Title: Breast cancer trials and meta-analyses: large-scale randomised evidence on long-term effects of breast cancer
Funder: Medical Research Council

Abstract: The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), coordinated by PHRU, was established in 1985 and includes almost all of the research groups worldwide that undertake randomised trials of treatment for women with breast cancer. In a series of collaborative meta-analyses, the global randomised evidence on particular therapeutic questions is brought together to compare the effects of different treatments on breast cancer recurrence, survival and other major outcomes. These analyses now include data on over 700,000 women in more than 800 clinical trials in 50 countries that have assessed surgical, radiotherapeutic, cytotoxic, hormonal and other treatments. The EBCTCG meta-analyses have demonstrated many real but moderate differences in long-term survival that were not reliably demonstrable in the separate trials (including effects on breast cancer mortality and side-effects such as second cancers and vascular events). The uniquely reliable evidence from EBCTCG’s high-profile publications, which have already attracted over 20,000 scientific citations, profoundly influence national guidelines, changing worldwide treatment patterns. The long-term survival gains identified are each only moderate, but, in combination, have been a major contributor to the striking worldwide reductions in breast cancer mortality seen over the last three decades: eg, UK breast cancer mortality at age 35-69 has been halved. Our current programme of work involves a number of individual patient data meta-analyses addressing new questions (eg HER2-directed therapies, chemotherapy dose intensification, neoadjuvant chemotherapy, duration of endocrine therapy, more extensive radiotherapy, breast cancer screening) as well as updating follow-up data for many of the questions addressed previously to assess longer-term outcome. Another focus is the collection of additional data (eg cell proliferation measures, gene expression indices, non-fatal bone fracture, heart disease and stroke) to investigate predictors of treatment response and long-term safety. Evidence of further moderate survival gains continues to emerge from these ongoing EBCTCG meta-analyses. But, each meta-analysis is a major undertaking: typically, it takes 1-2 years to plan, collate, check and correct individual patient data from relevant trials, then another 1-2 years to perform analyses and write collaborative publications. EBCTCG’s meta-analyses are sometimes inconclusive, highlighting the need, and informing the design of trials to generate new evidence. Because uncertainty remained about optimal duration of tamoxifen treatment, PHRU designed the aTTom and ATLAS trials that have randomised 18,000 women between 10 and 5 years of tamoxifen, showing that 15-year breast cancer mortality is improved with 10 years of treatment. Similar uncertainties about the value of breast cancer screening underlie PHRU’s collaboration in the NHSBSP/CEU trial of additional screening (n=3,000,000 randomised now, eventual target ~6,000,000, 10 times more than in all previous trials combined). Building on our worldwide collaborative group, a further aim of our ongoing programme is to design and implement new, large-scale trials (such as aTTom and ATLAS) addressing the key uncertainties about optimal breast cancer treatment identified through the EBCTCG meta-analyses.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS