The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Surgical outcomes of gallbladder cancer: the OMEGA retrospective, multicentre, international cohort study.

Background: Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC). Methods: The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity. Findings: On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84-1.29], p = 0.711 and HR 1.18 [0.95-1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79-1.17], p = 0.67 and HR 1.48 [1.16-1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02-1.74], p = 0.037) and OS (HR 1.26 [1.03-1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3-3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62-3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55-5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02-1.37], p = 0.031) but not OS (HR 1.05 [0.91-1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used. Interpretation: In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit. Funding: Cambridge Hepatopancreatobiliary Department Research Fund.

The MITRE trial protocol: a study to evaluate the microbiome as a biomarker of efficacy and toxicity in cancer patients receiving immune checkpoint inhibitor therapy.

BACKGROUND: The gut microbiome is implicated as a marker of response to immune checkpoint inhibitors (ICI) based on preclinical mouse models and preliminary observations in limited patient series. Furthermore, early studies suggest faecal microbial transfer may have therapeutic potential, converting ICI non-responders into responders. So far, identification of specific responsible bacterial taxa has been inconsistent, which limits future application. The MITRE study will explore and validate a microbiome signature in a larger scale prospective study across several different cancer types. METHODS: Melanoma, renal cancer and non-small cell lung cancer patients who are planned to receive standard immune checkpoint inhibitors are being recruited to the MITRE study. Longitudinal stool samples are collected prior to treatment, then at 6 weeks, 3, 6 and 12 months during treatment, or at disease progression/recurrence (whichever is sooner), as well as after a severe (≥grade 3 CTCAE v5.0) immune-related adverse event. Additionally, whole blood, plasma, buffy coat, RNA and peripheral blood mononuclear cells (PBMCs) is collected at similar time points and will be used for exploratory analyses. Archival tumour tissue, tumour biopsies at progression/relapse, as well as any biopsies from body organs collected after a severe toxicity are collected. The primary outcome measure is the ability of the microbiome signature to predict 1 year progression-free survival (PFS) in patients with advanced disease. Secondary outcomes include microbiome correlations with toxicity and other efficacy end-points. Biosamples will be used to explore immunological and genomic correlates. A sub-study will evaluate both COVID-19 antigen and antibody associations with the microbiome. DISCUSSION: There is an urgent need to identify biomarkers that are predictive of treatment response, resistance and toxicity to immunotherapy. The data generated from this study will both help inform patient selection for these drugs and provide information that may allow therapeutic manipulation of the microbiome to improve future patient outcomes. TRIAL REGISTRATION: NCT04107168 , ClinicalTrials.gov, registered 09/27/2019. Protocol V3.2 (16/04/2021).

Influence of organic selenium supplementation on the accumulation of toxic and essential trace elements involved in the antioxidant system of chicken.

The aim of the study was to investigate the interactions between selenium (Se) and various trace elements, both toxic and essential, involved in the antioxidant system. A total of 128 day-old chicks (Gallus gallus, broilers) were used to investigate the effect of Se yeast supplementation on the accumulation of cadmium (Cd), copper (Cu) iron (Fe) and zinc (Zn). There were four replicates of four dietary treatments: T1 (basal diet with no added Se, analyzed to contain 0.21 mg kg(-1)), T2 (T1 with 0.15 mg kg(-1) Se added), T3 (T1 with 0.3 mg kg(-1) Se) and T4 (T1 with 3.0 mg kg(-1) Se). At week 4 and 6, two chickens per replicate pen were sacrificed for whole blood, breast muscle and liver sampling. Samples were analyzed by ICP-MS. Supplementation with Se-yeast, not only increased Se concentration but also reduced Cd concentration in the tissues. Selenium was negatively correlated with Cd and positively correlated with Zn, Cu and Fe. Cadmium was negatively correlated with Zn and Cu. Zinc was positively correlated with Cu. Iron was negatively correlated with Cu and uncorrelated with Zn and Cd. The balance between Se, Cu, Fe and Zn is important for proper antioxidant defense since they are an integral part of various antioxidant enzymes.

Microsimulation and clinical outcomes analysis support a lower age threshold for use of biological valves.

OBJECTIVE: To characterise contemporary results of aortic valve replacement in relation to type of prosthesis and subsequent competing hazards. METHODS: 5470 procedures in 5433 consecutive patients with aortic valve replacement ± coronary artery bypass grafting (CABG) were studied. Microsimulation of survival and valve-related outcomes was performed based on meta-analysis and patient data inputs, with separate models for age, gender and CABG. Survival was validated against the UK Heart Valve Registry. RESULTS: Patient survival at 1, 5 and 10 years was 90%, 78% and 57%, respectively. The crossover points at which bioprostheses and mechanical prostheses conferred similar life expectancy (LE) was 59 years for men and women (no significant difference between prosthesis types between the ages of 56 and 69 for men, and 58 an 63 for women). The improvement in event-free LE for mechanical valves was greater at younger ages with a crossover point of 66 years for men and 67 years for women. Long-term survival was independently influenced by age, male gender and concomitant CABG, but not by type of prosthesis. In bioprostheses the most common long-term occurrence was structural deterioration. For men aged 55, 65 and 75 at initial operation it had a lifetime incidence of 50%, 30% and 13%, respectively. The simulation output showed excellent agreement with registry data. CONCLUSION: Bioprostheses can be implanted selectively in patients as young as 56 without significant adverse effects on life expectancy, although event-free life expectancy remains significantly lower with bioprostheses up to age of implant of 63.