Welcome to The Christie Research Publications Repository

The repository contains the research outputs from staff and students at The Christie NHS Foundation Trust and Cancer Research UK Manchester Institute.

Current Repository Content:

Over 7000 peer reviewed articles, reviews and selected publications from 1933 onwards.

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  • Unified classification and risk-stratification in Acute Myeloid Leukemia

    Tazi, Y.; Ossa, J. A.; Zhou, Y. Y.; Bernard, E.; Thomas, I.; Gilkes, A.; Freeman, S.; Pradat, Y.; Johnson, S.; Hills, R.; et al. (2022)
    Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.
  • RATIONALE-306: Randomized, global, placebo-controlled, double-blind phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC)

    Yoon, H.; Kato, K.; Raymond, E.; Hubner, Richard A; Shu, Y.; Pan, Y.; Jiang, Y.; Zhang, J.; Park, S.; Kojima, T.; et al. (2022)
    Background: Tislelizumab, an anti-programmed cell death protein 1 antibody, has demonstrated a survival benefit as second-line treatment in ESCC. Here, we report interim analysis (IA) data from the phase 3 RATIONALE-306 study, which evaluated the efficacy and safety of tislelizumab plus chemotherapy vs placebo plus chemo- therapy in patients with advanced or metastatic ESCC in the first-line setting. Methods: In this randomized, double-blind, global study, adults with unresectable locally advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were enrolled regardless of programmed death-ligand 1 (PD-L1) expression status. Patients were randomized (1:1) to receive tislelizumab 200 mg (Arm A) or placebo (Arm B) intravenously once every three weeks, both in combination with investigator-chosen chemotherapy (ICC; platinum [cisplatin or oxaliplatin] and fluo- ropyrimidine [capecitabine or 5-FU] or platinum and paclitaxel) until disease pro- gression per RECIST v1.1, intolerable toxicity, or withdrawal. Randomization was stratified by geographic region, prior definitive therapy and ICC. The primary endpoint was overall survival (OS) in the intent-to-treat (ITT) population. Hierarchical sequentially-tested secondary endpoints were progression-free survival (PFS), objec- tive response rate (ORR) by the investigator, OS in the PD-L1 score ≥10% subgroup, and health-related quality of life. Other secondary endpoints included duration of response (DoR) by the investigator, and safety. Results: Of 649 patients enrolled from 16 countries/4 regions (74.9% and 25.1% from Asia and non-Asian countries [Europe, Oceania, and North America]), 326 and 323 patients were randomized to Arms A and B, respectively (ITT population). At data cutoff (28/02/2022), median follow-up was 16.3 and 9.8 months in Arms A and B, respectively. The study met its primary endpoint at IA by demonstrating statistically significant improvement in OS in Arm A vs Arm B (median OS: 17.3 vs 10.6 months; HR 0.66 [95% CI 0.54, 0.80], p<0.0001). OS improvement was consistently observed across prespecified subgroups including ICC option, region, and PD-L1 expression status. In patients with PD-L1 score ≥10%, Arm A also demonstrated significant improvement in OS vs Arm B (median OS: 16.8 vs 10.0 months, HR 0.61 [95% CI 0.44, 0.85], p=0.0017). A significant improvement in PFS was observed in Arm A vs Arm B (median PFS: 7.3 vs 5.6 months; HR 0.62 [95% CI 0.52, 0.75], p<0.0001). Arm A was associated with a higher ORR (63.5% vs 42.4%, odds ratio 2.38 [95% CI 1.73, 3.27], p<0.0001) and more durable response (median DoR: 7.1 [95% CI 6.1, 8.1] vs 5.7 months [95% CI 4.4, 7.1]) than Arm B. Overall, similar proportions of patients in Arms A and B had ≥1 treatment-related treatment-emergent adverse event (TRAE; 96.6% and 96.3%), ≥Grade 3 TRAEs (66.7% vs 64.5%), and TRAEs leading to death (1.9% vs 1.2%), respectively. Serious TRAEs occurred in 28.7% vs 19.3%, and treatment- emergent AEs leading to discontinuation occurred in 31.8% vs 22.4% in Arms A vs B. No new safety signal for tislelizumab was observed. Conclusions: Tislelizumab plus chemotherapy as first-line treatment demonstrated a statistically significant and clinically meaningful improvement in OS over placebo plus chemotherapy in patients with advanced or metastatic ESCC, with a manageable safety profile.
  • Outcomes by primary tumour location in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study

    He, A.; Valle, Juan W; Lee, C.; Ikeda, M.; Potemski, P.; Morizane, C.; Cundom, J.; Tougeron, D.; Dayyani, F.; Rokutanda, N.; et al. (2022)
    Background: The double-blind, phase 3 TOPAZ-1 study (NCT03875235) evaluated the efficacy and safety of durvalumab plus gemcitabine and cisplatin (GemCis) as first-line treatment for patients with advanced biliary tract cancer (BTC; Oh D-Y et al. J Clin Oncol 2022;40[suppl 4]. Abs 378). Durvalumab plus GemCis significantly improved overall survival (OS) versus placebo plus GemCis and represents a potential new first- line treatment option. In BTC, primary tumour location (intrahepatic or extrahepatic cholangiocarcinoma [IHCC/EHCC], or gallbladder cancer [GBC]) may impact risk fac- tors, prognoses, and response to treatment. Methods: The aim of this exploratory subgroup analysis of TOPAZ-1 was to assess efficacy outcomes, OS, progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) per RECIST v1.1, by primary tumour location in pa- tients receiving durvalumab versus placebo. Patients with BTC were randomised 1:1 to receive durvalumab (1500 mg) or placebo on Day 1 Q3W, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on Day 1 and 8 Q3W, for up to 8 cycles, followed by durvalumab or placebo monotherapy until disease progression, unacceptable toxicity or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (IHCC vs EHCC vs GBC). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for OS and PFS using a Cox proportional hazards model, and odds ratios (ORs) and 95% CIs for ORR were calculated using the Cochran-Mantel Haenszel test. Results: Patient numbers with IHCC, EHCC and GBC were balanced between treatment arms; more patients had IHCC than EHCC or GBC (durvalumab: n¼190, n¼66, n¼85; placebo: n¼193, n¼65, n¼86, respectively). HRs for OS favoured durvalumab: HR was 0.76 (95% CI, 0.58-0.98) for IHCC, 0.76 (95% CI, 0.49-1.19) for EHCC, and 0.94 (95% CI, 0.65-1.37) for GBC. To aid in understanding the higher HR in GBC, regional analysis was performed: the OS HR for GBC in Asia was 0.82 (95% CI, 0.48-1.40) and in Europe plus North America (non-Asian countries minus South America) was 0.78 (95% CI, 0.44-1.37). PFS HR was 0.79 (95% CI, 0.64-0.99) for IHCC, 0.52 (95% CI, 0.35-0.78) for EHCC, and 0.90 (95% CI, 0.65-1.24) for GBC. ORR favoured durvalumab in IHCC (24.7% vs 15.5%; OR, 1.79; 95% CI, 1.07-2.97), EHCC (28.8% vs 15.6%; OR, 2.18; 95% CI, 0.92-5.16) and GBC (29.4% vs 27.9%; OR, 1.08; 95% CI, 0.55-2.09). Percentages of responders with a DoR of at least 9 and 12 months were higher with durvalumab versus placebo for all tumour locations (9-month: IHCC 28.3% vs 24.0%, EHCC 43.3% vs 23.3%, GBC 33.2% vs 27.5%; 12-month: IHCC 18.9% vs 12.0%, EHCC 43.3% vs 23.3%, GBC 27.6% vs 16.5%). Conclusions: In TOPAZ-1, the addition of durvalumab to GemCis appeared to improve efficacy outcomes (not formally tested for subgroup comparisons) for patients with IHCC, EHCC and GBC. Though the magnitude of efficacy improvement varied slightly between primary tumour locations, the benefit of durvalumab was observed consistently. These findings support durvalumab plus GemCis as a treatment option for BTC, irrespective of primary tumour location.
  • Prevention Of Breast and Endometrial cancer using Total Diet Replacement (PROBE-TDR) trial: protocol for a randomised controlled trial

    Clarke, Helen; Harvie, M.; Lombardelli, C.; Krizak, S.; Sellers, K.; Harrison, Hannah; Lim, Y. Y.; Parkin, C.; Patel, S.; Issa, B. G.; et al. (2022)
    Introduction Obesity and overweight are strong potentially modifiable risk factors for postmenopausal breast and endometrial cancer. Bariatric surgery can achieve considerable weight loss and risk reduction of weight-related cancer but is unlikely to be a feasible cancer prevention strategy. Total diet replacement (TDR) can also lead to significant weight reduction. This study aims to examine the cellular and molecular changes in breast and endometrial tissue in high-risk women following TDR-induced weight loss, as well as longer-term adherence to a 12-month TDR weight loss intervention. Methods and analysis PROBE-TDR (PRevention Of Breast and Endometrial cancer using Total Diet Replacement) is a prospective, non-blinded, randomised controlled trial of 47 women at increased risk of breast and/or endometrial cancer. Randomisation is 2:1 to either an immediate 12-month TDR weight loss programme (n=31) or delayed dietary intervention (control) (n=16). The TDR programme includes an initial 12-week period of TDR (850 kcal/ day) followed by a 40-week food-based diet, based on the nutritional principles of a Mediterranean diet, as either continued weight loss (~1500 kcal/ day) or weight loss maintenance (~2000 kcal/day). Menstrual phase-matched biopsies of the breast and endometrium will be assessed at baseline and at the end of the 12-week TDR in the immediate diet group, compared with women randomised to the control group following their usual diet. The trial will also assess longer-term adherence and weight loss success across the 12-month programme in both the immediate and control groups. Ethics and dissemination Approval for this study has been obtained from the Health Research Authority and Health and Care Research Wales (approval 20/ NW/0095). Results will be published in peer-reviewed journals, presented at conferences and shared with trial participants.
  • Real-world utility of full staging with 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) in addition to standard imaging in patients with non-metastatic non-resectable pancreatic ductal adenocarcinoma (PDAC)

    Wheatley, Roseanna; McNamara, Mairead G; Gleeson, J.; Hubner, Richard A; Manoharan, Prakash; Valle, Juan W; Lamarca, Angela; The University of Manchester/The Christie National Health Service Foundation Trust, Manchester, (2022)
    Background: Previous studies support 18FDG-PET utility for staging of patients (pts) with non-metastatic PDAC (M0-PDAC); while its use has been adopted in some countries (i.e. NICE guidelines in the United Kingdom), its use in this setting is vari- able, especially in relation to non-resectable disease. This study explored the utility of performing 18FDG-PET in real-world clinical practice for pts with a working diagnosis of non-resectable M0-PDAC based on cross-sectional imaging. Methods: Notes from consecutive pts with PDAC seen at The Christie NHS Foundation Trust (01/07/2018-02/02/2022; Audit Committee approval: 2020/2654) were reviewed. Eligible pts were those with a diagnosis of non-resectable M0-PDAC (with primary tumour in situ) who underwent full staging with an 18FDG-PET (standard practice for all pts during time period explored). The primary end-point was the percentage of pts identified to have distant metastases on 18FDG-PET. Secondary objectives: factors associated with presence of distant metastases, and impact of 18FDG-PET findings on patient outcomes (overall survival (OS); defined as the time from when pts were first seen for consideration of systemic therapies to time of death or last follow-up). Statistical analysis: STATA v.17, including logistic and Cox Regression. Results: A total of 1637 pts were screened; of these, 56 were eligible. Thirty pts (53.37%) were male; median age: 72 years (range 34-83); the majority had primary tumour located in the head (n¼40, 71.43%), ECOG performance Status (ECOG PS) 0/1 (n¼48, 85.71%) with none/mild comorbidities (37 pts, 66.07%; 22 pts (39.29%) had diabetes) and treatment naive (52 pts, 92.86%; 4 pts had received prior chemo- therapy (all FOLFIRINOX)); stage prior to 18FDG-PET: T4 (39 patients; 69.64%), regional lymph node disease (25 patients; 44.64%), M0 (56 patients; 100%). In 19 patients (33.93%) the 18FDG-PET identified presence of metastatic disease; with incidental findings in 12 patients (21.50%) (incidental findings were identified in 7 patients without evidence of distant metastatic disease in 18FDG-PET). Logistic regression identified T4 stage (vs T1/2/3 stage) as the only factor associate with higher risk of metastatic disease in 18FDG-PET (46.15% vs 5.88%; Odds Ration (OR) 13.71 (95% 1.65-113.81); p-value 0.015). At time of analysis 31 patients (55.36%) had died; median follow up was 8.54 months (95% CI 6.10-10.64). Estimated median OS for the whole population was 12.53 months (95% CI 9.16-14.74). Patients identified to have presence of distant metastases in 18FDG-PET had a shorter OS (8.07 months (95% CI 4.23-16.53) vs 14.38 (95% CI 11.01-19.17)); prognostic impact was confirmed in multivariable Cox Regression (HR 3.48 (95% CI 1.76-12.04); p-value 0.002) adjusted to other prognostic factors (PS (HR 3.48 (95% CI 1.57-7.71); p-value 0.002)). Conclusions: 18FDG-PET allows identification of otherwise occult metastatic disease in a third of the pts (this rate is higher for patients with stage T4 disease). Staging with 18FDG-PET in pts with non-resectable M0-PDAC should be considered standard of care to allow access to appropriate standard-of-care treatment options and recruit- ment into clinical trials. In addition, its prognostic implications could enable optimi- sation of patient information given, management of expectations and future care planning.

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