Christopher Poole

Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial

Summary Background Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. Methods In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2 at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m2 at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m2 at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. Findings All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0·95, 95% CI 0·85–1·08; p=0·44). 75·6% (95% CI 73·7–77·5) of patients in the experimental group and 74·3% (72·3–76·2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0·0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). Interpretation This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. Funding Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.

Randomized Trial of Two Intravenous Schedules of the Topoisomerase I Inhibitor Liposomal Lurtotecan in Women With Relapsed Epithelial Ovarian Cancer: A Trial of the National Cancer Institute of Canada Clinical Trials Group

PURPOSE Liposomal lurtotecan (OSI-211) is a liposomal formulation of the water-soluble topoisomerase I inhibitor lurtotecan (GI147211), which demonstrated superior levels of activity compared with topotecan in preclinical models. We studied two schedules of OSI-211 in a randomized design in relapsed ovarian cancer to identify the more promising of the two schedules for further study. PATIENTS AND METHODS Eligible patients had measurable epithelial ovarian, fallopian, or primary peritoneal cancer that was recurrent after one or two prior regimens of chemotherapy. Patients were randomly assigned to receive either arm A (OSI-211 1.8 mg/m(2)/d administered by 30-minute intravenous infusion on days 1, 2, and 3 every 3 weeks) or arm B (OSI-211 2.4 mg/m(2)/d administered by 30-minute intravenous infusion on days 1 and 8 every 3 weeks). The primary outcome measure was objective response, which was confirmed by independent radiologic review, and a pick the winner statistical design was used to identify the schedule most likely to be superior. RESULTS Eighty-one patients were randomized between October 2000 and September 2001. The hematologic toxic effects were greater on arm A than on arm B (grade 4 neutropenia, 51% v 22%, respectively), as was febrile neutropenia (26% v 2.4%, respectively). Of the 80 eligible patients, eight patients (10%) had objective responses; six responders (15.4%; 95% CI, 6% to 30%) were in arm A and two responders (4.9%; 95% CI, 1% to 17%) were in arm B. CONCLUSION The OSI-211 daily for 3 days intravenous schedule met the statistical criteria to be declared the winner in terms of objective response. This schedule was also associated with more myelosuppression than the schedule of OSI-211 administered in arm B.

Abstract P4-11-07: Comparison of multiparameter tests in the UK OPTIMA-Prelim trial

Introduction All published adjuvant chemotherapy trials in breast cancer have made the assumption that the proportional benefits of chemotherapy apply uniformly across molecular subgroups. However, it can be argued that chemotherapy effectiveness for luminal A breast cancer is low in comparison to other subtypes irrespective of tumour stage. A logical extension of this argument is that novel multiparametric tests that use biological features of breast cancers to assess risk may also inform chemotherapy benefit in luminal cancers. The OPTIMA trial is a multi-centre, partially blinded, randomised clinical trial with a non-inferiority endpoint, and an adaptive design, to compare standard treatment (chemotherapy followed by endocrine therapy) with multi-parameter test-guided treatment allocation to either chemotherapy followed by endocrine therapy or endocrine therapy alone. OPTIMA-prelim aimed to compare the predicted risk stratification, sub-type classification and cost effectiveness of different multiparameter tests performed on the same patient population. Methods Over 20 months of recruitment 285 patients were randomised to OPTIMA-prelim. Tissue was collected centrally, ER and HER2 status confirmed and samples provided for testing with Oncotype DX™, Prosigna™ (PAM50), Mammaprint™, Mammatyper™, IHC4-AQUA and IHC4 using conventional biomarkers. Sub-type classification was provided by Blueprint™, Mammatyper™ and Prosigna™. Each test was performed at central diagnostic laboratories (OncotypeDx, Mammaprint/Blueprint, Mammatyper) or in a central laboratory (Prosigna™/IHC4) strictly according to GLP practices. Results Samples from 181 patients randomised by January 2014 were tested and data analysed for this study. Patients were categorised as low/intermediate or high risk using predetermined cut-offs for each test. Oncotype DX predicted a proportion of low-risk tumours (79%; 95% CI 73-85%) similar to that predicted as either low or intermediate risk using Prosigna ROR_P (71%; 95% CI 64-78%) and IHC4 (69%; 95% CI 62-76%), whilst MammaPrint identified the fewest low-risk tumours (59%; 95% CI 52-66%). Strikingly, a comparison between tests showed modest agreement between tests when dichotomising results between high vs low/intermediate risk. Disagreement between different tests, in assigning individual tumours to risk categories, is not uncommon; for the four tests [Oncotype DX, MammaPrint, Prosigna ROR_P (low/int) and IHC4 (low/int)], only 71 (39%) tumours were classified as low/intermediate risk for all four tests and only 17 (9%) tumours were high risk for all four tests, 93 (52%) tumours were assigned to different risk categories by different tests. Similarly all three subtypes tests (Blueprint/Prosigna/Mammatyper) each assigned 59% of tumors to luminal A subtype but only 70% of these cases were classified as luminal A by all three assays. Conclusion Existing evidence on the comparative prognostic information provided by different tests suggests current multiparameter tests provide broadly equivalent risk information for the population of women with luminal breast cancers. However, for the individual patient, tests may provide differing risk categorisation or indeed subtype information. Acknowledgement This project was funded by the NIHR Health Technology Assessment (HTA) Programme (project 10/34/01). The opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or Department of Health. Citation Format: John MS Bartlett, Robert C Stein, Jane Bayani, Andrea Marshall, Janet A Dunn, Amy F Campbell, Carrie Cunningham, Monika Sobol, Peter Hall, Leila Rooshenas, Adrienne Morgan, Christopher Poole, Sarah E Pinder, David A Cameron, Nigel Stallard, Jenny Donovan, Christopher McCabe, Luke Hughes-Davies, Andreas Makris, on Behalf of the OPTIMA Trial Management Group. Comparison of multiparameter tests in the UK OPTIMA-Prelim trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-07.

Duplication of Chromosome 17 CEP Predicts for Anthracycline Benefit: A Meta-Analysis of 4 Trials.

ABSTRACT WITHDRAWN: This abstract was withdrawn by the authors prior to the start of the Symposium. Background: Current evidence for HER2/TOP2A as predictive biomarkers of anthracycline response is conflicting. An interim meta-analysis (Di Leo et al Cancer Res;69:99S SABCS2009) suggested a weak, statistically significant, association between TOP2A and anthracycline benefit. We previously showed duplication of chromosome 17 alpha satellite (CEP17) predicted sensitivity to anthracyclines independently in three trials (BR9601, NEAT and MA.5, Bartlett et al Cancer Res 69:74S/364S). We performed a retrospective meta-analysis, incorporating data from 4 trials (including the Belgium study), to test the hypothesis that CEP17 is a predictive biomarker for anthracycline benefit in order to provide a unifying hypothesis in trials for which previous biomarker data is conflicting.Methods: FISH was performed in 2 labs (Bartlett lab for BR9601/NEAT & Belgian studies & O9Malley lab for MA5). ER/PgR (IHC) etc were collected from trial Case Report Forms. BR9601/NEAT and Belgian study tumors were scored counting all cells with a minimum of one CEP17 signal/cell: in MA.5 a minimum of 2 CEP17 signals were required for cells to be scored. These methodological differences did not affect HER2/CEP17 ratios but necessitated different definitions for CEP17 duplication defined as >1.86 observed copies/cell for BR9601, NEAT and JB (Watters BCRT 2003 77:109-14) and >2.25 for MA.5 (Goetz 2004).Results: FISH was successful in 85% (2531/2975) of cases. CEP17 duplication was detected in 27.5% of tumors (BR9601=37.6%, NEAT=20.0%, MA5=40.2% & JB=28.5%) and was associated with poorer RFS & OS (HR 0.80 95%CI 0.7-0.92 p=0.011 & HR 0.79, 95%CI 0.68-9.92, p=0.018, respectively).A significant treatment*marker interaction was observed in a meta-analysis of all data (2531 cases) as univariate(p

Abstract P6-08-11: UK OPTIMA-prelim study demonstrates economic value in more clinical evaluation of multi-parameter prognostic tests in early breast cancer

Background There is uncertainty about the benefit of chemotherapy for some patients with ER-positive HER2-negative early breast cancer. Multi-parameter assays of gene expression may enhance the value of chemotherapy through personalised treatment decisions. An economic evaluation was undertaken in the context of the feasibility phase of an RCT (OPTIMA prelim) designed to validate prospectively the use of such an assay as a treatment decision tool in the UK National Health Service (NHS). The aim of the economic evaluation was to confirm value in an ongoing RCT and optimise its design for economic endpoints. Comparators included (i) All patients treated with chemotherapy, (ii) Oncotype DX, (iii) MammaPrint/BluePrint and (iv) Prosigna. Methods A model-based cost-effectiveness analysis was conducted to the standards of the UK National Institute for Care Excellence (NICE) reference case. A Markov model was constructed to simulate the care pathway of a cohort of patients with characteristics identified in the OPTIMA prelim study or, where unavailable, from the published literature. The costs (GBP) and benefits (QALYs) were estimated over a time horizon of the patient life-time. Alternative scenarios of recurrence rates and chemotherapy effect were explored in patients identified high or low risk by the tests and treated with and without chemotherapy. Scenarios included estimates based on the SWOG-8814 trial, the EBCTCG and outcomes forecasted using Adjuvant! Online. Uncertainty introduced by discrepancy in patient selection between tests was modelled using a Bayesian decision analytic framework. Probabilistic sensitivity analysis and value of information analysis was conducted using Monte Carlo simulation. Results There were 285 randomised patients. Multi-parameter analyses were performed on tumour samples and baseline factors were included in the model. The cost-effectiveness of all tests was uncertain. Uncertainty was predominantly driven by assumptions about long term recurrence rates in test-selected groups and the ability of tests to predict benefit from chemotherapy. The relationship between recurrence-free survival and life expectancy in test-selected groups and in patients who did or did not receive adjuvant chemotherapy was also important. The incremental cost-effectiveness ratio (ICER) for Oncotype DX compared with chemotherapy for all was cost-effective in many scenarios, ranging from GBP26,000 per QALY to resulting in increased QALYs with cost savings (dominate), depending on assumptions. The value of information analysis placed high societal value in further research into recurrence-free survival for test-directed chemotherapy, irrespective of the test evaluated. Conclusion There is substantial value in prospective comparative research into all tests evaluated, including long term outcomes, to resolve uncertainties in the clinical and economic optimal choice of test. Acknowledgements This project was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 10/34/01). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health. Citation Format: Peter S Hall, Alison F Smith, Armando Vargas-Palacios, Robert C Stein, John Bartlett, Jane Bayani, Andrea Marshall, Janet A Dunn, Amy F Campbell, Carrie Cunningham, Leila Rooshenas, Monika Sobol, Adrienne Morgan, Christopher Poole, Sarah E Pinder, David A Cameron, Nigel Stallard, Jenny Donovan, Luke Hugh-Davies, Helena Earl, Andreas Makris, Claire Hulme, Christopher McCabe. UK OPTIMA-prelim study demonstrates economic value in more clinical evaluation of multi-parameter prognostic tests in early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-11.