: The trial met its primary endpoint. Addition of capivasertib to fulvestrant for patients with endocrine resistant advanced breast cancer resulted in significantly longer PFS and an improvement in OS. The FAKTION results warrant further investigation of capivasertib for the treatment of ER positive breast cancer. Clinical trial information: NCT01992952.