The challenges of long-term follow-up data collection in non-commercial, academically-led breast cancer clinical trials: the UK perspective

BACKGROUND: Improved survival rates in early breast cancer and the chronic nature of disease relapse result in a large cohort of patients being available for long-term follow-up (LTFUP) in randomised controlled trials. Whilst of recognised scientific value to assess long-term treatment-related sequelae, the volume of this activity can be challenging for trialists and participating sites, and comes at a considerable cost to research funders and the National Health Service (NHS). A National Cancer Research Institute Breast Clinical Studies Group supported project aimed to characterise UK LTFUP data collection procedures in order to propose improvements. METHODS: Protocols and case report forms for UK non-commercial National Institute for Health Research portfolio early breast cancer randomised controlled trials were reviewed and a questionnaire sent to associated participating NHS sites. Responders were asked to give opinions on issues with follow-up and LTFUP data collection procedures and to suggest potential improvements to practice. Results were used to inform design of a proposed standard LTFUP case report form. RESULTS: Thirty-four trials, involving eight Clinical Trials Units were eligible for inclusion in the review. All trials requested follow-up at least annually up to 5 years, with two-thirds requesting LTFUP after that time point. Information relating to efficacy endpoints was captured for all trials via case report forms; however, precise detail on recording of recurrence, second malignancies and death varied. Separately, questionnaires were returned from 66 NHS sites. Main concerns identified included difficulties in identifying all adverse events from hospital notes, volume of work, bureaucratic data management practices in Clinical Trials Units and perceptions of prioritisation of recruitment over follow-up. CONCLUSION: Variation has existed with respect to detail of LTFUP information requested for UK trials. Improved communication, simplification and standardisation of data and associated collection methods are possible without compromising data requirements for efficient and effective trial reporting. Future use of routinely collected data, captured via electronic means, could transform practices and alleviate resource usage. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1745-6215-15-379) contains supplementary material, which is available to authorized users

Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial.

BACKGROUND: Adjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both. METHODS: In this multicentre, phase 3, randomised, controlled trial, we enrolled patients aged 18 years or older from 129 UK centres who had histologically confirmed node-positive or high-risk node-negative operable breast cancer, had undergone complete excision, and were due to receive adjuvant chemotherapy. Patients were randomly assigned to receive four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either classic cyclophosphamide, methotrexate, and fluorouracil (CMF; 600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs one to three vs four or more), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). The primary endpoint was TTR, defined as time from randomisation to first invasive relapse or breast cancer death, with intention-to-treat analysis of standard versus accelerated epirubicin and per-protocol analysis of CMF versus capecitabine. This trial is registered with ISRCTN, number 68068041, and with ClinicalTrials.gov, number NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (4371 women and 20 men) were recruited. At a median follow-up of 85·6 months (IQR 80·6-95·9) no significant difference was seen in the proportions of patients free from TTR events between the accelerated and standard epirubicin groups (overall hazard ratio [HR] 0·94, 95% CI 0·81-1·09; stratified p=0·42). At 5 years, 85·9% (95% CI 84·3-87·3) of patients receiving standard epirubicin and 87·1% (85·6-88·4) of those receiving accelerated epirubicin were free from TTR events. 4358 patients were included in the per-protocol analysis, and no difference was seen in the proportions of patients free from TTR events between the CMF and capecitabine groups (HR 0·98, 95% CI 0·85-1.14; stratified p=0·00092 for non-inferiority). Compared with baseline, significantly more patients taking CMF than those taking capecitabine had clinically relevant worsening of quality of life at end of treatment (255 [58%] of 441 vs 235 [50%] of 475; p=0·011) and at 12 months (114 [34%] of 334 vs 89 [22%] of 401; p<0·001 at 12 months) and had worse quality of life over time (p<0·0001). Detailed toxicity and quality-of-life data were collected from 2115 (48%) of treated patients. The most common grade 3 or higher adverse events in cycles 1-4 were neutropenia (175 [16%]) and fatigue (56 [5%]) of the 1070 patients treated with standard epirubicin, and fatigue (63 [6%]) and infection (34 [3%]) of the 1045 patients treated with accelerated epirubicin. In cycles 5-8, the most common grade 3 or higher adverse events were neutropenia (321 [31%]) and fatigue (109 [11%]) in the patients treated with CMF, and hand-foot syndrome (129 [12%]) and diarrhoea (67 [6%]) in the 1044 patients treated with capcitabine. INTERPRETATION: We found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche

Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer

Patient-derived xenograft (PDX) models in basic and translational breast cancer research

Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research

Can routine data be used to support cancer clinical trials? A historical baseline on which to build: retrospective linkage of data from the TACT (CRUK 01/001) breast cancer trial and the National Cancer Data Repository

Abstract Background Randomised clinical trials (RCTs) are the gold standard for evaluating new cancer treatments. They are, however, expensive to conduct, particularly where long-term follow-up of participants is required. Tracking participants via routine datasets could provide a cost-effective alternative for ascertaining follow-up information required to evaluate disease outcomes. This project explores the potential for routine data to inform cancer trials, using, the historical National Cancer Data Repository (NCDR) for English NHS sites and, for validation, mature data available from the TACT trial. Methods Datasets were matched using patients’ NHS number, date of birth (dob) and name/initials. Demographics, clinical characteristics and outcomes were assessed for agreement and completeness. Overall survival was compared between NCDR and TACT. Results A total of 3151 patients underwent linkage; 3047 (96.7%) of which had matched records. Extensive cleaning was required for some registry data fields, e.g. cause of death, whilst others had large amounts of missing data, e.g. tumour size (22.1%). Other data had high levels of matching such as dob (99.6%) and date of death (89.6%). There was no evidence of differential survival rates (8-year survival: TACT = 75% (95% CI 73, 76); NCDR = 76% (95% CI 74, 77)). Conclusions Data quality and completeness requires improvement before routine data could be used for RCTs. Introduction of new routine datasets, including COSD, is welcomed although reporting of disease-recurrence events remains a concern. Prospective validation of such datasets is required before RCTs can confidently switch patient follow-up to utilise routinely collected NHS-based data. TACT Trial registration Clinicaltrials.gov NCT00033683 , registered on 9 April 2002; ISRCTN79718493 , registered on 1 July 2001